tbuckley/cabot-search huggingface dataset:
Abstract 1961:Ikzf1haploinsufficiency contributes to the pathogenesis ofBCR-ABL1positive acute lymphoblastic leukemia
Authors: J Racquel Collins-Underwood, Christopher B. Miller, James R. Downing, Charles G. Mullighan
Journal: Cancer Research (2010)

Abstract Expression of the constitutively active tyrosine kinase BCR-ABL1 is the hallmark of two diseases with distinct pathologic and clinical features: chronic myeloid leukemia (CML), an expansion of relatively mature granulocytes that typically responds well to kinase inhibition, and pre-B cell acute lymphoblastic leukemia (ALL), an aggressive malignancy of lymphoid progenitors that has a dismal prognosis. The basis for this dichotomy has been poorly understood. We recently identified a near-obligate deletion of IKZF1 (encoding the lymphoid transcription factor IKAROS) in de novo BCR-ABL1 positive ALL, and at the progression of CML to lymphoid blast crisis, suggesting that perturbation of IKAROS activity is a key event in the pathogenesis of BCR-ABL1 lymphoid leukemia. To test this hypothesis, we have examined the effect of Ikaros haploinsufficiency in a retroviral bone marrow transplant model of murine BCR-ABL1 B-progenitor ALL. Unmanipulated marrow from either Ikzf1 wild type mice or mice heterozygous for an Ikzf1 null allele was transduced with MSCV bicistronic retrovirus expressing GFP and p185 BCR-ABL1 and transplanted into lethally irradiated C57BL/6 recipients. Recipients of MSCV-GFP-p185 BCR-ABL1-transduced Ikzf1+/− marrow developed leukemia with markedly increased penetrance and reduced latency in comparison to recipients of wild-type marrow (46 vs. 122 d, P&amp;lt;0.0001). The resulting leukemias resulted in bone marrow replacement by lymphoblasts, pancytopenia, extramedullary infiltration, and frequent clinical and histologic central nervous system involvement. The leukemias were of pre-B immunophenotype and uniformly transplantable into sublethally irradiated secondary recipients. Importantly, detailed enumeration of lymphoid subsets in Ikzf+/+ and +/− marrow did not demonstrate an expansion of lymphoid progenitors in Ikzf1+/− marrow, suggesting that the observed increased penetrance of B-ALL in Ikzf1+/− animals was not simply due to the expansion of targets of BCR-ABL1 transformation. Thus, Ikaros haploinsufficiency cooperates with BCR-ABL1 to induce an aggressive pre-B leukemia with clinical and pathologic features recapitulating human BCR-ABL1 ALL. These results support genomic analyses of human leukemia suggesting that IKAROS loss is important in the pathogenesis of this disease. Experiments evaluating the interaction of Ikzf1 loss with other targets of genomic alteration in BCR-ABL1 ALL (e.g. CDKN2A/B, PAX5), studies examining the role of Ikzf1 in responsiveness to kinase inhibitors, and genomic profiling studies are ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1961.
Abstract P4-06-28: Doxorubicin induces cellular senescence in human breast cancer cells and sensitizes them to cytotoxic T-lymphocytes
Authors: T Inao, Y Iida, H Kotani, M Harada
Journal: Cancer Research (2019)

Abstract [Background]“Cellular senescence” is a state in which cells undergo irreversible cell cycle arrest in response to various cellular stresses. Senescence is induced in not only normal cells but also cancer cells when anti-cancer agents trigger DNA damage. Recent studies have revealed additional feature of senescent cells: increased secretion of various secretory proteins, such as inflammatory cytokines, chemokines, growth factors, and MMPs. This newly recognized senescent phenotype, termed senescence-associated secretory phenotype (SASP), reportedly contribute to tumor recurrence and promotion. Alternatively, senescent cancer cells could be good targets in anti-cancer immunotherapy because they are cell cycle-arrested. [Objective]In this study, we determined whether ”cellular senescence” could be induced by a chemotherapeutic drug doxorubicin (DXR) and whether senescent cancer cells might increase their susceptibility to cytotoxic T-lymphocytes using human breast cancer cells. [Methods and Results]A triple-negative (negative for ER, PR, and HER2) human breast cancer cell line (MDA-MB-231) was used. This cell line was treated with DXR for 2 days and examined for their appearance microscopically. The DXR treatment (500 nM) decreased their proliferating ability and increased their cell size. Colony formation assay revealed that cancer cells significantly decreased the number of colonies even with lower doses (3 nM) of DXR. In immunoblot assay, the DXR treatment increased the protein expression of p21, which inhibits cell cycle. In a flow cytometric assay after staining with SPIDER-β-gal, the DXR treatment (500 nM) increased the expression of β-gal in MDA-MB-231 cells. The induction of SA-β-gal in DXR-treated cancer cells were also confirmed by confocal imaging. In addition, the DXR treatment (500 nM) for 2 days beforehand increased their subsequent ability to produce IL-6 and IL-8. Although the DXR treatment (500 nM) decreased the expression of epidermal growth factor receptor (EGFR) on cancer cells, this treatment sensitized them to anti-EGFR chimeric antigen receptor (CAR) T-lymphocytes in apoptosis assay. [Conclusion]These results suggest that a chemotherapeutic drug DXR can render MDA-MB-231 cells to be senescent and increase their sensitivity to antigen-specific cytotoxic T-lymphocytes. These findings may provide a rationale of combination of chemotherapy and T cell-based anti-cancer immunotherapy. Citation Format: Inao T, Iida Y, Kotani H, Harada M. Doxorubicin induces cellular senescence in human breast cancer cells and sensitizes them to cytotoxic T-lymphocytes [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 P4-06-28.
Abstract P5-07-12: Circular RNA NCAPG promotes breast cancer metastasis through acting as the sponge of miR-200s
Authors: Y He, J Tang
Journal: Cancer Research (2019)

Abstract Background Metastatic breast cancer remains incurable and underlying mechanisms are poorly understood. Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment that supports breast cancer metastasis. Circular RNAs are new class of endogenous noncoding RNAs. Unlike linear RNAs terminated with 5'caps and 3'tails, they uniquely have a covalently closed loop structure, making them stable and ideal candidate biomarkers. Here, we identified a circular RNA and explored for the first time how it played a dual role in epithelial to mesenchymal transition (EMT) and macrophage recruitment. Methods We first analyzed TCGA database about whether mesenchymal tumors could be more likely to recruit TAMs. ELISA assay was performed for determining expression level of chemokines (CSF-1, CCL2, CCL5, C5a, VEGFA, IL-34) after cell line MCF-7 finishing EMT. Next, we predicted microRNAs which could regulate CSF-1 expression and inhibit EMT using Targetscan database. Circular RNA was identified via comparing expression levels between mesenchymal-like and epithelial-like cells using circRNA microarrays. The specific mechanisms were explored via series of molecular biology assays in vitro and in vivo. Results Correlation analysis of relationship between EMT score and expression of all classical chemokines that could recruit macrophage revealed a positive association (r2&amp;gt;0.3, P&amp;lt;0.05) among 1079 breast cancer cases. Increased expression level of CSF-1 was found the most significant after EMT. miR-200b and miR-200c that inhibiting breast cancer EMT were confirmed targeting 3'UTR of CSF-1 mRNA and decreasing migration of TAMs. Circular RNA NCAPG (circNCAPG) was found highly expressed in mesenchymal-like cells and could promote breast cancer metastasis in vitro and in vivo. Poor clinical outcome was found in circNCAPG overexpression group among 141 breast cancer cases. CircNCAPG was proven to be located in cytoplasm and found could act as the sponge of miR-200b and miR-200c. Moreover, expression level of CSF-1 and ZEB-1 (also targeted by miR-200s and regulating key process of EMT) was found decreasing significantly after knocking down circNCAPG both in vitro and in vivo, leading to breast cancer metastasis inhibition. Conclusion Mesenchymal tumors have the ability to recruit more TAMs, therefore further promoting breast cancer metastasis. A new molecule: circNCAPG participates in this process via acting as the sponge of miR-200s and regulates CSF-1 and ZEB-1 expression, which warrants further study in clinical settings. Citation Format: He Y, Tang J. Circular RNA NCAPG promotes breast cancer metastasis through acting as the sponge of miR-200s [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 P5-07-12.
Abstract 5832: Overexpression of ODC1 is associated with poor outcome in childhood neuroblastoma and represents an important therapeutic target
Authors: Michelle Haber, Ngan Cheng, Janice Smith, Jayne Murray, Michael D. Hogarty, Wendy B London, Glenn M Marshall, Murray D. Norris
Journal: Cancer Research (2008)

Abstract MYCN gene amplification is a powerful predictor of poor clinical outcome in neuroblastoma, the most common solid tumor of young children. The mechanism by which MYCN amplification influences the prognosis of this disease has not been well defined. MYCN is a known transcription factor and available evidence indicates that ornithine decarboxylase (ODC1) is a critical downstream target for this oncoprotein. ODC1 is the rate-limiting enzyme in the synthesis of polyamines and overexpression of this gene has been observed in a range of tumor cells, including neuroblastoma. In particular, a number of studies have provided evidence for the oncogenic and transforming abilities of ODC1. To investigate the role of ODC1 in neuroblastoma, we used Real-Time PCR to analyze ODC1 expression in a large cohort (n=209) of primary untreated neuroblastomas from patients enrolled on POG biology protocol 9047. Older age, advanced stage, and MYCN amplification were all predictive of poor outcome in this cohort. ODC1 expression was significantly higher in MYCN-amplified tumors by comparison with non-amplified tumors (p&amp;lt;0.0001). Kaplan-Meier survival analysis indicated that high levels of ODC1 expression were strongly predictive of both event-free-survival (p&amp;lt;0.001) and overall survival (p&amp;lt;0.001) in this cohort as well as in patients whose tumors lacked MYCN amplification (p=0.01). Furthermore, a functionally important single nucleotide polymorphism within the ODC1 promoter (G316A) that has been shown previously to influence gene transcription rates, was found to be significantly associated with outcome in patients whose tumors lacked MYCN amplification (p&amp;lt;0.05). These data suggest that inhibiting ODC1 activity would have therapeutic advantage in treating neuroblastoma. To test this hypothesis, MYCN transgenic mice that spontaneously develop neuroblastoma closely mimicking the human disease, were treated either with cisplatin alone or in combination with the ODC1 inhibitor, Î±-difluoromethylornithine (DFMO). Importantly, DFMO therapy, either concomitant with or following cisplatin treatment, resulted in prolonged tumor-free survival (p&amp;lt;0.01) in these mice, by comparison with cisplatin administered alone. Similar results were obtained with cyclophosphamide treatment in combination with DFMO. No overt toxicity attributable to DFMO therapy was noted in treated mice. Collectively, these findings provide strong evidence that ODC1 contributes to the malignant phenotype of neuroblastoma and suggest that targeting this oncogene for suppression of polyamine synthesis is potentially a valuable therapeutic approach for inhibiting neuroblastoma growth.
Abstract P5-05-06: Progesterone receptor (PR) isoform-specific expansion of breast cancer stem-like cells occurs through a phospho-PR/FOXO1 driven signaling axis
Authors: TH Truong, AR Dwyer, CH Diep, CA Lange
Journal: Cancer Research (2019)

Abstract Luminal breast cancers account for ˜75% of cases and are positive for progesterone receptor (PR) and estrogen receptor (ER) expression. PR is a classical ER-target gene and is used as a biomarker of ER activity; however, a growing body of evidence supports the role of PR as an important modifier of ER actions and a key driver of luminal breast cancer progression. Progesterone signaling is mediated by two PR isoforms: full-length PR-B and truncated PR-A, which lacks the N-terminal 164 amino acids. Little is known about PR isoform-specific actions in PR-expressing breast tumors, given that total PR expression is measured clinically. Herein, we sought to identify phenotypic differences in luminal breast cancer cells (T47D) overexpressing PR-A (T47D-YA) or PR-B (T47D-YB). We demonstrate that PR-B expression is required for anchorage-independent colony formation, while PR-A expressing cells fail to proliferate in soft agar. PR-B driven proliferation has been mapped to PR phosphorylation events, which include MAPK or CDK consensus sites such as Ser294. We demonstrate that in contrast to previous reports, PR-A is well phosphorylated at Ser294 in response to progestins (e.g. R5020) using our custom phospho-PR (Ser294) polyclonal antibody. Interestingly, Ser294 phosphorylation of PR-A occurs more rapidly and robustly following hormone treatment compared to PR-B expressing cells. Our findings indicate that PR-A is a dominant driver of stem-like expansion in breast cancer cells. PR-A tumorspheres exhibited enriched ALDH+ and CD44+/CD24- populations compared to PR-B and promoted heightened gene expression of stem-like genes (e.g. FOXO1). We demonstrate that the PR target gene and co-activator FOXO1 promotes both PR-A and PR-B phosphorylation at Ser294 and augments tumorsphere formation. Direct inhibition of FOXO1 levels abrogates phospho-PR (Ser294) levels and tumorsphere formation in PR expressing cells. Finally, we show that Ser294 is required for PR-A induced expression of stem-like genes (e.g. FOXO1) and stem-like behavior as measured by ALDH+/CD44+ tumorspheres. Taken together, our data reveal unique functions of PR isoforms as modulators of distinct and opposing pathways (i.e. proliferation versus stem-like expansion) in luminal breast cancer models. A clear understanding of PR isoform-specific actions, phosphorylation events, and the role of co-factors such as FOXO1 may lead to novel biomarkers of advanced tumor behavior and reveal new approaches to pharmacologically target PR isoforms in luminal breast cancers. Citation Format: Truong TH, Dwyer AR, Diep CH, Lange CA. Progesterone receptor (PR) isoform-specific expansion of breast cancer stem-like cells occurs through a phospho-PR/FOXO1 driven signaling axis [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 P5-05-06.
High reprint orders in medical journals and pharmaceutical industry funding: case-control study
Authors: Richard Smith
Journal: BMJ (2012)

The paper

“High reprint orders in medical journals and pharmaceutical industry funding: case-control study” by Adam E Handel and colleagues ( BMJ 2012;344:e4212).

Abstract

Objectives —To assess the extent to which funding and study design are associated with high reprint orders.

Design —Case-control study.

Setting —Top articles by size of reprint orders in seven journals, 2002-9.

Participants — Lancet , Lancet Neurology , Lancet Oncology (Lancet Group), BMJ , Gut , Heart , and Journal of Neurology, Neurosurgery and Psychiatry (BMJ Group) matched to contemporaneous articles not in the list of high reprint orders.

Main outcome measures —Funding and design of randomised controlled trials or other study designs.

Results —Median reprint orders for the seven journals ranged from 3000 to 126 350. Papers with high reprint orders were more likely to be funded by the drug industry than were control papers (industry funding versus other or none: odds ratio 8.64, 95% confidence interval 5.09 to 14.68, and mixed funding versus other or none: 3.72, 2.43 to 5.70).

Conclusions —Funding by the drug industry is associated with high numbers of reprint orders.

The authors of this study set out to discover whether articles published in medical journals that had many reprints of the article purchased were more likely to be funded by the drug industry. (“Reprints” refers to purchased permission to reproduce journal articles in bulk, allowing the article to be distributed to a new audience. The money from reprint purchases is an important source of income for some journals). A second question in this study was whether those articles with high reprint orders were more likely to have a particular design.

Articles published in medical journals, particularly the best known ones, can have considerable impact. A study showing a drug to be highly effective might, for instance, lead to a surge in …
Abstract P4-01-03: Withdrawn
Authors: S Di Cosimo, V Appierto, S Pizzamiglio, J Baselga, M Piccart, J Huober, M Izquierdo, L de la Pena, F Hilbers, E de Azambuja, M Untch, L Pusztai, KI Pritchard, P Nuciforo, AV Salomon, FW Symmans, G Apolone, F de Braud, P Verderio, MG Daidone
Journal: Cancer Research (2019)

Abstract This abstract was withdrawn by the authors. Citation Format: Di Cosimo S, Appierto V, Pizzamiglio S, Baselga J, Piccart M, Huober J, Izquierdo M, de la Pena L, Hilbers F, de Azambuja E, Untch M, Pusztai L, Pritchard KI, Nuciforo P, Salomon AV, Symmans FW, Apolone G, de Braud F, Verderio P, Daidone MG. 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 P4-01-03.
Cardia and cardiac tumor: endoscopic ultrasound video
Authors: Rasoul Sotoudehmanesh, Mohamad Eloubeidi
Journal: Endoscopy (2019)

A 62-year-old man presented with a 2-month history of progressive dysphagia and weight loss. Esophagogastroduodenoscopy revealed a tumor in the cardia, and a biopsy showed adenocarcinoma. He had a history of recurrent embolic cerebrovascular accidents 3 years ago and underwent warfarin therapy after these events. He was referred for locoregional staging of cardia tumor by endoscopic ultrasound (EUS).
Abstract BL1: Modeling Immune Response: Lessons Learned from Mouse Models of Cancer Development
Authors: L Coussens
Journal: Cancer Research (2019)

Abstract The concept that leukocytes are critical components of solid tumors is now generally accepted, however, their role(s) in regulating aspects of cancer progression, and/or response to cytotoxic, targeted and/or immune therapy is only beginning to be understood. Utilizing de novo mouse models of mammary tumor development, we now appreciate that CD4+ T lymphocytes differentially regulate myeloid cell recruitment, activation and effector function, and in turn, activated tumor-infiltrating myeloid cells foster malignancy and repress anti-tumor immunity by a diversity of mechanisms. Treatment of tumor-bearing mice with therapeutic agents disrupting lymphocyte-myeloid interactions, myeloid activation, or myeloid functionality generally slow primary tumor growth kinetics when combined with cytotoxic therapy; however, their impact on metastases is variable. Similar to organ-specific regulatory programs co-opted to foster primary tumor growth, regulation of metastatic seeding and outgrowth is also regulated by tissue- and organ-specific mechanisms. Based on this, it stands to reason that therapeutic strategies may not be efficacious in both primary and metastatic locations. To be presented will be our recent insights into organ-specific regulation of primary and metastatic mammary cancer development by adaptive and innate immune cells regulating pro- and/or anti-tumor immunity, and new studies evaluating how attenuating protumor properties of select lymphoid and myeloid cells can be exploited to enhance therapeutic responses to cytotoxic and immune-based therapy. LMC acknowledges generous support from the NIH / NCI, the Department of Defense Breast Cancer Research Program Era of Hope Scholar Expansion Award, Susan G. Komen Foundation, the Breast Cancer Research Foundation, the Brenden-Colson Center for Pancreatic Health, and a Stand Up To Cancer – Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant. Citation Format: Coussens L. Modeling Immune Response: Lessons Learned from Mouse Models of Cancer Development [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 BL1.
What non-academic achievements will look good on my CV?
Authors: Caroline Elton
Journal: BMJ (2016)

caroline@careerplanningfordoctorsanddentists.com

Dear Caroline

What non-academic achievements stand you in good stead for competitive job posts later on?

Greig Bowie, third year medical student, University of Glasgow

Several years ago I was running a workshop for hospital consultants on effective recruitment and selection. One consultant owned up to the fact that as an applicant to medical school she had lied and said that she was a grade 8 pianist when actually she couldn’t even read music. It had clearly been worrying her for years, and she used the workshop as an opportunity to come clean and get her guilty secret off her chest.

Her strategy had been a high risk one. If the admissions panel had asked her what music …
The Role of Sexual Hormones on the Enteroinsular Axis
Authors: Sandra Handgraaf, Jacques Philippe
Journal: Endocrine Reviews (2019)

Abstract Sex steroid estrogens, androgens, and progesterone, produced by the gonads, which have long been considered as endocrine glands, are implicated in sexual differentiation, puberty, and reproduction. However, the impact of sex hormones goes beyond these effects through their role on energy metabolism. Indeed, sex hormones are important physiological regulators of glucose homeostasis and, in particular, of the enteroinsular axis. In this review, we describe the roles of estrogens, androgens, and progesterone on glucose homeostasis through their effects on pancreatic α- and β-cells, as well as on enteroendocrine L-cells, and their implications in hormonal biosynthesis and secretion. The analysis of their mechanisms of action with the dissection of the receptors implicated in the several protective effects could provide some new aspects of the fine-tuning of hormonal secretion under the influence of the sex. This knowledge paves the way to the understanding of transgender physiology and new potential therapeutics in the field of type 2 diabetes.
Choosing your career path
Authors: Claire S Atkins
Journal: BMJ (2011)

You wouldn’t buy a car without taking a test drive so why choose a career without trying it out first?

The days when a senior house officer could sample a variety of specialties before deciding on one are gone. Just 16 months after qualifying junior doctors must decide which of the 59 medical specialties in the UK to follow.1

The UK Foundation Programme Office has introduced taster weeks. These give the trainee a glimpse into life as a doctor in that …