tbuckley/cabot-search huggingface dataset:
Clinical and Molecular Characterization of Primary Plasma Cell Leukemia
Authors: Sandra Susanibar, Pingping Qu, Antje Hoering, Sharmilan Thanendrarajan, Jorge Jo Kamimoto, Meera Mohan, Pankaj Mathur, Shadiqul Hoque, Muthukumar Radhakrishnan, Phil Farmer, Nathan Petty, Frits van Rhee, Maurizio Zangari, Faith E. Davies, Daisy Alapat, Barlogie Bart, Gareth J. Morgan, Carolina D. Schinke
Journal: Blood (2017)
How important is my decile score?
Authors: Sophia Bourne
Journal: BMJ (2017)

Dear Sophia

Medical students seem to get stressed about their decile score and where they rank within the year. How important is this?

Daniyal Jafree, fourth year medical student, University College London

Your decile ranking is an indicator of your performance throughout medical school compared with the rest of your year group. Your medical school should be able to provide you with information on how the decile score is calculated and how scores are weighted …
Abstract A14: A cholesterol metabolite acts on the host to increase breast cancer metastasis
Authors: Amy Eun Joo Baek, Erik Russell Nelson
Journal: Cancer Research (2016)

Abstract With a woman's lifetime risk of developing invasive breast cancer at one in eight, breast cancer remains the most common cancer and the second leading cause of cancer death in women. Despite the success of frontline endocrine therapies, relapse with resistant metastatic disease is common, and triple negative disease remains without a targeted therapy. Importantly, breast cancer associated mortality is most often due to the metastatic spread of the disease. Therefore, there continues to be a need for studies that may lead to the development of new chemopreventive strategies and/or lifestyle changes that reduce breast cancer metastasis. In this regard, both obesity and elevated cholesterol are risk factors for metastatic relapse, while patients receiving cholesterol-lowering drugs such as HMG-CoA reductase inhibitors (statins) display an increased relapse-free survival time. Therefore, clinical observations strongly implicate cholesterol in the metastatic progression of, although the underlying mechanisms remain unknown. Thus, we initiated a series of studies to evaluate the mechanisms by which cholesterol promotes breast cancer metastasis. Using murine models of mammary cancer, we find that elevated cholesterol does indeed increase metastasis. Further, statins attenuated the metastatic effects of a high fat diet, implicating cholesterol as a primary mediator of this pathology. Importantly, the pro-metastatic effects of cholesterol required the presence of CYP27A1, the enzyme responsible for its conversion to 27-hydroxycholesterol (27HC). We have recently shown that 27HC is an endogenous ligand for the both the estrogen receptors (ERs) and liver X receptors (LXRs). Interestingly, however, the metastatic effects of 27HC were also prevalent in ER-negative models. While LXR activation did have a modest effect on epithelial to mesenchymal transition (EMT), we find that the robust pro-metastatic effects of 27HC are mediated in a cancer cell-extrinsic manner. Specifically, we find that 27HC alters myeloid cell recruitment and function at distal metastatic sites, and thereby facilitates cancer cell colonization and growth by modulating the host environment. In summary, our data strongly suggest that by altering the host immune system, 27HC is the down-stream mediator of the effects of obesity and cholesterol on breast cancer metastasis. These results provide additional support for development of specific CYP27A1 inhibitors and immune-modulatory therapies for the prevention and treatment of breast cancer metastasis. This work was supported by an NIH-NCI grant to ERN (4R00CA172357-03). Citation Format: Amy Eun Joo Baek, Erik Russell Nelson. A cholesterol metabolite acts on the host to increase breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A14.
Abstract 850: Evaluating preclinical efficacy of anti-HER2 drug combinations using ER+/HER2 mutant models
Authors: Vaishnavi Devarakonda, LaTerrica Williams, Sinem Seker, Jonathan T. Lei, Purba Singh, Airi Han, Meenakshi Anurag, Kimberly R. Holloway, Alana L. Welm, Matthew J. Ellis, Shyam M. Kavuri
Journal: Cancer Research (2019)

Abstract Targeting HER2 is one of the greatest successes in oncology, and has resulted in the generation of a wide array of HER2-targeting agents. Our genomic approaches are revealing other mechanisms of HER2 activation, such as our discovery of activating HER2 mutations in different cancer types. From initial breast cancer and SUMMIT trial data, the pan-HER drug neratinib as monotherapy showed initial clinical response in ER+ breast cancer, but with frequent early relapse. This study investigates the preclinical efficacy of anti HER2 agents alone or in combination with endocrine therapy agents or in combination with CDK4/6 inhibitors using ER+/HER2 mutant cell lines and ex vivo HER2 mutant patient derived xenograft (PDX) model. ER+ breast cancer cell lines (T47D and MCF7) stably expressing HER2V777L, and ER+/HER2 mutant PDX model (HER2G778_P780 dup) were used to examine HER2 signaling. We found that MCF7/T47D cells expressing HER2V777L and HER2G778_P780 dup PDX tumors showed strongly activated autophosphorylation of HER2 and increased expression of CDK4, CDK6, phospho-Rb, and cyclin D1 as compared to MCF7/T47D cells expressing HER2WT or ER+/non-HER2mut PDX model, suggesting that HER2 mutations preferentially depend on CDK4/6 signaling for cell growth. Additionally, we showed that activating MCF7 HER2V777L cause resistance to endocrine therapy treatment (fulvestrant IC50 &amp;gt;5μM). Further, we show that neratinib alone is effective at higher concentrations (IC50 &amp;lt; 2μM) in MCF7/HER2V777L cells. Next we showed that abemaciclib alone exhibited moderate activity against MCF7 HER2V777L cells (IC50 &amp;lt; 0.4μM) and additional activity in combination with neratinib (IC50 &amp;lt; 0.06μM) was seen. Moreover, ex vivo HER2G778_P780 dup cells are relatively resistant to fulvestrant alone (IC50 &amp;lt; 0.2μM), neratinib alone (IC50 &amp;lt; 0.006μM), abemaciclib alone (IC50 &amp;lt; 0.04μM), and neratinib in combination with abemaciclib (IC50 &amp;lt; 0.005μM), suggesting that patients harboring ER+/HER2-mutant tumors may benefit from neratinib in combination with abemaciclib. Therefore, we propose that simultaneous targeting of both HER2 and the CDK4/6 axis is required for maximal inhibition of ER+ breast cancers harboring HER2 activating mutations. Citation Format: Vaishnavi Devarakonda, LaTerrica Williams, Sinem Seker, Jonathan T. Lei, Purba Singh, Airi Han, Meenakshi Anurag, Kimberly R. Holloway, Alana L. Welm, Matthew J. Ellis, Shyam M. Kavuri. Evaluating preclinical efficacy of anti-HER2 drug combinations using ER+/HER2 mutant models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 850.
Abstract P2-01-21: Not presented
Authors: SM Hyder, MT Cook, Y Liang
Journal: Cancer Research (2019)

Abstract This abstract was not presented at the conference. Citation Format: Hyder SM, Cook MT, Liang Y. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-21.
Unprecedented Parallel Photosynthetic Losses in a Heterotrophic Orchid Genus
Authors: Craig F Barrett, Brandon T Sinn, Aaron H Kennedy
Journal: Molecular Biology and Evolution (2019)

Heterotrophic plants are evolutionary experiments in genomic, morphological, and physiological change. Yet, genomic sampling gaps exist among independently derived heterotrophic lineages, leaving unanswered questions about the process of genome modification. Here, we have sequenced complete plastid genomes for all species of the leafless orchid genus Hexalectris, including multiple individuals for most, and leafy relatives Basiphyllaea and Bletia. Our objectives are to determine the number of independent losses of photosynthesis and to test hypotheses on the process of genome degradation as a result of relaxed selection. We demonstrate four to five independent losses of photosynthesis in Hexalectris based on degradation of the photosynthetic apparatus, with all but two species displaying evidence of losses, and variation in gene loss extending below the species level. Degradation in the atp complex is advanced in Hexalectris warnockii, whereas only minimal degradation (i.e., physical loss) has occurred among some "housekeeping" genes. We find genomic rearrangements, shifts in Inverted Repeat boundaries including complete loss in one accession of H. arizonica, and correlations among substitutional and genomic attributes. Our unprecedented finding of multiple, independent transitions to a fully mycoheterotrophic lifestyle in a single genus reveals that the number of such transitions among land plants is likely underestimated. This study underscores the importance of dense taxon sampling, which is highly informative for advancing models of genome evolution in heterotrophs. Mycoheterotrophs such as Hexalectris provide forward-genetic opportunities to study the consequences of radical genome evolution beyond what is possible with mutational studies in model organisms alone.
Abstract 12059: Incidental Findings in Cardiomyopathy and Channelopathy Genes Among 5891 Individuals Undergoing Whole-exome Sequencing. What Should be Reported?
Authors: Elisa Mastantuono, Thomas Wieland, Riccardo Berutti, Peter Lichtner, Tim Strom, Thomas Meitinger, Lia Crotti
Journal: Circulation (2015)

Background: Whole-exome-sequencing (WES) is becoming a common molecular diagnostic test for patients with genetic disorders. However, this technique allows the identification not only of mutations responsible for the disease under investigation, but also of variants potentially causing other diseases, the so called “incidental findings” (IFs). The American College of Medical Genetics and Genomics (ACMG) stated that IFs should be reported based on clinical validity and utility and indicated a list of 56 actionable genes. Among these, nearly half (20/56) are major genes associated with channelopathies and cardiomyopathies. Despite these recommendations, most of the studies so far published, reported also mutations in minor genes among the actionable findings. Methods: WES was performed in 5891 individuals without known channelopathies or cardiomyopathies. Exome data were first filtered based on genotype quality. Subsequently, a frequency filter was applied, considering 1000 Genomes, ExAC and our internal exome database. Variants reported as pathogenic in ClinVar or novel but expected to be pathogenic (nonsense, frameshift and splice) were further investigated, following the ACMG guidelines. Major (20) and minor (73) genes associated with channelopathies and cardiomyopathies were evaluated. Results: We identified 3514 variants in the 93 genes under investigation, after applying the quality and frequency filters. Eight variants were classified as pathogenic and 52 as likely pathogenic and they were detected in around 1% of the individuals. The vast majority (85%) of pathogenic or likely pathogenic variants were located in the 20 actionable genes indicated by ACMG. The inclusion of minor genes increased the number of variants of unknown significance (VUS), from 865 to 3454. Conclusion: Our data support the ACMG recommendations in reporting only IFs identified in the 20 major cardiac actionable genes. Indeed, the inclusion of minor genes is mainly increasing the number of VUS, without significantly impacting the number of pathogenic and likely pathogenic variants. The percentage of individuals with potentially clinical relevant variants in these genes is too high in relation to the disease-prevalence: a cardiologic evaluation is warranted.
Abstract P1-15-18: Not presented
Authors: HJ Choi, SW Kim, JM Ryu, I Kim, SJ Nam, J Yu, SK Lee, JE Lee
Journal: Cancer Research (2019)

Abstract This abstract was not presented at the conference. Citation Format: Choi HJ, Kim SW, Ryu JM, Kim I, Nam SJ, Yu J, Lee SK, Lee JE. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-18.
Making sense of our actions
Authors: Joanna E Perthen
Journal: BMJ (2011)

David Eagleman’s Incognito presents the brain architecture as a “team of rivals”: a collection of neural subsystems that have overlapping functions and competing aims, creating a complex, conflict based organisation. In this framework, consciousness is analogous to the chief executive officer of a company, responsible for planning and setting goals, aware only of the headline events and representing the tip of the iceberg. This book’s title refers to the fact that much of the brain’s activity occurs outside of our control and below our levels of awareness. Thus the brain acts “incognito,” controlling most of what we do, think, and feel using neural circuits that are inaccessible …
EUROPEAN ENDOSCOPIC SUTURING REGISTRY FOR BARIATRIC PATIENTS
Authors: G Lopez-Nava, I Bautista-Castaño, S Perretta, A Formiga
Journal: Endoscopy (2019)

Full-thickness endoscopic suturing has demonstrated multiple uses, including endoscopic sleeve gastroplasty (ESG) as a primary bariatric procedure and a reduction of dilated gastrojejunal anastomosis (TORe: transoral outlet reduction) in patients who have weight regain after bariatric surgery. This prospective observational multicenter registry allows monitoring feasibility, safety and weight loss of patients that underwent endoscopic suturing with Overstich system (Apollo Endosurgery).
Abstract PD4-02: Withdrawn
Authors: MJ Wong, R Patel, WB DeMartini, JE Todderud, S Okamoto, DM Ikeda
Journal: Cancer Research (2019)

Abstract This abstract was withdrawn by the authors. Citation Format: Wong MJ, Patel R, DeMartini WB, Todderud JE, Okamoto S, Ikeda DM. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD4-02.
Abstract P1-04-01: Estrogen receptor β agonists inhibits syngeneic mammary tumor growth through cell-cycle arrest by modulating cell-cycle regulators
Authors: K Ramasamy, C Samayoa, NK Krishnegowda, A Thurlapati, RK Vadlamudi, RR Tekmal
Journal: Cancer Research (2019)

Abstract Breast Cancer is the main cause of cancer-associated mortality in women worldwide. The estrogen receptors (ER's) play an important role in normal mammary gland development, as well as in breast cancer. Estrogen Receptor α is expressed in 70% of breast cancers, where it contributes to increased cell proliferation and decreased cell death. Endocrine therapies such as anti-estrogens and aromatase inhibitors target ERα signaling and improve outcomes of these patients. Syngeneic, immunocompetent mouse models are essential for elucidating the mechanisms and for evaluating novel strategies for the treatment of breast cancer. In contrast to the tumor-inducing role of ERα, ERβ has been shown to have tumor suppressive activities in various cancer, including the breast cancer. Compounds that selectively activate ERβ hold promise because they could potentially avoid the unwanted effects of ERα activation, while exploiting the tumor-suppressive function of ERβ. In the present study, we assessed the antitumor effects of ERβ agonists using three different syngeneic mouse models; D2A1 (BALB/c) and MM51 (FVB) syngeneic models and ex-vivo culture of highly metastatic cell line E0771 (C57/B6). Effect on in vitro cancer cell growth was evaluated by cell proliferation and clonogenic assays. Cell cycle distribution was analysed by flow cytometry. Our results demonstrate that ERβ agonists LY500307 and S-Equol not only inhibited the growth of all three mouse mammary tumor cell lines, but also reduced the colony formation ability. ERβ agonists also induced the cell-cycle arrest in time and dose-dependent manner. In mechanistic studies, ERβ agonists LY500307 and S-Equol, modulated the protein levels of cyclin-dependent kinases (CDKs) (4, 6, and 2), cyclins (D1 and E), in a differential manner in these three cell lines. Our in vivo studies of D2A1 and MM51 cells demonstrates that ERβ agonist LY500307 inhibited the tumor growth and the effect was more pronounce in combination with aromatase inhibitor letrozole. Ex-vivo model of E0771 cells showed that LY500307 has potential to dramatically reduce the proliferation of mouse mammary tumor growth.Together, these results identify potential molecular targets and anticancer effects of ERβ agonists in mouse mammary tumors. Citation Format: Ramasamy K, Samayoa C, Krishnegowda NK, Thurlapati A, Vadlamudi RK, Tekmal RR. Estrogen receptor β agonists inhibits syngeneic mammary tumor growth through cell-cycle arrest by modulating cell-cycle regulators [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-04-01.
Abstract P6-14-05: Withdrawn
Authors: MR Esser, JJ Rowe, ML McCann, M Nicholas-Alexander, EP Helck, SM Lewis
Journal: Cancer Research (2019)

Abstract This abstract was withdrawn by the authors. Citation Format: Esser MR, Rowe JJ, McCann ML, Nicholas-Alexander M, Helck EP, Lewis SM. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-14-05.
When is the best time to undertake a PhD?
Authors: Caroline Elton
Journal: BMJ (2017)

Dear Caroline

When is the best time to undertake a PhD? Some medical schools offer it as an intercalated option—is this wise?

Dom Mahoney, second year medical student, University of Bristol

As with many things in life, there are pros and cons to any one course of action. On the plus side, if you are able to complete a PhD during an intercalated year, this means that you might be able to get your research degree “done and dusted” as part of your undergraduate clinical training. …
Abstract P5-07-16: Role of collagen X in enhancing the metastatic potential of breast cancer cells using a MDA-MB-231 cell line model
Authors: K McKiernan, H Jimenez, M McEachern, J Hubbard, M O'Connell
Journal: Cancer Research (2019)

Abstract Breast cancer is the second highest cause of cancer related deaths for women in developed countries. Breast cancer patients with distant metastasis at the time of diagnosis have an estimated 5-year relative survival rate of 26% as compared to a 99% survival rate of patients who have localized tumors. Evidence suggests that collagens play a role in enhancing the metastatic capability of breast cancer cells. Short chain collagen, collagen X, is encoded by the collagen type x alpha 1 chain (COL10A1) gene and is normally expressed exclusively by hypertrophic chondrocytes during endochondral ossification. Recently, COL10A1 gene expression has been found to be overexpressed in various tumor types, including breast tumors. It is hypothesized that an increase in COL10A1 expression may play a role in breast cancer metastasis. The goal of our project was to evaluate the role of collagen X in breast cancer metastasis using the MDA-MB-231 breast cancer cell line. Stable cell lines were generated to express either GFP only (MDA-VEC) or GFP tagged COL10A1 (MDA-COL). GFP and COL10A1 transcript and protein levels were examined to confirm overexpression of collagen X and transwell assays were used to determine changes in the invasive capability of the cells. Cells overexpressing collagen X demonstrated a higher rate of invasion suggesting that collagen X may play a role in enhancing the metastatic potential of breast cancer cells. Understanding the role collagen X plays in breast cancer metastasis may provide a mechanism for developing diagnostic and prognostic strategies for identifying patients whose breast cancer is more prone to metastasize. Citation Format: McKiernan K, Jimenez H, McEachern M, Hubbard J, O'Connell M. Role of collagen X in enhancing the metastatic potential of breast cancer cells using a MDA-MB-231 cell line model [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-07-16.
CD103-positive CSC exosome promotes EMT of clear cell renal cell carcinoma: role of remote MiR-19b-3p
Authors: Lu Wang, Guang Yang, Danfeng Zhao, Jiaqi Wang, Yang Bai, Qiang Peng, Hongzhi Wang, Ruizhe Fang, Guang Chen, Zhichao Wang, Keliang Wang, Guangbin Li, Yinhui Yang, Ziqi Wang, Pengyu Guo, Li Peng, Dayong Hou, Wanhai Xu
Journal: Molecular Cancer (2019)

Clear cell renal cell carcinoma (CCRCC) is characterized by a highly metastatic potential. The stromal communication between stem cells and cancer cells critically influences metastatic dissemination of cancer cells.The effect of exosomes isolated from cancer stem cells (CSCs) of CCRCC patients on the progress of epithelial-mesenchymal transition (EMT) and lung metastasis of CCRCC cells were examined.CSCs exosomes promoted proliferation of CCRCC cells and accelerated the progress of EMT. Bioactive miR-19b-3p transmitted to cancer cells by CSC exosomes induced EMT via repressing the expression of PTEN. CSCs exosomes derived from CCRCC patients with lung metastasis produced the strongest promoting effect on EMT. Notably, CD103+ CSC exosomes were enriched in tumor cells and in lung as well, highlighting the organotropism conferred by CD103. In addition, CD103+ exosomes were increased in blood samples from CCRCC patients with lung metastasis.CSC exosomes transported miR-19b-3p into CCRCC cells and initiated EMT promoting metastasis. CD103+ acted to guide CSC exosomes to target cancer cells and organs, conferring the higher metastatic capacity of CCRCC to lungs, suggesting CD103+ exosomes as a potential metastatic diagnostic biomarker. ᅟ.
Bitten by the bug
Authors: Michelle Hall
Journal: BMJ (2012)

So, I’m a hypochondriac. A self confessed hypochondriac. I have hypochondriasis about being a hypochondriac. But I was sure. I was scratching, my skin was burning, and no amount of antihistamine was curing it. I had scabies.

It had started when I went to visit friends in their student house. I was told that two of the friends had experienced a rash and that they put it down to a couch in their rented accommodation. Of course, my skin started to crawl. I tried to be vigilant, but, because of the shortage of beds in the house, I had to share with one of my friends, who kept me awake all night with incessant scratching.

I returned home and the nightmare …
Planning an elective in the UK
Authors: Caroline Elton
Journal: BMJ (2014)

Dear Caroline

I’m in my penultimate year of medical school and have to start planning my elective. Many of my friends want to go abroad, and some of them are looking into remote placements in the developing world. My problem is that I don’t want to stray that far and would much rather stay in the United Kingdom for my elective. I find flying stressful and the idea of travelling to some far flung corner of the world is terrifying. But will I get a lower grade on my elective assignment if I do an elective in the UK?

Anon, fourth year medical student, University of Sheffield

It’s not uncommon for medical students to stay in the United Kingdom for their electives and doing so will not result in an automatic downgrading of your marks. Of course, many students use the elective window as a chance to squeeze in some exotic travelling, but the elective period is a unique opportunity for you to develop as a medical professional rather than building your CV as an …