tbuckley/cabot-search huggingface dataset:
Androgen receptor expression in circulating tumor cells of metastatic breast cancer patients.
Authors: Ingeborg Elisabeth de Kruijff, Anieta M. Sieuwerts, Wendy Onstenk, A. Jager, Paul Hamberg, Felix De Jongh, Marcel Smid, Mieke A. Timmermans, John W.M. Martens, Stefan Sleijfer
Journal: Journal of Clinical Oncology (2018)

1087 Background: The androgen receptor (AR) is of clinical relevance in metastatic breast cancer (mBC): AR has been associated with resistance to endocrine therapy and could be a potential target for therapy, especially in the triple negative (TN) subtype. A minimal-invasive way to determine AR expression is by characterization of circulating tumor cells (CTCs). We therefore assessed AR mRNA expression in CTCs (CTC-AR) from mBC patients representing different breast cancer subtypes in relation to outcome on endocrine therapy and 25 genes related to the ER and AR pathways. Furthermore, we assessed AR in matched primary tumors and CTC samples taken at advanced disease. Methods: AR and AR- and ER-related gene expression levels were measured in CellSearch-enriched CTCs from 133 mBC patients with ≥5 CTCs and in 48 matched formalin-fixed paraffin embedded primary tissues using quantitative reverse-transcriptase PCR. AR was considered positive if the expression was 1 standard deviation higher than the expression measured in 12 healthy blood donors. mBC subtypes were established based on ER, PR and HER2-status of the primary tumor (9 unknowns). Results: 31% of the CTC samples were AR-positive (AR+). The HER2+ subtype had most frequently AR+ CTCs (4/8, 50%), which was significantly higher than observed in the TN subtype (2/16, 13%) (p = 0.046). The ER+/HER2- subtype had 35% (27/78) AR+ samples and the ER+/HER2+ 23% (5/22). There was no significant difference between PFS in ER-targeting treated patients and CTC-AR-status (17 AR+ / 41 AR-negative (AR-) cases, p = 0.991). 65% of the matched CTC samples and primary tissues were discordant with respect to AR, observing both switches from AR+ to AR- and vice versa. Conclusions: AR can be determined in RNA isolated from CTCs from different mBC subtypes, with in our set 31% AR-positive samples. Because there was a 65% discordancy between AR in CTC samples and the primary tumor, it seems that AR should be determined in CTCs, but more research should be conducted in a larger set. In our current analysis patients had similar outcome on ER-targeting therapy regardless of their CTC-AR status. Thus, determination of AR expression in CTCs might be a promising tool to select mBC patients for AR inhibiting agents.
Ethics and the Legalization of Physician-Assisted Suicide
Authors: Lois Snyder Sulmasy, Paul S. Mueller
Journal: Annals of Internal Medicine (2018)

Letters5 June 2018Ethics and the Legalization of Physician-Assisted SuicideLois Snyder Sulmasy, JD and Paul S. Mueller, MD, MPHLois Snyder Sulmasy, JDAmerican College of Physicians, Philadelphia, Pennsylvania (L.S.S.) and Paul S. Mueller, MD, MPHMayo Clinic, Rochester, Minnesota (P.S.M.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/L18-0083 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:We appreciate the comments on the ACP's position paper on PAS. It is clear that we all desire the best care for dying patients.Dr. Reimer asks whether we are listening to our patients. The ACP shares this concern and would respond that yes, we are. We agree that PAS is complicated. The ACP has considered the complexity through extensive debate and in the context of the patient-centered, ethically reasoned, and evidence-based approach that is the foundation of our position statements. Although respect for patient autonomy is a fundamental ethical principle, it is not the only one—it must ... Author, Article, and Disclosure InformationAffiliations: American College of Physicians, Philadelphia, Pennsylvania (L.S.S.)Mayo Clinic, Rochester, Minnesota (P.S.M.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-0938. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoEthics and the Legalization of Physician-Assisted Suicide: An American College of Physicians Position Paper Lois Snyder Sulmasy , Paul S. Mueller , and Ethics and the Legalization of Physician-Assisted Suicide E. Wesley Ely Ethics and the Legalization of Physician-Assisted Suicide Banu E. Symington Ethics and the Legalization of Physician-Assisted Suicide Allen H. Roberts II Ethics and the Legalization of Physician-Assisted Suicide Timothy L. Gieseke Ethics and the Legalization of Physician-Assisted Suicide Christie Reimer Metrics Cited byComparing Advance Care Planning in Young-Onset Dementia in the USA vs Belgium: Challenges Partly Related to Societal Context 5 June 2018Volume 168, Issue 11Page: 834-835KeywordsAmyotrophic lateral sclerosisCardiopulmonary resuscitationDisclosureDrugsEuthanasiaPatientsPeriodic acid SchiffSuicide ePublished: 5 June 2018 Issue Published: 5 June 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Protein Kinase C-β Dictates B Cell Fate by Regulating Mitochondrial Remodeling, Metabolic Reprogramming, and Heme Biosynthesis
Authors: Carlson Tsui, Nuria Martinez-Martin, Mauro Gaya, Paula Maldonado, Miriam Llorian, Nathalie M. Legrave, Merja Rossi, James I. MacRae, Angus J. Cameron, Peter J. Parker, Michael Leitges, Andreas Bruckbauer, Facundo D. Batista
Journal: Immunity (2018)

PKCβ-null (Prkcb−/−) mice are severely immunodeficient. Here we show that mice whose B cells lack PKCβ failed to form germinal centers and plasma cells, which undermined affinity maturation and antibody production in response to immunization. Moreover, these mice failed to develop plasma cells in response to viral infection. At the cellular level, we have shown that Prkcb−/− B cells exhibited defective antigen polarization and mTORC1 signaling. While altered antigen polarization impaired antigen presentation and likely restricted the potential of GC development, defective mTORC1 signaling impaired metabolic reprogramming, mitochondrial remodeling, and heme biosynthesis in these cells, which altogether overwhelmingly opposed plasma cell differentiation. Taken together, our study reveals mechanistic insights into the function of PKCβ as a key regulator of B cell polarity and metabolic reprogramming that instructs B cell fate.
Mechanisms of immune evasion in triple-negative breast cancer patients.
Authors: Javier Ignacio Orozco, Ayla O. Manughian-Peter, Matthew P. Salomon, Steven O'Day, Dave S. B. Hoon, Diego M. Marzese
Journal: Journal of Clinical Oncology (2018)

1096 Background: Immunotherapy has shown promising results in enhancing response rates for patients with triple-negative breast cancer (TNBC). The success of immunotherapy is affected by poor tumor antigen presentation. This immune evasion is facilitated by genetic and epigenetic alterations, including aberrant RNA splicing (AS). Here we examined the role of PTBP1, a key RNA splicing factor related to immune evasion in TNBC. Methods: Clinical and gene expression data from 3,614 breast cancer patients included in the METABRIC and TCGA projects were evaluated to identify the impact of PTBP1 on TNBC. Univariate and multivariate statistical modeling was performed to test the association of PTBP1 expression with relapse-free survival (RFS), disease-free survival (DFS), and overall survival (OS). CRISPR-Cas9 technology, followed by RNA sequencing (RNA-Seq) was utilized to identify differentially activated pathways in a TNBC cell model (MDA-MB-231). A portrait of infiltrating immune cells was compiled using the xCELL algorithm. Immunofluorescence (IF) and immunohistochemistry (IHC) were employed to validate our findings in TNBC cell lines, tissue microarrays, and FFPE specimens (n = 110). Results: We found that PTBP1 is significantly upregulated in patients with TNBCs (P< 0.001). TNBC patients with high PTBP1 presented significantly shorter RFS (P= 0.018; HR = 1.66, 95%CI 1.1-2.5; n = 255), DFS (P= 0.017; HR = 3.2, 95%CI 1.16-8.3; n = 151), and OS (P= 0.037; HR = 1.48, 95%CI 1.02-2.15; n = 162). To explore potential mechanisms linking PTBP1 expression and poor survival, CRISPR-guided knockout of PTBP1, followed by RNA-seq identified a significant enhancement on antigen presentation pathways, confirmed by IF staining. xCELL analysis showed that TNBC tumors with high PTBP1 present an immune infiltration profile compatible with immune evasion (low CD4+ naïve and memory T cells, low CD8+ T cells, low tumor-associated macrophages, and high suppressor T cells). These observations were further confirmed by IHC evaluation of TNBC clinical specimens. Conclusions: This study suggests an important and relatively unexplored role of AS in immune evasion, identifying new prognostic and potentially therapeutic targets for patients with aggressive TNBC.
Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial
Authors: Kohei Shitara, Mustafa Özgüroğlu, Yung-Jue Bang, Maria Di Bartolomeo, Mario Mandalà, Min-Hee Ryu, Lorenzo Fornaro, Tomasz Olesiński, Christian Caglevic, Hyun C Chung, Kei Muro, Eray Goekkurt, Wasat Mansoor, Raymond S McDermott, Einat Shacham-Shmueli, Xinqun Chen, Carlos Mayo, S Peter Kang, Atsushi Ohtsu, Charles S Fuchs, Guillermo Lerzo, Juan Manuel O'Connor, Guillermo Ariel Mendez, James Lynam, Niall Tebbutt, Mark Wong, Andrew Strickland, Chris Karapetis, David Goldstein, Paul Vasey, Jean-Luc Van Laethem, Eric Van Cutsem, Scott Berry, Mark Vincent, Bettina Muller, Felipe Rey, Angela Zambrano, Joaquin Guerra, Merete Krogh, Lene Baeksgaard, Mette Yilmaz, Anneli Elme, Andrus Magi, Paivi Auvinen, Tuomo Alanko, Markus Moehler, Volker Kunzmann, Thomas Seufferlein, Peter Thuss-Patience, Eray Goekkurt, Thomas Hoehler, Georg Haag, Salah-Eddin Al-Batran, Hugo Castro, Karla Lopez, Mynor Aguilar Vasquez, Mario Sandoval, Ka On Lam, Sinead Cuffe, Cathy Kelly, Ravit Geva, Einat Shacham-Shmueli, Ayala Hubert, Alex Beny, Baruch Brenner, Aprile Giuseppe, Alfredo Falcone, Evaristo Maiello, Rodolfo Passalacqua, Vincenzo Montesarchio, Hiroki Hara, Keisho Chin, Tomohiro Nishina, Yoshito Komatsu, Nozumo Machida, Shuichi Hironaka, Taroh Satoh, Takao Tamura, Naotaoshi Sugimoto, Haruhiko Cho, Yashushi Omuro, Ken Kato, Masahiro Goto, Ichinosuke Hyodo, Kazuhiro Yoshida, Hideo Baba, Taito Esaki, Junji Furuse, Wan Zamaniah Wan Mohammed, Carlos Hernandez Hernandez, Juan Casas Garcia, Adriana Dominguez Andrade, Katriona Clarke, Geir Hjortland, Nils Glenjen, Tomasz Kubiatowski, Jassem Jacek, Marek Wojtukiewicz, Sergey Lazarev, Yuri Lancukhay, Sergey Afanasayev, Vladimir Moiseyenko, Vladimir Kostorov, Svetlana Protsenko, Vadim Shirinkin, Dina Sakaeva, Natalia Fadeeva, Wei Peng Yong, Chau Hsien Matthew Ng, Barbara Robertson, Bernardo Rapaport, Graham Cohen, Lydia Dreosti, Paul Ruff, Conrad Jacobs, Gregory Landers, Waldemar Szpak, Sang-Young Roh, Jeeyun Lee, Yeul Hong Kim, Yung-Jue Bang, Hyun Cheol Chung, Min-Hee Ryu, Maria Alsina Maqueda, Federico Longo Munoz, Andres Cervantes Aguilar, Enrique Aranda Aguilar, Pilar Garcia Alfonso, Fernando Rivera, Jaime Feliu Batle, Roberto Pazo Cid, Kun-Huei Yeh, Jen-Shi Chen, Yee Chao, Chia-Jui Yen, Mustafa Özgüroğlu, Oguz Kara, Suayib Yalcin, Daniel Hochhauser, Ian Chau, Al Benson, Veena Shankaran, Walid Shaib, Philip Philip, Vivek Sharma, Robert Siegel, Weijing Sun, Zev Wainberg, Ben George, Andrea Bullock, Samuel Myrick, Josephine Faruol, Richard Siegel, Timothy Larson, Carlos Becerra, Suresh Ratnam, Donald A. Richards, Stephen L. Riche
Journal: The Lancet (2018)
PTH-092 Clinical validity and utility of faecal calprotectin in primary care
Authors: GJ Walker, L Moore, N Heerasing, PJ Hendy, C Bewshea, JR Goodhand, NA Kennedy, C Calvert, T Ahmad
Journal: Gut (2017)

Introduction  Faecal Calprotectin (FC) is recommended in primary care (1°care) to help differentiate inflammatory bowel disease (IBD) from irritable bowel syndrome (IBS), although data to justify this practice are limited. 1,2  In 2014 we introduced FC to 1°care and in parallel conducted a large prospective observational study to assess the clinical validity and utility of FC in this setting, and develop an integrated decision tool.  Method  GPs from 57 local practices were recommended to submit an FC test for patients with suspected or possible IBD. Criteria for testing included age   Results  1143 FC tests were submitted (Jan’14-Mar’16), with 761 used in this interim analysis. 458 (59%) were female and median age was 30 years. 50 (7%) patients were diagnosed with IBD, one (0.2%) with an adenoma ≥1 cm and none with CRC. FC≥100 µg/g had a sensitivity=0.92, specificity=0.75, PPV=0.21, NPV=0.99 (AUROC=0.83 [95%CI 0.79–0.87]) for IBD. False negative FC tests occurred in 4 patients later diagnosed with IBD. Red-flag symptoms were reported in 411 (54%) of all patients, 194 (47%) of whom were not referred to 2°care. FC was negative in 520 (68%), and yet 169 (33%) of this group were sill referred to GI services. Multivariable logistic regression demonstrated FC (log 10 FC=OR 48.2, p 2  0.50). Based on pre-test referral intentions FC saved 252 referrals. The median time from GP referral to IBD diagnosis was 45 days (IQR 25–98).  Conclusion  FC is a sensitive and specific test in the primary care setting to distinguish IBD from IBS. It reduces referrals and subsequent endoscopic investigations in patients  References  . Waugh N,  et al . doi:10.3310/hta17550(2013)  . NICE DG11 (2013).  Disclosure of Interest  None Declared
Clinical, Dopaminergic, and Metabolic Correlations in Parkinson Disease
Authors: Feng-Tao Liu, Jing-Jie Ge, Jian-Jun Wu, Ping Wu, Yilong Ma, Chuan-Tao Zuo, Jian Wang
Journal: Clinical Nuclear Medicine (2018)

Neuroimaging indicators of Parkinson disease have been developed and applied in clinical practices. Dopaminergic imaging reflects nigrostriatal dopaminergic dysfunction, and metabolic network imaging offers disease-related metabolic changes at a system level. We aimed to elucidate the association between Parkinsonian symptoms and neuroimaging, and interactions between different imaging techniques.We conducted a dual-tracer PET study for the combined assessments of dopaminergic binding (C-CFT) and glucose metabolism (F-FDG) in 103 participants with Parkinson disease (65 male and 38 female subjects). The detailed clinical rating scores were systematically collected in all members. The interactions among dopaminergic bindings, metabolic changes, and clinical manifestations were evaluated at voxel, regional, and network levels.Striatal DAT binding correlated with akinesia-rigidity (P < 0.001) but not with tremor; the metabolic PET imaging, nonspecific to the dopaminergic dysfunction, disclosed a set of brain regions correlating with the cardinal symptoms, including tremor. In addition, the unilateral symptom correlated with the contralateral nigrostriatal dopamine loss, but with bilateral metabolic changes, suggesting their differences in the application of disease-related mechanistic studies. Further imaging-imaging correlation study revealed that dopaminergic dysfunction correlated with widely distributed metabolic changes in Parkinson disease, and the modest correlations supported the findings on the clinical-imaging correlation.In this dual-tracer PET study, we demonstrated the robust interactions among dopaminergic dysfunction, metabolic brain changes and clinical manifestations at voxel, regional, and network levels. Our findings might promote the understanding in the proper application of dopaminergic and metabolic PET imaging in Parkinson disease and offer more evidence in support of Parkinsonian pathophysiological mechanisms.
The impact of body composition on vertebral fractures during aromatase inhibitors therapy: A cross-sectional study.
Authors: Rebecca Pedersini, Sara Monteverdi, Filippo Maffezzoni, Antonella Turla, Lucia Vassalli, Melanie Claps, Filippo Rodella, Vito Amoroso, Elisa Roca, Gherardo Mazziotti, Roberto Maroldi, Andrea Giustina, Alfredo Berruti, Edda Simoncini
Journal: Journal of Clinical Oncology (2018)

e12504 Background: Aromatase-inhibitors (AIs) decrease the bone mineral density (BMD) and increase the risk of clinical fractures but the mechanism underlying the increased fracture risk (FR) is not fully elucidated. In healthy post menopausal women obesity is associated with lower FR due the protective effect of elevated estrogen levels. However this mechanism cannot be extended to AI treated pts since estrogens are deeply inhibited. We designed a cross sectional study to explore the effect of Fat body mass (FBM) on the risk of morphometric vertebral fracture (VF) in postmenopausal estrogen receptor positive breast carcinoma (BC) submitted to adjuvant AI therapy. Methods: From October 2013 to May 2017 315 EBC patients (pts) were recruited. All pts underwent a dual-energy X-ray absorptiometry (DXA) for the assessment of BMD, morphometric evaluation of VFs and body composition at baseline and after at least one year of AI therapy. Results: 187 pts were AI naive and 128 AI treated, and the prevalence of VFs was 21,9% and 31.2%, respectively. VFs in AI naïve pts were associated with older age (68 vs 62 years, p = 0.000) and lower BMD values at femoral neck (0.656 vs 0.698 gr/cm2, p = 0.02). Conversely, they were associated with higher Body Mass Index (27.26 vs 24.97, p = 0,046) and Fat Body Mass (29296.6 vs 23605.6 g, p = 0,022) in AI-treated patients. Conclusions: A high prevalence of radiological VFs was detected in EBC pts on AIs. Contrary to expectation VFs were associated with BMI and FBM but not with BMD. These data suggest a major contribution of altered bone quality in the fracture risk in AI treated pts. Data on trabecular bone score (a parameter of bone quality) TBS will be available at the meeting
Colorimetric <i>in situ</i> assay of membrane-bound enzyme based on lipid bilayer inhibition of ion transport
Authors: Juan Zhang, Defeng Li, Xiquan Yue, Meiling Zhang, Ping Liu, Genxi Li
Journal: Theranostics (2018)

Membrane-bound enzymes (MBEs), which make up a very high proportion of intracellular enzymes, catalyze a variety of activities that are currently analyzed by various techniques after purification.However, due to their amphipathic character, the purification of MBEs is difficult.Therefore, the most productive approach represents in situ analysis of MBEs in the cellular membrane.Methods: In this study, using membrane-bound α-glucosidase (α-Glu) as an example, we have developed a colorimetric in situ assay for MBEs based on the inhibitory effect of lipid bilayer on ion transport.The enzyme substrate could mediate the self-assembly of phospholipid PEG derivative around magnetic nanospheres that were modified with boronic acid.The formation of lipid bilayer could inhibit the leaking of iron ions under acidic conditions.However, the product of the catalytic reaction had no capability for self-assembly of the lipid bilayer, leading to the release of iron ions from the magnetic nanospheres under acidic pH.Results: The colorimetric in situ assay for MBEs could not only analyze the activity of membrane-bound α-Glu located on Caco-2 cells but could also evaluate the α-Glu inhibitors in cell medium.Conclusions: The simple, economic, and efficient method proposed here offers a potential application for high-throughput testing of α-Glu and its inhibitors.Our study also outlines a strategy for exploring the colorimetric method to detect the activities of MBEs in situ.
Impact of survivorship care plan (SCP) document on cancer survivors’ understanding of their cancer care and follow up.
Authors: Farhan Shahzad Imran, Heather Gorea, Brittany Heatherington, Susan Hodes, Nancy Mary Pictor, Cathy Reda-Cheplowtiz, Jeanine S Santelli, Alyssa Vanzo, Saad Jamshed
Journal: Journal of Clinical Oncology (2018)

53 Background: Follow up care for cancer survivors is often sidelined due to the lack of well-defined guidelines. A “Survivorship care plan (SCP)” document has been proposed to summarize key aspects of cancer care and the future follow up plan. Survey results of cancer survivors who had not received an SCP were compared with those who did receive an SCP. Methods: Surveys were mailed to patients who had completed cancer therapy with curative intent over two phases; phase I included patients who did not receive an SCP and phase II included patients who had received an SCP. The survey was designed to test understanding of diagnosis (stage), care team, symptoms of relapse, surveillance plan, and side effects of treatment. Microsoft Excel was used to calculate descriptive statistics on the quantitative data and frequency counts for the qualitative data. Results: During Phase I, 162 cancer survivors completed the survey and reported diagnosis of colon (2%), lung (6%) or breast (90%) cancer. During Phase II, 107 cancer survivors completed the survey and reported diagnosis of colon (2%), lung (8%), breast (44%) or other (44%) cancer. For both phases, only 2% patients could not correctly identify their cancer diagnosis. Only 12% Phase I and 18% Phase II patients were unable to identify the stage of their cancer at diagnosis. Phase I patients were better able to recall discussing their follow up plan with their provider (95%) and which tests should be performed as part of their cancer surveillance (86%) when compared to Phase II patients (90% and 78%, respectively). Phase II patients were better able to identify factors associated with their cancer where 57% accurately listed symptoms suggesting cancer recurrence and 52% correctly listed potential long-term side effects of cancer treatment. Only 20% and 17% Phase I patients correctly listed examples of each, respectively. Conclusions: Although it is intuitive that an SCP would improve patient understanding, we found a less than expected impact. Patients scored similarly or less favorable in most aspects with the distribution of the SCP, but were better able to identify signs and symptoms of disease recurrence and potential side effects of treatment.