tbuckley/cabot-search huggingface dataset:
Extensive RNA editing and splicing increase immune self-representation diversity in medullary thymic epithelial cells
Authors: Miri Danan-Gotthold, Clotilde Guyon, Matthieu Giraud, Erez Y. Levanon, Jakub Abramson
Journal: Genome biology (2016)

In order to become functionally competent but harmless mediators of the immune system, T cells undergo a strict educational program in the thymus, where they learn to discriminate between self and non-self. This educational program is, to a large extent, mediated by medullary thymic epithelial cells that have a unique capacity to express, and subsequently present, a large fraction of body antigens. While the scope of promiscuously expressed genes by medullary thymic epithelial cells is well-established, relatively little is known about the expression of variants that are generated by co-transcriptional and post-transcriptional processes. Our study reveals that in comparison to other cell types, medullary thymic epithelial cells display significantly higher levels of alternative splicing, as well as A-to-I and C-to-U RNA editing, which thereby further expand the diversity of their self-antigen repertoire. Interestingly, Aire, the key mediator of promiscuous gene expression in these cells, plays a limited role in the regulation of these transcriptional processes. Our results highlight RNA processing as another layer by which the immune system assures a comprehensive self-representation in the thymus which is required for the establishment of self-tolerance and prevention of autoimmunity.
Effect of epigenetic modulation on interleukin-6 (IL-6) gene expression with adjuvant selenomethionine (Se-Met) with imatinib mesylate (IM) in remission of chronic myelogenous leukemia (CML-cp) patients.
Authors: Eugene McPherson
Journal: Journal of Clinical Oncology (2012)

e17022 Background: Histone deacetylase (HDAC) are enzymes involved remodeling chromatin and epigenetic regulation of gene expression. Histone deacetylase inhibitors (HDACI) can reverse aberrant epigenetic changes in CML stem cells. BCR-abl tyrosine kinase inhibitors IM is effective in inducing remission in CML-cp patients but residual leukemia stem cells (LSC) may give rise to resistance and relapse. Pan-HDACI may arrest this with downregulation of IL-6, and NFkb activation when adjuvant Se-Met is combined with IM. Methods: CML-cp , CML-bc cases were presented with evidence of overexpression of BCR-abl fusion protein reported previously in elderly patients. A 91 YOF with CML-cp , subclinical hypothyroidism with elevated IL-6, CRP, sIL-2R, VEGF, NFkb, and IGF-1 was treated for seven years with adjuvant Se-Met, IM and levothyroxine ith normalization, minmal toxicity and extended trending down of IL-6, CRP,sIL-2R. Results: After seven years of adjuvant therapy with Se-Met, IM, and Levothyroxine a significant reduction of IL-6, CRP of 9.8075 down from 30.783 mg/L. Subsequuent normalization of the other pro-inflammatory cytokines were normalized. Conclusions: HDACI activity expressed in synergism of Se-Met with IM and Levothyroxine may lower the apoptotic threshold in CML-cp stem cells decreasing BCR-abl expression and rescuing quiescent progenitor cells that may prolong remission and decrease disease relapse.
Increased Risk for Treatment-Related Mortality of Bone Marrow Transplantation in GSTM1-Positive Recipients.
Authors: Seitaro Terakura, Makoto Murata, Tetsuya Nishida, Nobuhiko Emi, Yoshiki Akatsuka, Stanley R. Riddell, Yasuo Morishima, Yoshihisa Kodera, Tomoki Naoe
Journal: Blood (2005)
MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death
Authors: Mohammad K. Eldomery, Zeynep C. Akdemir, F.-Nora Vögtle, Wu-Lin Charng, Patrycja Mulica, Jill A. Rosenfeld, Tomasz Gambin, Shen Gu, Lindsay C. Burrage, Aisha Al Shamsi, Samantha Penney, Shalini N. Jhangiani, Holly H. Zimmerman, Donna M. Muzny, Xia Wang, Jia Tang, Ravi Medikonda, Prasanna V. Ramachandran, Lee-Jun Wong, Eric Boerwinkle, Richard A. Gibbs, Christine M. Eng, Seema R. Lalani, Jozef Hertecant, Richard J. Rodenburg, Omar A. Abdul-Rahman, Yaping Yang, Fan Xia, Meng C. Wang, James R. Lupski, Chris Meisinger, V. Reid Sutton
Journal: Genome Medicine (2016)

Mitochondrial presequence proteases perform fundamental functions as they process about 70 % of all mitochondrial preproteins that are encoded in the nucleus and imported posttranslationally. The mitochondrial intermediate presequence protease MIP/Oct1, which carries out precursor processing, has not yet been established to have a role in human disease. Whole exome sequencing was performed on four unrelated probands with left ventricular non-compaction (LVNC), developmental delay (DD), seizures, and severe hypotonia. Proposed pathogenic variants were confirmed by Sanger sequencing or array comparative genomic hybridization. Functional analysis of the identified MIP variants was performed using the model organism Saccharomyces cerevisiae as the protein and its functions are highly conserved from yeast to human. Biallelic single nucleotide variants (SNVs) or copy number variants (CNVs) in MIPEP, which encodes MIP, were present in all four probands, three of whom had infantile/childhood death. Two patients had compound heterozygous SNVs (p.L582R/p.L71Q and p.E602*/p.L306F) and one patient from a consanguineous family had a homozygous SNV (p.K343E). The fourth patient, identified through the GeneMatcher tool, a part of the Matchmaker Exchange Project, was found to have inherited a paternal SNV (p.H512D) and a maternal CNV (1.4-Mb deletion of 13q12.12) that includes MIPEP. All amino acids affected in the patients' missense variants are highly conserved from yeast to human and therefore S. cerevisiae was employed for functional analysis (for p.L71Q, p.L306F, and p.K343E). The mutations p.L339F (human p.L306F) and p.K376E (human p.K343E) resulted in a severe decrease of Oct1 protease activity and accumulation of non-processed Oct1 substrates and consequently impaired viability under respiratory growth conditions. The p.L83Q (human p.L71Q) failed to localize to the mitochondria. Our findings reveal for the first time the role of the mitochondrial intermediate peptidase in human disease. Loss of MIP function results in a syndrome which consists of LVNC, DD, seizures, hypotonia, and cataracts. Our approach highlights the power of data exchange and the importance of an interrelationship between clinical and research efforts for disease gene discovery.
Prognostic factors for survival after first recurrence of melanoma.
Authors: T. Tu, M. W. Ma, S. Monni, A. E. Rose, D. Polsky, R. S. Berman, R. L. Shapiro, A. C. Pavlick, M. Mazumdar, I. Osman
Journal: Journal of Clinical Oncology (2010)

8542 Background: Recurrence will occur in about 20% of all primary melanoma survivors. While it is established that primary melanoma staging is predictive of overall survival, prognostic determinants of post-recurrence survival have not been characterized. The identification of these prognostic factors will allow for more informed therapeutic decisions at recurrence. Moreover, the importance of tumor proliferation in melanoma prognosis has recently been recognized with the addition of mitotic rate to the American Joint Committee on Cancer staging system. The role of tumor proliferation at the time of recurrence, however, as predictive of post-recurrence survival in melanoma has not been studied. Methods: Recurrent melanoma patients prospectively enrolled at New York University Medical Center from 2002–2008 were studied. Associations between primary tumor characteristics, first recurrence clinical variables, recurrent tumor proliferation (as measured by the cellular proliferation marker Ki-67), and post-recurrence survival were examined by Cox regression analysis. Ki-67 expression was assessed using immunohistochemistry. Overexpression was defined as > 20% of invasive tumor cells with nuclear immunoreactivity. Results: 251 recurrent melanoma patients with a median follow-up time of 3.6 years from the date of primary diagnosis were identified, of whom 116 had accessible first recurrence tissue. On univariate analysis, several first recurrence variables were significant (p < 0.05), but ulceration was the only primary tumor characteristic associated with a shorter post-recurrence survival (p = 0.039). On multivariate analysis, a shorter disease-free survival, a distant recurrence, and recurrent tumor Ki-67 overexpression were predictive of reduced post-recurrence survival (p = 0.029, < 0.001, 0.018, respectively). Conclusions: Our study suggests that first recurrence variables are more clinically relevant predictors of post-recurrence survival in melanoma compared to primary tumor characteristics. Data also support the prognostic utility of tumor proliferation at recurrence in post-recurrence survival, emphasizing the role of recurrent tumor biology in prognosis. No significant financial relationships to disclose.
KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1
Authors: Yu Gao, Hongzhao Li, Xin Ma, Yang Fan, Dong Ni, Yu Zhang, Qingbo Huang, Kan Liu, Xintao Li, Lei Wang, Liangyou Gu, Yuanxin Yao, Qing Ai, Qingshan Du, Erlin Song, Xu Zhang
Journal: Cancer Research (2016)

The transcription factor KLF6 has an essential role in the development and metastasis of multiple human cancers. Paradoxically, KLF6 expression was found to be attenuated in primary metastatic clear cell renal cell carcinoma (ccRCC), such that it is unclear how KLF6 affects malignant progression in this setting. In this study, we demonstrate that KLF6 attenuation in renal cells is sufficient to promote E2F1-mediated epithelial-mesenchymal transition and metastatic prowess. In a mouse xenograft model of human ccRCC, silencing KLF6 increased tumor cell proliferation and malignant character, whereas E2F1 silencing reversed these properties. These effects were corroborated in a metastatic model system, where we observed a greater number of pulmonary metastatic lesions formed by ccRCC cells where KLF6 was silenced and E2F1 enforced. Analysis of clinical specimens of ccRCC revealed that low levels of KLF6 and high levels of E2F1 correlated closely with ccRCC development. Overall, our results established the significance of activating the KLF6-E2F1 axis in aggressive ccRCC, defining a novel critical signaling mechanism that drives human ccRCC invasion and metastasis. Cancer Res; 77(2); 330-42. ©2016 AACR.
Recombinant B-Domain Deleted Porcine Factor VIII (OBI-1) Safety and Efficacy in the Treatment of Acquired Hemophilia A: Interim Results.
Authors: Jean St. Louis, Rebecca Kruse-Jarres, Anne Greist, Amy D. Shapiro, Hedy Smith, Anja B Drebes, Jay N. Lozier, Edward D. Gomperts
Journal: Blood (2012)
HD12 Randomised Trial Comparing 8 Dose-Escalated Cycles of BEACOPP with 4 Escalated and 4 Baseline Cycles in Patients with Advanced Stage Hodgkin Lymphoma (HL): An Analysis of the German Hodgkin Lymphoma Study Group (GHSG), University of Cologne, D-50924 Cologne, Germany.
Authors: Andreas Engert, Jeremy Franklin, Rolf-Peter Mueller, Hans-Theodor Eich, Axel Gossmann, Hans Konrad Mueller-Hermelink, Thomas Cerny, Jana Markova, Anthony D. Ho, Lothar Kanz, Richard Greil, Wolfgang Hiddemann, Beate Pfistner, Volker Diehl
Journal: Blood (2006)
Longitudinal Genomic Analyses In Chronic Lymphocytic Leukemia (CLL) Patients Reveal Clonal Relationship and Genomic Evolution In Disease Progression and After Therapy
Authors: Esteban Braggio, Neil E. Kay, Scott Van Wier, Stephanie Smoley, Jeanette Eckel-Passow, Traci Sassoon, Daniel L. Van Dyke, Diane F. Jelinek, Tait Shanafelt, Renee Tschumper, Mike Barrett, Thomas J. Kipps, John C. Byrd, Rafael Fonseca
Journal: Blood (2010)
Utilisation du virus de la variole comme arme biologique : place de la vaccination en France
Authors: D Lévy-Bruhl, N Guérin
Journal: Eurosurveillance (2001)

Le Ministere Francais de la Sante a, dans le cadre de son plan de lutte contre le bioterrorisme, demande a l'Institut de Veille Sanitaire d'evaluer le risque epidemique en cas d'introduction du virus de la variole et de proposer des recommandations concernant d'eventuelles strategies vaccinales a mettre en œuvre. Une evaluation de la balance benefice/risque de differents scenarios de vaccination, incluant la vaccination de l'ensemble de la population francaise, a ete realisee pour differents niveaux d'intensite de la menace d'action terroriste. A l'issue de cette analyse, il apparait que, dans la situation actuelle, aucune action de vaccination n'apparait justifiee. Meme en cas de menace averee, la vaccination des personnels de soins les plus exposes et surtout celle des sujets contacts des cas devront constituer les strategies prioritaires.
Using Smudge Cells Percentage on Routine Blood Smear in Chronic Lymphoytic Leukemia As Prognostic Factor: Senegalese Experience
Authors: Abibatou Sall, Awa Oumar Touré, Fatimata Bintou Sall, Abdoulaye Sène, Cedric Aumont, Moussa Seck, Blaise Félix Faye, Tandakha Ndiaye Dièye, Saliou Diop, Sophie Reynaud, Martine Raphaël
Journal: Blood (2015)
Endothelial Progenitor Cells (EPCs) Isolated from the Rhesus Macaque but Not the Mouse Are Phenotypically and Functionally Similar to Human EPCs.
Authors: David A. Ingram, Laura E. Mead, Daniel B. Moore, Theresa Krier, Ann Farese, Thomas MacVittie, Mervin C. Yoder
Journal: Blood (2004)
Stimulation of B-Cell Mature Malignancies with the CpG-Oligonucleotide DSP30 and Interleukin-2 for Improved Detection of Chromosome Abnormalities.
Authors: Aurelia Meloni-Ehrig, Jeanne Meck, Nicole Christacos, JoAnn Kelly, Ludmila Matyakhina, Steven Schonberg, Bruce Gorman, Ramesh Babu, Patricia Stone, Steven Gersen, Alma Ganezer, Tracy Giacobbe, Lisa Brailey, Connie Novick, Jennifer Otani, Nasrin Shahbazi, Calvin Croft, Rafael Perez, Philip Mowrey
Journal: Blood (2009)
Imatinib Mesylate Versus Allogeneic Hematopoietic Stem Cell Transplantation For Patients With Chronic Myeloid Leukemia In Chronic Phase
Authors: Liu Xiaoli, Guanlun Gao, Xuan Zhou, Na Xu, Yajuan Xiao, Rui Cao, Changxin Yin, Hongsheng Zhou, Yongqiang Wei, Yu Zhang, Dan Xu, Bing Xu, Ru Feng, Qifa Liu, Jing Sun, Fanyi Meng
Journal: Blood (2013)
Effect of distance to radiation treatment facility on use of radiation therapy after mastectomy in elderly women
Authors: R. S. Punglia, J. C. Weeks, B. A. Neville, C. C. Earle
Journal: Journal of Clinical Oncology (2006)

6030 Background: Post-mastectomy radiation therapy (PMRT) has been shown to improve survival in patients at high risk for local or regional recurrence. However, radiation therapy necessitates daily travel to treatment centers for several weeks. We sought to study the effect of distance to the nearest radiation treatment facility on receipt of PMRT in elderly women. Methods: Using the linked Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) database, we analyzed 19,787 women with Stage I or II breast cancer who received mastectomy as definitive surgery between 1991 and 1999. Multivariable logistic regression was used to investigate the association of travel distance with receipt of PMRT after adjusting for clinical and sociodemographic factors. Results: Overall, 2,075 (10.5%) patients treated with mastectomy received PMRT. In addition to cancer and patient characteristics, increasing distance from the nearest radiation treatment facility was independently associated with a decreased likelihood of receiving PMRT, (OR = 0.996 per additional mile, p = 0.01). The decline in PMRT use appeared at distances greater than 25 miles and was statistically significant for those patients living greater than 75 miles from the nearest radiation facility (odds of receiving PMRT of 0.58 [95% CI: 0.34–0.99] versus those living within 25 miles of such a facility). In secondary analyses, the effect of distance was only significant in women aged 75–80 years (OR = 0.992 per additional mile, p = 0.03), and those above the age of 80 (OR = 0.989, p = 0.02). When analyses were conducted separately by geographic region, the effect of distance was only significant in the Midwest (OR = 0.992, p = 0.014). The effect of distance was not significant (OR = 1.00, p = 0.87) among women with positive nodes, but was significant in women with no positive nodes (OR = 0.992, p = 0.013). Conclusions: Oncologists must be cognizant of the potential barrier to quality care that is posed by travel distance, especially for elderly patients. Mechanisms to ameliorate the effect of distance on receipt of radiation therapy by assisting individuals with transportation limitations or policies to decrease the centralization of RT services, may help to remove barriers to potentially life-saving treatment. No significant financial relationships to disclose.
Phase II trial of ixabepilone in patients with metastatic breast cancer (MBC) who are resistant to an anthracycline, a taxane and capecitabine
Authors: E. Thomas, E. A. Perez, P. Mukhopadhyay, G. Lerzo, X. Pivot, L. D. Bosserman, B. Mullaney, L. Vahdat, G. N. Hortobagyi
Journal: Journal of Clinical Oncology (2006)

660 Background: Patients (pts) with MBC previously treated with an anthracycline, a taxane and capecitabine have very limited treatment options. Ixabepilone is the first semi-synthetic analog in a new class of cytotoxic agents, the epothilones. It has shown activity in breast and other tumors. Methods: This single-arm Phase II trial was designed to assess the objective response rate (ORR) of ixabepilone in MBC pts resistant to an anthracycline, a taxane and capecitabine. Pts had to be resistant to each regimen as defined by progression within 8 wks in the metastatic setting or recurrence within 6 months (mo) of adjuvant anthracycline/taxane. Capecitabine must have been given in the metastatic setting. Response was assessed by an independent radiology review committee (IRRC; primary analysis) and by each investigator per RECIST. Ixabepilone was administered IV at 40 mg/m 2 over 3 h every 3 wks. Results: A total of 126 pts were treated: median age 51 yrs (range 30–78), Karnofsky PS range 70–100% and 70% pts had baseline liver metastases. 88% pts had received ≥2 prior metastatic regimens. 113 pts were response evaluable (had target disease by IRRC and met eligibility criteria for prior therapy). Median duration of response was 5.3 mo. Stable disease (SD) was the best response in 50% pts and 14% pts had SD ≥6 mo duration. Median PFS was 3.1 mo. Pts received a median of 4 cycles (range 1–16). The most common Grade 3/4 treatment-related adverse events were sensory peripheral neuropathy (14%), fatigue (10%), myalgia (7%), and stomatitis (6%). The neuropathy was cumulative and reversible. Time to resolution (to Grade 1 or baseline) for Grade 3/4 neuropathy was 5.4 wks by Kaplan-Meier analysis. Grade 3/4 neutropenia and thrombocytopenia occurred in 54% and 7% of pts, respectively. Febrile neutropenia was reported in 3% pts. Conclusions: Ixabepilone demonstrates promising clinical activity and a manageable safety profile in patients highly resistant to standard chemotherapy. [Table: see text] [Table: see text]
Chromosomal and FISH Study of 286 Patients with Primary Myelofibrosis (PMF) Reveals Cryptic Abnormalities and Identifies Lesions Associated with Favorable Prognosis and Disease Progression,
Authors: Vesna Najfeld, John Mascarenhas, Steven Fruchtman, Samuel Cytryn, Marina Kremyanskaya, Joseph Tripodi, Ronald Hoffman
Journal: Blood (2011)
BMA calls for national prescription drug helpline
Authors: Zosia Kmietowicz
Journal: BMJ (2016)

The UK government should set up a national helpline to support people with prescription drug addiction, the BMA has said.

The need for a nationwide telephone advice service is one of three recommendations that have been identified by the BMA, charities, patient groups, and medical bodies as part of a new effort to tackle prescription drug dependence.1 …
An intergroup randomized controlled clinical trial (RCT) of chemotherapy plus radiation (RT) versus RT alone for pure and mixed anaplastic oligodendrogliomas: Initial report of RTOG 94–02
Authors: G. Cairncross, W. Seiferheld, E. Shaw, R. Jenkins, B. Scheithauer, D. Brachman, J. Buckner, K. Fink, L. Souhami, W. Curran
Journal: Journal of Clinical Oncology (2004)

1500 Background: Anaplastic oligodendrogliomas (AOs) and anaplastic oligoastrocytomas (AOAs) are treated with surgery and RT at diagnosis. They also respond to procarbazine, lomustine and vincristine (PCV), raising the possibility that PCV plus RT at diagnosis may improve outcome. Furthermore for AOs, response to PCV and long survival have been associated with 1p and 19q allelic loss. Methods: A RCT was conducted to test whether dose-intense, pre-RT PCV prolongs overall survival (primary endpoint) or progression-free survival (secondary endpoint) versus RT alone. Serious toxicity rates and quality of life were other endpoints. Patients with AOs or AOAs confirmed by central review, who were age ≥18 years, had a Karnofsky score (KPS) ≥60 and consented, were study-eligible. Tumor sections and peripheral blood were also collected. Results: 291 eligible patients were randomized; 60% were male, 68% were < age 50, 88% had a resection, 90% had a KPS ≥ 80 and 70% had an AO. 148 patients had PCV plus RT and 143 had RT alone; the arms were balanced for prognostic factors. Median survivals were similar for both groups; 4.8 years for PCV plus RT and 4.5 years for RT (HR 1.04, 95% CI 0.74–1.45; p=0.830). Progression-free survival tended to be longer after combined treatment; 2.6 years for PCV plus RT versus 1.9 years for RT (HR 1.34, 95% CI 1.00–1.80; p=0.053). During PCV, 95 patients had grade 3 or 4 toxicity and one died. Grade 3 and 4 RT toxicities were infrequent in both groups. Tissues were available on 206 tumors; 92 (46%) had 1p and 19q loss. Irrespective of treatment, patients whose tumors lacked 1p and 19q lived longer than other patients; median survival not reached versus 2.8 years (HR 0.31, 95% CI 0.20–0.48; p<0.001). Longer follow-up is needed to ascertain treatment-specific outcomes for cases with 1p and 19q loss. Conclusions: Pre-RT PCV does not impart a survival advantage for histologically-defined AOs and AOAs, but may prolong progression-free survival at the expense of greater acute toxicity. As reported, 1p and 19q loss is a powerful prognostic marker in oligodendroglial tumors. No significant financial relationships to disclose.
The Ladies Trial: Premature termination of the LOLA arm and increased adverse events incidence after laparoscopic lavage may be influenced by inter-hospital and inter-operator variability? Take-home messages from a center with laparoscopic colorectal expertise
Authors: Salomone Di Saverio, Arianna Birindelli, Fausto Catena, Massimo Sartelli, Edoardo Segalini, Michele Masetti, Elio Jovine
Journal: International Journal of Surgery (2016)
A Pedigree Harboring a Germ-Line N-Terminal C/EBPα Mutation and Development of Acute Myeloblastic Leukemia with a Somatic C-Terminal C/EBPα Mutation.
Authors: Tomoko Nanri, Naokuni Uike, Toshiro Kawakita, Eisaku Iwanaga, Koyu Hoshino, Hiroaki Mitsuya, Norio Asou
Journal: Blood (2006)
Mutational Analysis of Mir-29 Family Members in Chronic Lymphocytic Leukemia
Authors: Jana Lochmanova, Marek Mraz, Veronika Navrkalova, Barbora Dvorakova, Boris Tichy, Karla Plevova, Ludmila Sebejova, Jitka Malcikova, Sarka Pavlova, Vladimir Benes, Tobias Rausch, Yvona Brychtova, Michael Doubek, Martin Trbusek, Jiri Mayer, Sarka Pospisilova
Journal: Blood (2011)