tbuckley/cabot-search huggingface dataset:
NF-κB signaling and its relevance to the treatment of mantle cell lymphoma
Authors: Swathi Balaji, Makhdum Ahmed, Elizabeth Lorence, Fangfang Yan, Krystle Nomie, Michael Wang
Journal: Journal of Hematology & Oncology (2018)

Mantle cell lymphoma is an aggressive subtype of non-Hodgkin B cell lymphoma that is characterized by a poor prognosis determined by Ki67 and Mantle Cell International Prognostic Index scores, but it is becoming increasingly treatable. The majority of patients, especially if young, achieve a progression-free survival of at least 5 years. Mantle cell lymphoma can initially be treated with an anti-CD20 antibody in combination with a chemotherapy backbone, such as VR-CAP (the anti-CD20 monoclonal antibody rituximab administered with cyclophosphamide, doxorubicin, and prednisone) or R-CHOP (the anti-CD20 monoclonal antibody rituximab administered with cyclophosphamide, doxorubicin, vincristine, and prednisone). While initial treatment can facilitate recovery and complete remission in a few patients, many patients experience relapsed or refractory mantle cell lymphoma within 2 to 3 years after initial treatment. Targeted agents such as ibrutinib, an inhibitor of Bruton’s tyrosine kinase, which has been approved only in the relapsed setting, can be used to treat patients with relapsed or refractory mantle cell lymphoma. However, mantle cell lymphoma cells often acquire resistance to such targeted agents and continue to survive by activating alternate signaling pathways such as the PI3K-Akt pathway or the NF-κB pathways. NF-κB is a transcription factor family that regulates the growth and survival of B cells; mantle cell lymphoma cells depend on NF-κB signaling for continued growth and proliferation. The NF-κB signaling pathways are categorized into canonical and non-canonical types, wherein the canonical pathway prompts inflammatory responses, immune regulation, and cell proliferation, while the non-canonical leads to B cell maturation and lymphoid organogenesis. Since these pathways upregulate survival genes and tumor-promoting cytokines, they can be activated to overcome the inhibitory effects of targeted agents, thereby having profound effects on tumorigenesis. The NF-κB pathways are also highly targetable in that they are interconnected with numerous other pathways, including B cell receptor signaling, PI3K/Akt/mTOR signaling, and toll-like receptor signaling pathways. Additionally, elements of the non-canonical NF- κB pathway, such as NF-κB-inducing kinase, can be targeted to overcome resistance to targeting of the canonical NF- κB pathway. Targeting the molecular mechanisms of the NF-κB pathways can facilitate the development of novel agents to treat malignancies and overcome drug resistance in patients with relapsed or refractory mantle cell lymphoma.
12-Hydroxyeicosatetraenoic acid levels are increased in actinic keratoses and squamous cell carcinoma
Authors: Vivian Laquer, Ryan W. Dellinger, Irene Mannering, Angela Gomez Garcia, Vivek Abraham, Janelle Pavlis, Feng Liu-Smith, Sebastien De Feraudy, Frank L. Meyskens, Kristen M. Kelly
Journal: Journal of the American Academy of Dermatology (2018)
NCCN Guidelines Insights: Neuroendocrine and Adrenal Tumors, Version 2.2018
Authors: Manisha H. Shah, Whitney S. Goldner, Thorvardur R. Halfdanarson, Emily Bergsland, Jordan D. Berlin, Daniel Halperin, Jennifer Chan, Matthew H. Kulke, Al B. Benson, Lawrence S. Blaszkowsky, Jennifer Eads, Paul F. Engstrom, Paul Fanta, Thomas Giordano, Jin He, Martin J. Heslin, Gregory P. Kalemkerian, Fouad Kandeel, Sajid A. Khan, Wajih Zaheer Kidwai, Pamela L. Kunz, Boris W. Kuvshinoff, Christopher Lieu, Venu G. Pillarisetty, Leonard Saltz, Julie Ann Sosa, Jonathan R. Strosberg, Craig A. Sussman, Nikolaos A. Trikalinos, Nataliya A. Uboha, Jonathan Whisenant, Terence Wong, James C. Yao, Jennifer L. Burns, Ndiya Ogba, Griselda Zuccarino-Catania
Journal: Journal of the National Comprehensive Cancer Network (2018)

The NCCN Guidelines for Neuroendocrine and Adrenal Tumors provide recommendations for the management of adult patients with neuroendocrine tumors (NETs), adrenal gland tumors, pheochromocytomas, and paragangliomas. Management of NETs relies heavily on the site of the primary NET. These NCCN Guidelines Insights summarize the management options and the 2018 updates to the guidelines for locoregional advanced disease, and/or distant metastasis originating from gastrointestinal tract, bronchopulmonary, and thymus primary NETs.
Correction: The state of the antivaccine movement in the United States: A focused examination of nonmedical exemptions in states and counties
Authors: Jacqueline K. Olive, Peter J. Hotez, Ashish Damania, Melissa S. Nolan
Journal: PLoS Medicine (2018)

After publication of this article, the authors became aware of an error in the quoted number of philosophical-belief vaccine nonmedical exemptions (NMEs) in Allegheny County, Pennsylvania.The quoted number of 424 exemptions resulted from an inadvertent doubling of the correct number of 212.The authors apologize for this error.All the data and analyses in the paper have now been thoroughly checked, and we can verify that, while the error affected all entries in the Pennsylvania county-level dataset, no data from other states were affected.Therefore, the authors would like to correct the text and figures of the article as follows, to remove Allegheny County from the maps and rankings of areas with >400 kindergarteners with NMEs in 2016-2017.In addition to Allegheny County, NME rates for all counties in Pennsylvania have been corrected in Fig 2.There were also two minor errors in presentation that need to be corrected, regarding the list of states in the second summary point and an asterisk missing from Fig 1.The first sentence of the second Summary point should read "Since 2009, the number of philosophical-belief vaccine nonmedical exemptions (NMEs) has risen in 12 of the 18 states that currently allow this policy: Arizona (AZ), Arkansas (AR), Idaho (ID), Maine (ME), Minnesota (MN), Missouri (MO), North Dakota (ND), Ohio (OH), Oklahoma (OK), Oregon (OR), Texas (TX), and Utah (UT)."We would also like to amend the third Summary point, to substitute the names of the counties from which data were derived for the names of cities within those counties.The first sentence of the third Summary point should read "Several US "hotspot" metropolitan areas stand out for their very large numbers of NMEs.They include King County, WA, Spokane County, WA, and Multnomah County, OR, in the Northwest; Maricopa County, AZ, Salt Lake County, UT, Utah County, UT, Harris County, TX, Tarrant County, TX, Collin County, TX, and Travis County, TX, in the Southwest; and Oakland County, MI, Macomb County, MI, Wayne County, MI, and Jackson County, MO, in the Midwest."Fig 1 has been corrected to add an asterisk next to Arizona.Fig 2 now shows corrected NME rates for all counties in Pennsylvania.Pennsylvania's county level NME rates have been verified with the original source, provided by the Pennsylvania Department of Health, to ensure accuracy.The third paragraph of the section subtitled "Going granular" should read "Furthermore, we examined total numbers of kindergarteners with NMEs per county to identify focal areas with large numbers of potentially vulnerable pediatric populations.County NME totals were also provided by state health departments.The exception is MO, whose private kindergarten (2015-2016) and public kindergarten (2014-2015) enrollment numbers were taken together from the National Center for Education Statistics (nces.ed.gov) to derive NME raw counts.
B cell development is critically dependent on NFATc1 activity
Authors: Sabrina Giampaolo, Gabriela Wójcik, Stefan Klein-Hessling, Edgar Serfling, Amiya K. Patra
Journal: Cellular and Molecular Immunology (2018)

B cell development in bone marrow is a precisely regulated complex process. Through successive stages of differentiation, which are regulated by a multitude of signaling pathways and an array of lineage-specific transcription factors, the common lymphoid progenitors ultimately give rise to mature B cells. Similar to early thymocyte development in the thymus, early B cell development in bone marrow is critically dependent on IL-7 signaling. During this IL-7-dependent stage of differentiation, several transcription factors, such as E2A, EBF1, and Pax5, among others, play indispensable roles in B lineage specification and maintenance. Although recent studies have implicated several other transcription factors in B cell development, the role of NFATc1 in early B cell developmental stages is not known. Here, using multiple gene-manipulated mouse models and applying various experimental methods, we show that NFATc1 activity is vital for early B cell differentiation. Lack of NFATc1 activity in pro-B cells suppresses EBF1 expression, impairs immunoglobulin gene rearrangement, and thereby preBCR formation, resulting in defective B cell development. Overall, deficiency in NFATc1 activity arrested the pro-B cell transition to the pre-B cell stage, leading to severe B cell lymphopenia. Our findings suggest that, along with other transcription factors, NFATc1 is a critical component of the signaling mechanism that facilitates early B cell differentiation.
Estrogen Receptors: New Directions in the New Millennium
Authors: Sylvia C Hewitt, Kenneth S Korach
Journal: Endocrine Reviews (2018)

Nineteen years have passed since our previous review in this journal in 1999 regarding estrogen receptors. At that time, we described the current assessments of the physiological activities of estrogen and estrogen receptors. Since that time there has been an explosion of progress in our understanding of details of estrogen receptor–mediated processes from the molecular and cellular level to the whole organism. In this review we discuss the basic understanding of estrogen signaling and then elaborate on the progress and current understanding of estrogen receptor actions that have developed using new models and continuing clinical studies.
SAT0533 Polvas – retrospective registry of polish patients with anca-associated vasculitides
Authors: K. Wójcik, J. Kur-Zalewska, A. Masiak, A. Dębska-Ślizień, J. Jeleniewicz, K. Jakuszko, P. Głuszko, M. Wisłowska, I. Brzosko, A. Hawrot-Kawecka, J. Musiał
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Vascultides are a heterogeneous group of rare diseases with unknown etiology and the clinical spectrum ranging from life–threatening systemic disease to minor isolated skin changes. Present nomenclature and definitions of systemic vasculitides have been proposed in 2012 at the International Chapel Hill Consensus Conference.<sup>1</sup> Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) belong to the small to medium-size vessel systemic diseases comprising granulomatosis with polyangitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). <h3>Objectives</h3> We decided to retrospectively analyse a large cohort of Polish AAV patients coming from referral centres – members of the Scientific Consortium of the Polish Vasculitis Registry (POLVAS).<sup>2,3</sup> <h3>Methods</h3> We conducted a systematic multicenter retrospective study of adult patients diagnosed with AAV between Jan 1990 and Dec 2016 Patients were enrolled to the study by 9 referral centres (14 clinical wards: – rheumatology – 10, nephrology – 2, metabolic diseases – 1, clinical immunology −1) from 7 Voivodships populated by 22,3 mln inhabitants (58,2% of the Polish population). Patient data have been collected according to the uniform protocol in the POLVAS registry. <h3>Results</h3> Distribution of AAV in the Polish population resembles that of north European cohorts.<sup>4</sup> In POLVAS registry 417 (66.7%) patients were diagnosed with GPA, 106 (17.0%) with MPA and 102 (16,3%) with EGPA. Male-to-female ratios were almost 1:1 for GPA (210/207) and MPA (54/52), but EGPA wasd twice more frequent among women (34/68). Clinical manifestations and organ involvement were analysed both by clinical phenotype (GPA, MPA, EGPA) and ANCA specificity (anti-PR3+, and anti-MPO+)Analysis by ANCA specificity showed no apparent difference as compared to phenotype analysis. Clinical manifestations of different AAV in the polish population seems very similar to other European countries. <h3>Conclusions</h3> This is the first multicenter retrospective study of the Polish patients sufferng from with AAV. Demographic characteristics and disease manifestations of AAV patients in POLVAS registry follow the same pattern as those from other European countries.<sup>4</sup> <h3>References</h3> [1] Jennette JC, et al. Arthritis Rheum2013Jan;65(1):1–11. [2] Padjas A, et al. Pol Arch Med Wewn2014;124(3):143–4. [3] Musia&amp;x0142; J, Wójcik K. Pol Arch Intern Med2017Jan 31;127(1):71–72. [4] Bajema, et al. Kidney Int Rep2017;1018–1031. <h3>Disclosure of Interest</h3> None declared
Change in systemic inflammation markers and CEA levels as predictive marker for chemotherapy response and prognosis in metastatic colorectal cancer.
Authors: In-Ho Kim, In Hee Lee, Ji Eun Lee, Seong Taek Oh, Jun Ki Kim, Myung Ah Lee
Journal: Journal of Clinical Oncology (2016)

e15053 Background: This study aimed to evaluate the value of systemic inflammation markers and carcinoembryonic antigen (CEA) levels as predicting chemotherapy response and prognosis in metastatic colorectal cancer (mCRC). Methods: We retrospectively evaluated 503 patients who received first-line palliative chemotherapy for mCRC between Jan, 2008 and Dec, 2014. We evaluated the changes in neutrophil-to-lymphocyte ratio (NLR) and modified Glasgow Prognostic Score (mGPS) before and after chemotherapy. These were categorized into group A (low to low), group B (high to low), group C (low to high), and group D (high to high). The CEA-response was defined as CEA-CR (CEA normalization), CEA-PR (≥50% decrease in CEA levels), CEA-PD (≥50% increase in CEA levels), and CEA-SD (non-CR/PR/PD). Overall and progression-free survivals were evaluated according to NLR, mGPS and CEA levels. Results: High NLR (P = 0.001) and mGPS (P = 0.002) were correlated with elevated CEA levels. In multivariate analysis, high pre-chemotherapy NLR (OS: P = 0.001; PFS: P = 0.011), mGPS (OS: P = 0.003; PFS: P = 0.046) and CEA levels (OS and PFS: P < 0.001) were independently associated with poor survival. Patients in the NLR-A group (Overall response rate [ORR] = 61.9%, disease control rate [DCR] = 87.8%) and NLR-B group (ORR = 61.6%, DCR = 90.2%) exhibited significantly better chemotherapy response than patients in the NLR-C (ORR = 42.1%, DCR = 73.6%) and NLR-D groups (ORR = 23.9%, DCR = 67.2%) (P < 0.001). Continuously high NLR, or change to high NLR were also associated with poor survival but continuously low NLR or reduced NLR showed good prognosis (OS and PFS: P < 0.001). Better CEA-response had better response to chemotherapy based on RECIST criteria (P < 0.001). CEA-response was also an independent prognostic marker for OS and PFS (all P < 0.001) in multivariate analysis. Conclusions: The level of inflammatory markers was significantly associated with level of CEA. The pre chemotherapy levels of systemic inflammation markers and CEA were associated with OS or PFS. In addition, the change patterns in NLR and CEA levels can be also prognostic marker and predictive marker for chemotherapy response.
Recognizing Blind Spots — A Remedy for Gender Bias in Medicine?
Authors: Loren G. Rabinowitz
Journal: New England Journal of Medicine (2018)

Interview with Dr. Loren Rabinowitz on the hurdles and frustrations that female medical trainees face in a sexist culture. (08:58)Download For young women in medicine, self-advocacy can feel impossible. Small steps such as taking ownership of our roles as physicians, enlisting allies, and educating our trainees, students, and patients can provide a starting point for the movement toward workplace equality.
Prevention of Fatal C3 Glomerulopathy by Recombinant Complement Receptor of the Ig Superfamily
Authors: Xiaoxu Wang, Menno Van Lookeren Campagne, Kenneth J. Katschke, Damodar Gullipalli, Takashi Miwa, Yoshiyasu Ueda, Yuan Wang, Matthew Palmer, Guolan Xing, Wen-Chao Song
Journal: Journal of the American Society of Nephrology (2018)

Background C3 glomerulopathy (C3G) is a life-threatening kidney disease caused by dysregulation of the alternative pathway of complement (AP) activation. No approved specific therapy is available for C3G, although an anti-C5 mAb has been used off-label in some patients with C3G, with mixed results. Thus, there is an unmet medical need to develop other inhibitors of complement for C3G. Methods We used a murine model of lethal C3G to test the potential efficacy of an Fc fusion protein of complement receptor of the Ig superfamily (CRIg-Fc) in the treatment of C3G. CRIg-Fc binds C3b and inhibits C3 and C5 convertases of the AP. Mice with mutations in the factor H and properdin genes (FH m/m P −/− ) develop early-onset C3G, with AP consumption, high proteinuria, and lethal crescentic GN. Results Treatment of FH m/m P −/− mice with CRIg-Fc, but not a control IgG, inhibited AP activation and diminished the consumption of plasma C3, factor B, and C5. CRIg-Fc–treated FH m/m P −/− mice also had significantly improved survival and reduced proteinuria, hematuria, BUN, glomerular C3 fragment, C9 and fibrin deposition, and GN pathology scores. Conclusions Therapeutics developed on the basis of the mechanism of action of soluble CRIg may be effective for the treatment of C3G and should be explored clinically.
Analysis of consumer food purchase data used for outbreak investigations, a review
Authors: Frederik T Møller, Kåre Mølbak, Steen Ethelberg
Journal: Eurosurveillance (2018)

BackgroundInvestigations of food-borne outbreaks are frequently unsuccessful and new investigation methods should be welcomed. Aim: Describe the use of consumer purchase datasets in outbreak investigations and consider methodological and practical difficulties. Methods: We reviewed published papers describing the use of consumer purchase datasets, where electronic data on the foods that case-patients had purchased before onset of symptoms were obtained and analysed as part of outbreak investigations. Results: For the period 2006-17, scientific articles were found describing 20 outbreak investigations. Most outbreaks involved salmonella or Shiga toxin-producing Escherichia coli and were performed in eight different countries. The consumer purchase datasets were most frequently used to generate hypotheses about the outbreak vehicle where case-interviews had not been fruitful. Secondly, they were used to aid trace-back investigation, where a vehicle was already suspected. A number of methodological as well as (in some countries) legal and practical impediments exist. Conclusions: Several of the outbreaks were unlikely to have been solved without the use of consumer purchase datasets. The method is potentially powerful and with future improved access to big data purchase information, may become a widely applicable tool for outbreak investigations, enabling investigators to quickly find hypotheses and at the same time estimate odds ratios or relative risks hereof. We suggest using the term 'consumer purchase data' to refer to the approach in the future.
Identification and Characterization of Novel Conserved Domains in Metazoan Zic Proteins
Authors: Takahide Tohmonda, Akiko Kamiya, Akira Ishiguro, Takashi Iwaki, Takahiko J Fujimi, Minoru Hatayama, Jun Aruga
Journal: Molecular Biology and Evolution (2018)

Zic family genes encode C2H2-type zinc finger proteins that act as critical toolkit proteins in the metazoan body plan establishment. In this study, we searched evolutionarily conserved domains (CDs) among 121 Zic protein sequences from 22 animal phyla and 40 classes, and addressed their evolutionary significance. The collected sequences included those from poriferans and orthonectids. We discovered seven new CDs, CD0-CD6, (in order from the N- to C-terminus) using the most conserved Zic protein sequences from Deuterostomia (Hemichordata and Cephalochordata), Lophotrochozoa (Cephalopoda and Brachiopoda), and Ecdysozoa (Chelicerata and Priapulida). Subsequently, we analyzed the evolutionary history of Zic CDs including the known CDs (ZOC, ZFD, ZFNC, and ZFCC). All Zic CDs are predicted to have existed in a bilaterian ancestor. During evolution, they have degenerated in a taxa-selective manner with significant correlations among CDs. The N terminal CD (CD0) was largely lost, but was observed in Brachiopoda, Priapulida, Hemichordata, Echinodermata, and Cephalochordata, and the C terminal CD (CD6) was highly conserved in conserved-type-Zic possessing taxa, but was truncated in vertebrate Zic gene paralogues (Zic1/2/3), generating a vertebrate-specific C-terminus critical for transcriptional regulation. ZOC was preferentially conserved in insects and in an anthozoan paralogue, and it was bound to the homeodomain transcription factor Msx in a phylogenetically conserved manner. Accordingly, the extent of divergence of Msx and Zic CDs from their respective bilaterian ancestors is strongly correlated. These results suggest that coordinated divergence among the toolkit CDs and among toolkit proteins is involved in the divergence of metazoan body plans.
Time to design a “real health system”
Authors: Joachim P Sturmberg
Journal: BMJ (2018)

Changing how we think about healthcare improvement, as Braithwaite suggests,1 does not tackle the key questions facing healthcare systems as “socially designed complex adaptive systems.”2

How many people require healthcare—from whom and where? Most of us are healthy enough to not require health professional services. Kerr White’s groundbreaking study in 1961 showed that health and …