tbuckley/cabot-search huggingface dataset:
Genes reveal traces of common recent demographic history for most of the Uralic-speaking populations
Authors: Kristiina Tambets, Bayazit Yunusbayev, Georgi Hudjashov, Anne-Mai Ilumäe, Siiri Rootsi, Terhi Honkola, Outi Vesakoski, Quentin Atkinson, Pontus Skoglund, Alena Kushniarevich, Sergey Litvinov, Maere Reidla, Ene Metspalu, Lehti Saag, Timo Rantanen, Monika Karmin, Jüri Parik, Sergey I. Zhadanov, Marina Gubina, Larisa D. Damba, Marina Bermisheva, Tuuli Reisberg, Khadizhat Dibirova, Irina Evseeva, Mari Nelis, Janis Klovins, Andres Metspalu, Tõnu Esko, Oleg Balanovsky, Elena Balanovska, Elza K. Khusnutdinova, Ludmila P. Osipova, Mikhail Voevoda, Richard Villems, Toomas Kivisild, Mait Metspalu
Journal: Genome biology (2018)

The genetic origins of Uralic speakers from across a vast territory in the temperate zone of North Eurasia have remained elusive. Previous studies have shown contrasting proportions of Eastern and Western Eurasian ancestry in their mitochondrial and Y chromosomal gene pools. While the maternal lineages reflect by and large the geographic background of a given Uralic-speaking population, the frequency of Y chromosomes of Eastern Eurasian origin is distinctively high among European Uralic speakers. The autosomal variation of Uralic speakers, however, has not yet been studied comprehensively. Here, we present a genome-wide analysis of 15 Uralic-speaking populations which cover all main groups of the linguistic family. We show that contemporary Uralic speakers are genetically very similar to their local geographical neighbours. However, when studying relationships among geographically distant populations, we find that most of the Uralic speakers and some of their neighbours share a genetic component of possibly Siberian origin. Additionally, we show that most Uralic speakers share significantly more genomic segments identity-by-descent with each other than with geographically equidistant speakers of other languages. We find that correlated genome-wide genetic and lexical distances among Uralic speakers suggest co-dispersion of genes and languages. Yet, we do not find long-range genetic ties between Estonians and Hungarians with their linguistic sisters that would distinguish them from their non-Uralic-speaking neighbours. We show that most Uralic speakers share a distinct ancestry component of likely Siberian origin, which suggests that the spread of Uralic languages involved at least some demic component.
Id1 and Id3 genes to confer poor prognosis in <i>KRAS</i>-mutant (KM) lung adenocarcinoma (LA) patients: Effect of gene silencing on metastatic rate to the liver and on survival.
Authors: Marta Roman, Ines Lopez, Leyre Zubiri Oteiza, Rodrigo Sanchez, Diego Salas, Itziar Gardeazabal, Iosune Baraibar, Marta Santisteban, Silvestre Vicent, Isabel Gil-Aldea, Maite Martinez Aguillo, Berta Hernandez, José María López-Picazo, Alfonso Gurpide, Jose Luis Perez-Gracia, Ignacio Gil-Bazo
Journal: Journal of Clinical Oncology (2016)

e20653 Background: Inhibitor of differentiation 1 (Id1) and 3 (Id3) genes confer poor prognosis being involved in LA spreading to the liver. KM may constitute a poor prognosis and a pro-metastatic feature. Here we study Id genes’ role in KM LA and liver metastasis (LM). Methods: 424 LA patients were studied to assess the survival impact of Id1 and Id3 mRNA levels depending on KRAS status. The KM human LA cell line H1792-TGL-604 was used to address the impact of Id1 and Id3 genes on tumor cell proliferation and migration. A murine model of LM from LA was generated using immunocompromised mice by tumor cells intrasplenic injection. shRNA silencing was used to determine the impact of Idgenes. Two groups of mice inoculated with shRNA-Id1 and shRNA-Id1-Id3 tumor cells, were compared to those inoculated with twildtype (WT) cell line. FDG-PET was used to monitor LM. The effect of tumor cells genotype in the overall survival (OS) of the animals was also studied. Results: Id1 and Id3 mRNA higher tumor levels predicted a shorter OS among patients with KM but not in KRAS-wildtype LA (p = 0.02 and p = 0.03, respectively). In vitro, the proliferation rate of cells silenced for Id1 and Id1/Id3 genes was 20.1% CI95% (0.17, 0.23) and 31% CI95% (0.245, 0.37), compared to 60.1% CI95% (0.54, 0.67), in the WT cell line (p < 0.001). Tumor cells’ migration also decreased from 22.1% CI95% (16.7, 27.4) in the WT cells to 1.88% CI95% (1, 2.76) and 0.29% CI95% (0.03, 0.55) in the Id1 and Id1/Id3-silenced cells, respectively (p < 0.001). SUVmax50 values also showed a reduction in the metastatic rate of mice inoculated with shId1-cells [0.71 CI95% (0.66, 0.76)], and with shId1shId3-cells, [0.71 CI95% (0.62, 0.81)], compared to the mice inoculated with WT cells, 1.86 [SD 0.51, CI 95% (1, 2.49)]; p < 0.001. Moreover, these mice showed a significant delay in LM onset, leading to an increased survival: 61 and 46 days CI95% (59.21, 62.79) respectively, compared to 28 days in the WT group (p < 0.01). Conclusions: Higher Id1 and Id3 mRNA tumor levels predicted a shorter OS in a large series of KM LA patients. Id1 and Id1/Id3 silencing in human KM tumor cells of LA decreased and delayed LM development in an in vivo model.
Abstract 20158: Short Term Outcomes of the Cone Procedure for Ebstein’s Anomaly in Young Pediatric Patients Are Comparable to Adult Patients
Authors: Mariana Chávez Rodríguez, Christopher W Baird, Sitaram Emani, Puja Banka, Edward Walsh, Minmin Lu, Michele J Borisuk, Pedro J del Nido, Gerald R Marx
Journal: Circulation (2017)

Introduction: Good short and midterm outcomes have been reported in adults for the Cone procedure for Ebstein’s anomaly of the tricuspid valve. We hypothesized that since the Cone procedure uses on...
Geriatric oncology (GO) and education: Is the research community really involved in presenting data about elderly and learning in cancer?
Authors: Aldo A. Dettino, Ludmilla T.D. Chinen, Solange M. Sanches, Helano C. Freitas, Ana Carolina Sigolo Levy Diniz, Marcelo Calil Machado Netto, Milena Shizue Tariki, Ulisses Ribaldo Nicolau, Marcello Ferretti Fanelli
Journal: Journal of Clinical Oncology (2016)

e21522 Background: Education in GO is of extreme importance, due to epidemiology and since aging is a important risk factor for cancer. The oncology community has to deal with how to educate the workforce for the load of patients in the future. Meetings/M are good to broadcast elderly (E) treatment education. However, GO was an area of interest for only 1% of ASCO Annual m attendees in 2014-5 (http://am.asco.org/attendee-demographics), turning some thoughts needed about improving GO interest for assistance, research and teaching. Methods: Data collection and review of searches and abstracts from ASCO m 2009 to 1/2016 (in http://meetinglibrary.asco.org/abstracts). Keywords (K) were: education, or learning, afterwards each combined with E, or GO. Also, filters for content type and date were applied. Results: For GO, 913 entries were found, with 153 abstracts and 5 posters (P) (including 2 entries=abstracts of 2016). Excluding 2016 (present year): range of entries 68-225/year, median 120; range of abstracts 7-28/y, median 24. Associating GO+education as K: 627 entries, 17 abstracts (including 1 abstract of 2016), without P. When excluding the 2 entries of 2016: range of entries 52-193/year, median 77; with a range of abstracts of only 0-4/y, median 3. Crossing GO+learning, only 2 entries, with only 1 abstract in 2014. In addition, using E as K, 2154 entries were found (60 in 2016, including 28 abstracts, 13 P, 13 presentations and 6 of slides in 2016)), with 1038 abstracts and 357 posters. As with GO, excluding 2016: range of entries 206-379/year, median 293; range of abstracts 118-179/y, median 138. With associating E+education as K: 192 entries, 32 abstracts (including 1 abstract of 2016), without P as well. When excluding 2016: range of entries 1-55/year, median 34; with a range of abstracts of only 1-8/y, median 5. Crossing E+learning, only 8 entries, with only 2 abstracts (2012 and 2010). Conclusions: Low growth has been seen in GO or E issues and abstracts vs ASCO meetings growth, specially related to research presented about those issues and teaching. More brodcasting of GO in m are urgently needed. # of abstracts/y. Year GO E 09 7 118 10 27 179 11 24 138 12 19 149 13 18 162 14 28 127 15 28 137
Whole exome sequencing (WES) in hormone-receptor positive (HR+) metastatic breast cancer (MBC) to identify mediators of resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i).
Authors: Seth Andrew Wander, Ofir Cohen, Gabriela N Johnson, Dewey Kim, Flora Luo, Pingping Mao, Utthara Nayar, Karla Helvie, Lori Marini, Samuel Freeman, Gad Getz, Levi A. Garraway, Eric P. Winer, Nancy U. Lin, Nikhil Wagle
Journal: Journal of Clinical Oncology (2018)

12016 Background: Combining CDK4/6i with endocrine therapy results in prolongation of disease control in HR+ MBC, though resistance invariably occurs. There is a critical need to understand mechanisms governing response and resistance to these agents. Methods: WES was performed on 51 baseline metastatic tumor biopsies obtained at treatment initiation with CDK4/6i in combination with various anti-estrogens. Tumor samples were classified as sensitive (S, from patients with clinical benefit) or intrinsically resistant (IR, from patients without clinical benefit). WES was also performed in 11 acquired resistance (AR) specimens obtained from responding patients after progression. In 6 patients, WES was performed on matched pre-treatment S and post-progression AR specimens. Putative resistance drivers were introduced into HR+/HER2- breast cancer cells (T47D, MCF7) via lentiviral infection or knockout via CRISPR. Sensitivity of the modified cell lines to anti-estrogens and CDK4/6i was characterized. Results: WES of 62 tumors revealed multiple potential mechanisms of resistance to CDK4/6i (Table), including biallelic RB1 inactivation, AKT1 mutation (mut) and/or amplification (amp), RAS mut, AURKA amp, IGF1R amp, ERBB2 mut, and FGFR2 mut and/or amp. Introduction of candidates into HR+ breast cancer cells conveyed resistance to CDK4/6i in vitro, including loss of Rb and overexpression of AKT1, AURKA, FGFR2, mut-KRAS, and mut-ERBB2. Additional sequencing efforts and characterization of variants is ongoing and will be presented. Conclusions: These results provide new insight into the diverse spectrum of genomic events driving resistance to CDK4/6i and set the stage for additional mechanistic studies. For patients with AKT1, RAS, AURKA, IGF1R, ERBB2, and FGFR2-dependent resistance, clinical trials incorporating novel combinations of targeted therapies could be designed to circumvent or overcome resistance. Phenotype S IR AR IR+AR (%) Tumor samples (n) 21 30 11 41 RB1 biallelic inactivation 0 3 1 4 (10) IGF1R amp 0 2 1 3 (7) RAS mut 0 2 1 3 (7) AKT1 mut or amp 1 3 2 5 (12) FGFR2 mut or amp 0 3 0 3 (7) AURKA amp 0 7 4 11 (27) HER2 mut 1 1 3 4 (10)
An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos
Authors: Christopher R. Gignoux, Dara G. Torgerson, Maria Pino-Yanes, Lawrence H. Uricchio, Joshua Galanter, Lindsey A. Roth, Celeste Eng, Donglei Hu, Elizabeth A. Nguyen, Scott Huntsman, Rasika A. Mathias, Rajesh Kumar, Jose Rodriguez-Santana, Neeta Thakur, Sam S. Oh, Meghan McGarry, Andres Moreno-Estrada, Karla Sandoval, Cheryl A. Winkler, Max A. Seibold, Badri Padhukasahasram, David V. Conti, Harold J. Farber, Pedro Avila, Emerita Brigino-Buenaventura, Michael Lenoir, Kelley Meade, Denise Serebrisky, Luisa N. Borrell, William Rodriguez-Cintron, Shannon Thyne, Bonnie R. Joubert, Isabelle Romieu, Albert M. Levin, Juan-Jose Sienra-Monge, Blanca Estela del Rio-Navarro, Weiniu Gan, Benjamin A. Raby, Scott T. Weiss, Eugene Bleecker, Deborah A. Meyers, Fernando J. Martinez, W. James Gauderman, Frank Gilliland, Stephanie J. London, Carlos D. Bustamante, Dan L. Nicolae, Carole Ober, Saunak Sen, Kathleen Barnes, L. Keoki Williams, Ryan D. Hernandez, Esteban G. Burchard
Journal: Journal of Allergy and Clinical Immunology (2018)
Factors affecting the outcome of adjuvant therapy in stage III pancreatic cancer.
Authors: Mridula Krishnan, Lakshmi Manogna Chintalacheruvu, Nicholas B George, Carlos J Silva, Nabin Khanal, Ryan W Walters, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2016)

e15712 Background: Adjuvant therapy after curative resection is associated with survival benefit in stage III pancreatic cancer. Previously, an NCDB trial including 11,526 patients showed significant survival benefit of chemoradiation between 1998-2002. We analyzed the factors affecting outcome of adjuvant therapy in stage III pancreatic cancer. Methods: This is a retrospective study of stage III pancreatic cancer between 2000 and 2013 in the National Cancer Data Base (NCDB) that evaluates 70% new cancer diagnosis. Patients were stratified based upon adjuvant therapy they received. Unadjusted Kaplan–Meier and multivariable Cox regressions were performed. Results: We analyzed 24,354 patients with stage III pancreatic cancer (No adjuvant therapy – 5798, Radiation – 562, Chemotherapy – 8671, Chemoradiotherapy – 9323). Median survival with no adjuvant therapy was 3.78 months when compared to chemotherapy, radiation and combined which were 6.97, 8.08 and 11.86 months, respectively. On Multivariate analysis, advancing age and patients with Medicaid had worse survival while Spanish origin and lower Charlson comorbidity score had better survival.Adjuvant therapy was associated with poorer survival at 12 months, but survival benefit was seen at 18 months, slightly more so with chemoradiation (Hazards Ratio-HR 0.38) versus chemotherapy (HR 0. 42) or radiation alone (HR 0.40). Conclusions: Our study is the largest trial using the NCDB addressing the effects of adjuvant therapy in stage III pancreatic cancer. Within the limits of our study, survival benefit with adjuvant therapy was more apparent with longer duration from the date of diagnosis. Factors affecting survival with adjuvant therapy. HR p Spanish origin 0.835 <0.05 Charlson Scorea 0 0.835 <0.05 1 0.888 <0.05 Therapy differences at 12 months for a 70 year oldb Radiation 1.346 <0.05 Chemotherapy 1.393 <0.05 Chemoradiation 1.260 <0.05 Therapy differences at 18 months for a 70 year oldb Radiation 0.401 <0.05 Chemotherapy 0.420 <0.05 Chemoradiation 0.380 <0.05 Reference : a = 2,b = no adjuvant treatment. HR = hazard ratio. Reference = no adjuvant treatment; higher HR indicates worse survival.
P05.84 Clinical and radiological patterns of brain radiation necrosis after ion beam radiotherapy for head and neck tumors
Authors: A Picca, G Berzero, L Diamanti, P Bini, A Bacila, L Farina, S Bernini, E D’Ippolito, L Preda, A Iannalfi
Journal: Neuro-Oncology (2018)

beam radiotherapy (IBRT) is increasingly used for the treatment of head/neck cancers in order to spare radiosensitive structures. The occurrence of brain radiation necrosis (RN) following this modality has been reported in small case series, although its long-term outcome has not been clarified yet. The aim of this study is to define the clinical and radiological course of brain RN after IBRT, with a focus on neuropsychological (NPS) deficits and epilepsy. Patients were prospectively identified from 07/2014 to 10/2017 during their follow-up at CNAO Foundation. Inclusion criteria were: 1) history of IBRT for a head/neck cancer; 2) age ≥18 years at the time of IBRT; 3) new MRI alterations compatible with brain RN. Enrolled patients underwent multimodal evaluations (including neurological examination, contrast brain MRI, EEG,and NPS testing), at the time of RN detection, after three months and then every six months. A total of 22 patients were identified. All of them had received IBRT for intracranial extraparenchymal tumors. Median age at the time of IBRT was 49 years (range 29–64). IBRT consisted of protons in 9 cases and of carbon ions in 13 cases. Median total dose was 68.8 Gy[RBE] (range 14–76.8). Six patients had been previously irradiated. Median time from the end of IBRT to RN identification was 16 months (range 3–37). In 86% of cases, RN was identified during scheduled MRI scans. RN was located in the temporal lobes in 21 cases (95%). At the time of RN detection, 71% of the patients tested had NPS deficits. Six patients developed seizures (27%). Patients were followed for a median of 23 months (range 4–41). Sixteen patients (73%) needed corticosteroid therapy and 9 (41%) were started on antiepileptic drugs. At last follow-up, 35% of patients still had multidomain NPS deficits. Within the first six months of follow-up, 74% of patients had the appearance of new enhancing lesions o enlargement of previously described lesions on MRI, though in most cases RN was reduced at last radiological follow-up. The incidence of RN peaks during the second year after IBRT. Although in most cases RN was identified during scheduled MRI scans, cognitive deficits and symptomatic epilepsy were detected in a large proportion of patients. Long-term outcome is not predictable, as some patients tend to improve over time, while others develop new symptoms. Corticosteroids and antiepileptic drugs are needed in most patients to control symptoms.
PD.1.02 Real-World Prevalence of PD-L1 Expression in Advanced Non–Small-Cell Lung Cancer: The Global, Multicenter EXPRESS Study
Authors: R. Salanova, M. Dietel, N. Savelov, P. Micke, G. Bigras, T. Hida, B. Piperdi, T. Burke, S. Khambata-Ford, A. Deitz
Journal: Journal of Thoracic Oncology (2018)
RARE-32. EXTRA-ARTICULAR TENOSYNOVIAL GIANT CELL TUMOR OF DIFFUSE TYPE IN THE TEMPORAL AREA WITH BRAIN PARENCHYMAL INVASION
Authors: Young Seok Park, Chang Gok Woo, Hyeong Cheol Moon
Journal: Neuro-Oncology (2018)

Tenosynovial giant cell tumor of diffuse type is a locally aggressive neoplasm that most commonly arises in the lower extremities. However, pure extra-articular TGCT of diffuse type invading the brain parenchyma of the temporal area without involvement of the joint has not been reported to date. Herein, we report for the first time a case of an extra-articular tenosynovial giant cell tumor of diffuse type in the temporal region with brain parenchymal invasion. Imaging studies revealed an intracranial expansile mass in the temporal bone without involvement of the temporomandibular joint. The unusual location of the tumor without involvement of the joint and the presence of brain parenchymal invasion made this case challenging to diagnose. The patient underwent temporal craniotomy, and the mass was completely removed. The patient underwent temporal craniotomy, and the mass was completely removed. The tumor had invaded the cerebral parenchyma of the temporal lobe; it showed adhesion to the adjacent dura and no association with the adjacent joint. The cut section of the mass was solid and yellow to brown with necrosis and hemorrhage. Microscopically, the tumor showed densely cellular sheets of mononuclear cells, irregularly distributed osteoclast-like giant cells, and hemosiderin pigments. Specifically, the mononuclear cell population was composed of small polygonal or spindle cells with pale eosinophilic cytoplasm and large mononuclear cells with ovoid or kidney-shaped nuclei displaying prominent nucleoli and vesicular chromatin, which exhibited little pleomorphism. The tumor cells were positive for CD68 on immunohistochemical staining. Most extra-articular tumors present as a periarticular mass with frequent involvement of the adjacent joint and cystic lesions in the adjacent bone, although on rare occasions, these lesions can be purely extra-articular. Wide excision is the treatment of choice; however, complete excision of the lesion is often impaired by the need to save an adjacent joint. Therefore, radiotherapy is recommended.
CLL cells cumulate genetic aberrations prior to the first therapy even in outwardly inactive disease phase
Authors: María Hernández-Sánchez, Jana Kotaskova, Ana E Rodríguez, Lenka Radova, David Tamborero, María Abáigar, Karla Plevova, Rocío Benito, Nikola Tom, Miguel Quijada-Álamo, Vasileos Bikos, Ana África Martín, Karol Pal, Alfonso García de Coca, Michael Doubek, Nuria López-Bigas, Jesús-María Hernández-Rivas, Sarka Pospisilova
Journal: Leukemia (2018)

Over the past few years, several large-scale studies using next-generation sequencing (NGS) of whole-genomes (WGS) and whole-exomes (WES) have defined the mutational landscape of chronic lymphocytic leukemia (CLL) [1][2][3][4].NGS studies have also revealed the clonal heterogeneity in CLL and showed that clonal evolution contributes to the variability in clinical course among CLL patients [3].Clonal evolution is considered a key condition in CLL progression and relapse after treatment.Most CLL cases are diagnosed during the inactive disease phase, genetic aberrations' underlying progress in CLL activity leading to the need for therapy are poorly understood and should be explored.A large number of frequently mutated genes have been identified and several putative driver mutations likely to confer selective growth advantage to CLL tumor cells have been proposed [1][2][3].In addition, clonal shifts between paired treatment-naïve and relapsed CLL samples have been reported due to pre-existing subclone expansion under therapeutic pressure, demonstrating that clonal evolution likely underlies CLL relapse [3, 5].Nevertheless, there are still a limited amount of longitudinal WES studies analyzing consecutive CLL samples before treatment intervegntion [6].The acquisition of driver mutations accompanied by selectively neutral passenger changes during disease prior to therapy influence is therefore poorly documented.Here, WES was performed on consecutive treatment-naïve samples of CLL patients from three groups with different disease course: Active disease (AD) group: patients with an active disease before the second analyzed time-point (TP2); Stable disease (SD) group: cases with a period of stable phase after diagnosis followed by progression within 3 years after; and Indolent disease (ID) group: those with a long-term stable indolent disease.Moreover, we applied a novel integrative bioinformatics tool called "Cancer Genome Interpreter" to identify driver mutations [7].Thirty-five CLL patients were included in the WES study.In total, 70 tumor samples -(two tumor time-points (TP) for each patient) -as well as 26 matched germline samples, were sequenced.Three groups of patients were characterized based on the disease activity at the second TP:
Blocking the formation of induced multiple myeloma stem-like cells through PI3K/AKT/mTOR pathway.
Authors: Bingshan Liu, Danyang Wang, Yongping Song
Journal: Journal of Clinical Oncology (2017)

e19518 Background: Multiple myeloma (MM) is still an incurable disease. There are many different treatment options and most patients in the early treatment will have a good effect, but some patients will relapse due to acquired drug resistance. The purpose of this study is to investigate the existence of MM stem cells and its relationship with drug resistence. Methods: A total of 53 patients were recruited who underwent MM between 2010 and 2012. We analysed the expression of stem cell markers (Nanog, Oct4 and Sox2) and their relationship with clinical characteristics and 3– year disease free survival (DFS) or overall survival (OS). Then we chose MM cell line RPMI 8226 for the study, explored the possible mechanism of chemotherapy tolerance. Results: We found that that expression levels of Nanog, Oct4 and Sox2 were 11.3% (6/53), 17.0% (9/53) and 20.8% (11/53), respectively. Only positive expression of Sox2 had relationship with ISS stage ( p= 0.049). Furthermore, positive expression of Sox2 ( p= 0.039) was significantly associated with poor DFS. And after induced treatments, RPMI 8226 cells changed, including cell morphology, cell cycle, apoptosis, stem cell markers and changes in signal transduction pathways. Inhibiting PI3K/AKT/mTOR pathway can improve sensitivity to chemotherapy and radiotherapy. Conclusions: These findings demonstated stem cells markers had significant meanings in MM patients’ prognosis. There may be stem-like cells in MM, which is insensitivity to radiotherapy or chemotherapy, and blocking PI3K/AKT/mTOR pathway can reverse it.