tbuckley/cabot-search huggingface dataset:
Association for Palliative Medicine should act on claims of toxic culture
Authors: Richard Scheffer
Journal: BMJ (2019)

The Association for Palliative Medicine’s response to claims of a culture of fear and intimidation in palliative medicine around assisted dying is troubling, implying that those making the claims may have ulterior motives.12 This is a perfect example of how discussion of assisted dying in palliative medicine is often “stifled.”

I have witnessed the distorted way this matter is treated in …
Abstract P1-08-28: Impact of surgery and time to surgery on breast cancer survival in the United States, 2004–2014 (N=2,211,245)
Authors: M Singh, SD Konduri, GC Bobustuc, RA Rovin, AB Kassam
Journal: Cancer Research (2019)

Abstract Background: Surgery is very common for patients diagnosed with breast cancer. Its impact on survival depends on diagnostic, patient, tumor-related, and other-treatment factors. Moreover, time to surgery from the date of diagnosis is also a critical factor affecting outcome. Objective: In this study we investigated the impact of surgery on survival in breast cancer patients using two methods: (1) multivariate regression; and (2) propensity score matching. For the patients undergoing surgical intervention, we aimed to identify the optimum time from diagnosis to surgery. Methods: The study population was taken from the National Cancer Database over the years 2004 through 2014. Of 2,211,245 patients, 99.1% were female, 0.9% male, 85% non-Hispanic white, 10.5% black, 0.7% Hispanic, and 14.5% other races. Mean age of the patient population was 60.0 ± 13.4 years (range: 18–90). The majority of the patients (92.9%) underwent a surgical procedure. Results: Overall, the patients who did not undergo surgery were 6.7 times more likely to die within the study time period (95% confidence interval [CI]: 6.7–6.8, p&amp;lt;0.001) than those who did. However, after adjusting for patients' demographics, tumor-related factors, cancer stages, and combination of other treatments, the risk for dying of patients without surgery was 2.3 times higher (hazard ratio [HR]: 2.3, 95% CI: 2.3–2.4, p&amp;lt;0.001). In the propensity-matched cohort of 51,630 patients that was divided equally into two groups — those who underwent surgery and those who did not — the risk of mortality remained 2.4 times higher for patients without surgery (HR: 2.4, 95% CI: 2.3–2.4, p&amp;lt;0.001). Regarding time to surgery from the date of diagnosis, patient survival was best for the patients whose time to surgery ranged from 31 to 60 days. The next best timeframe was 61 to 90 days, followed by 30 days or fewer, then 91 to 120 days, and finally 120 and more days (p&amp;lt;0.001). Conclusion: Using two different statistical methods, surgery is clearly an independent predictor of survival for patients with breast cancer. After matching for other factors, patients not having surgery were more than twice as likely to die as their surgical counterparts. Time to surgery from the date of diagonosis confirmed ealier findings that surgery is most benificial within 2–3 months from the date of diangosis. These findings can provide clinical guidance to clinicians and patients for planning treatment. Citation Format: Singh M, Konduri SD, Bobustuc GC, Rovin RA, Kassam AB. Impact of surgery and time to surgery on breast cancer survival in the United States, 2004–2014 (N=2,211,245) [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 P1-08-28.
Abstract P6-20-17: Targeting SHP2 for the treatment of HER2-positive breast cancer
Authors: Y Agazie, Z Hartman
Journal: Cancer Research (2019)

Abstract Approximately 20% of breast cancer (BC) is caused by overexpression of the human epidermal growth factor receptor 2 (HER2). As a result, several antibody-based and small molecule-based anti-HER2 therapies have been developed. These drugs have benefited BC patients by improving overall survival and quality of life. However, development of resistance and disease recurrence have been the major clinical challenges. One way to overcome these clinical problems is to develop alternative therapeutic strategies. Multiple lines of evidence show that targeting the Src homology phosphotyrosyl phosphatase 2 (SHP2) in HER2-positive BC may prove beneficial both in treatment-naïve and anti-HER2 therapy-resistant forms of the disease. For instance, silencing SHP2 expression in HER2-positive breast cancer cells or conditional knockout in ErbB2 transgenic mice blocks HER2 overexpression and associated signaling, leading to loss of cell transformation and tumorigenesis. To test the clinical translational significance of SHP2 targeting, we have invented a specific small molecule SHP2 inhibitor named WGMDY (US 9,932,288) that has shown promising anti-cancer effects. The results obtained so far show that inhibition of SHP2 with WGMDY blocks HER2 expression, suppresses cell proliferation and anchorage independent growth, and induces regression of preformed xenograft tumors. These findings suggest that SHP2 might be an excellent drug target for HER2-positive BC and WGMDY has a promising potential to serve as a lead compound for developing anti-SHP2 drugs. Citation Format: Agazie Y, Hartman Z. Targeting SHP2 for the treatment of HER2-positive breast cancer [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 P6-20-17.
Healthcare needs leaders
Authors: Toby Pitts-Tucker
Journal: BMJ (2012)

Last summer, BBC Panorama footage of appalling abuse at Winterbourne View residential hospital shocked the UK. Experts proclaimed the need for reform, an outraged press published images of wrongdoing, and the Care Quality Commission (CQC) promised greater vigilance and more stringent measures to deal with offending institutions.

Yet this reaction seems to miss the point. The CQC cannot hope to inspect as many institutions as it would like, and whistleblowing has always been difficult to promote. To see why, one need only look at the difficulty anaesthetist Stephen Bolsin had in finding employment in the UK …
Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance
Authors: Ladan Mashouri, Hassan Yousefi, Amir Reza Aref, Ali mohammad Ahadi, Fatemeh Molaei, Suresh K. Alahari
Journal: Molecular Cancer (2019)

Tumor-derived exosomes (TDEs) participate in formation and progression of different cancer processes, including tumor microenvironment (TME) remodeling, angiogenesis, invasion, metastasis and drug-resistance. Exosomes initiate or suppress various signaling pathways in the recipient cells via transmitting heterogeneous cargoes. In this review we discuss exosome biogenesis, exosome mediated metastasis and chemoresistance. Furthermore, tumor derived exosomes role in tumor microenvironment remodeling, and angiogenesis is reviewed. Also, exosome induction of epithelial mesenchymal transition (EMT) is highlighted. More importantly, we discuss extensively how exosomes regulate drug resistance in several cancers. Thus, understanding exosome biogenesis, their contents and the molecular mechanisms and signaling pathways that are responsible for metastasis and drug-resistance mediated by TDEs may help to devise novel therapeutic approaches for cancer progression particularly to overcome therapy-resistance and preventing metastasis as major factors of cancer mortality.
Uncovering the Role of RNA-Binding Protein hnRNP K in B-Cell Lymphomas
Authors: Miguel Gallardo, Prerna Malaney, Marisa J L Aitken, Xiaorui Zhang, Todd M Link, Vrutant Shah, Sanzhar Alybayev, Meng-Han Wu, Laura R Pageon, Huaxian Ma, Rodrigo Jacamo, Li Yu, Zijun Y Xu-Monette, Haley Steinman, Hun Ju Lee, Dos Sarbassov, Inmaculada Rapado, Michelle C Barton, Joaquin Martinez-Lopez, Carlos Bueso-Ramos, Ken H Young, Sean M Post
Journal: JNCI Journal of the National Cancer Institute (2019)

Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is an RNA-binding protein that is aberrantly expressed in cancers. We and others have previously shown that reduced hnRNP K expression downmodulates tumor-suppressive programs. However, overexpression of hnRNP K is the more commonly observed clinical phenomenon, yet its functional consequences and clinical significance remain unknown.
Abstract A57: Glutathione depletion overcomes chemotherapy resistance in aggressive medulloblastoma stem-like cells
Authors: Beatriz Dias Barbieri, Marina Marçola, Clarissa Rocha, Oswaldo Keith Okamoto
Journal: Clinical Cancer Research (2018)

Abstract Drug resistance is one of the main limiting steps for the successful treatment of most cancers. Additionally, the presence of cancer cells with stem cell traits favors the process of treatment resistance, tumor recurrence, and spreading. Glutathione (GSH) is a major antioxidant intracellular molecule and has been positively correlated with the development of drug resistance. The purpose of this study was to verify whether GSH depletion potentiates the effect of chemotherapy in stem-like cells from the medulloblastoma cell line Daoy. Cells expressing normal (control tumor cells) or high levels of the pluripotency factor OCT4A (stem-like cells) were treated with a combination of BSO (glutathione inhibitor), cisplatin, and temozolomide (TMZ). Cell viability was assessed through MTT and apoptosis assays. Initially, the concentration of BSO required to deplete the GSH in both Daoy and Daoy-OCT4A cells was established (50 and 58 μM, respectively), as well as the IC50 of each chemotherapeutic drug. Both cells were sensitive to cisplatin (IC50 = 0.494 μM for Daoy and 0.215 μM for Daoy-OCT4A), but resistant to TMZ. The highest dose of TMZ used (500 μM) reduced the viability of Daoy cells to 56%, but only to 80% in Daoy-OCT4A cells, denoting the chemoresistant phenotype of these cancer stem-like cells. Next, the ideal combination of the three compounds was defined. For Daoy cells, it was BSO 50 μM + cisplatin 0.8 μM + TMZ 0.8 μM. As for Daoy-OCT4A cells, it was BSO 58 μM + cisplatin 0.215 μM + TMZ 500 μM. Daoy-OCT4A cells required a higher dose of TMZ than control Daoy cells to attain similar death rates; however, the combined treatment was effective for both cells. When combining these three drugs, a synergistic effect was observed for Daoy-OCT4A cells, reducing cell viability to ~17%, in comparison with treatment of cisplatin+TMZ alone. As for Daoy cells, an additive effect was observed and viability was reduced to ~15%, in comparison with cisplatin+TMZ alone. This indicates that the use of a glutathione inhibitor in combination with cisplatin and TMZ may be useful in the treatment of medulloblastoma, even in the case of aggressive tumors. Similarly, this approach may also be useful in the development of therapeutic strategies for other chemoresistant tumors. Citation Format: Beatriz Dias Barbieri, Marina Marçola, Clarissa Rocha, Oswaldo Keith Okamoto. Glutathione depletion overcomes chemotherapy resistance in aggressive medulloblastoma stem-like cells [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A57.
Abstract A73: GD3 ganglioside-enriched extracellular vesicles stimulate melanocyte migration
Authors: Andreia H. Otake, Ana Paula M. Duarte, Renata de Freitas Saito, Alexandre F. Ramos, Roger Chammas
Journal: Clinical Cancer Research (2018)

Abstract Gangliosides are sialic acid-containing glycosphingolipids located mainly in outlet membrane plasma. Tumors usually accumulate gangliosides as disialoganglioside GD3 which is widely expressed in melanomas and neuroblastomas. GD3 has been associated with tumor progression, conferring tumorigenic characteristics to cells such as increased proliferation and migration. In order to investigate the role of GD3 in cell migration, we have transfected the GD3 synthase gene (ST8Sia I) in a melanocyte cell line. In this work we have demonstrated that overexpression of GD3 upon transfection of GD3 synthase was associated with an increased migratory response towards laminin-1. GD3 and 9-O-acetyl-GD3 gangliosides, which colocalize with integrins in cell lamellipodia, are positive modulators of integrin function in the migratory response while GD3 was left behind as a molecular footprint. Indeed, addition of exogenous GD3 to the cells stimulated cell migration whereas exogenously added GM3 inhibited it. However, depletion of gangliosides using a glucosylceramide synthase inhibitor led cells more migratory. Glycosphingolipids content modulates FGF-2-induced cell migration as we demonstrated that FGF-2 induces cell migration. However, this effect was abolished after using glucosylceramide synthase inhibitor, suggesting that GD3 may modulate the motogenic activity of FGF-2. Finally, we showed that GD3 synthase transfected melanocytes release extracellular vesicles (EVs) enriched in GD3. These EVs are responsible for modulating cell migration response due to increase average velocity of GD3 negative cells as we showed in a real-time wound-healing assay. This study shows that EVs from a subset of GD3 positive cells may contribute to the horizontal signaling propagation to a different subset of GD3 negative cells. Thus, data present here led us to an important insight into how EVs carrying GD3 ganglioside could participate in intercellular communication modulating cellular migration. Citation Format: Andreia H. Otake, Ana Paula M. Duarte, Renata de Freitas Saito, Alexandre F. Ramos, Roger Chammas. GD3 ganglioside-enriched extracellular vesicles stimulate melanocyte migration [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A73.
What are the pros and cons of taking a year out during medical school?
Authors: Caroline Elton
Journal: BMJ (2017)

Dear Caroline

I know of some students who are taking gap years in the middle of their degree, commonly after an intercalated year. What are the pros and cons of taking a year out during medical school?

Eleanor Wilson, third year medical student, University College London

I started off by asking a clinical colleague this question, and this is what she said: “I can’t see any pros. No problem doing a BSc, but taking more than …
THE POLYP-BASED RESECT-AND-DISCARD STRATEGY: A PROSPECTIVE STUDY
Authors: C Hammar, M Frenn, H Pohl, J Foucher, M Bouin, E Deslandres, S Bouchard, D Renteln
Journal: Endoscopy (2019)

Post-polypectomy surveillance intervals are determined taking pathology results into consideration. Study aim was to compare a novel polyp-based resect-and-discard strategy (PBRD) with optical polyp diagnosis and pathology based surveillance interval assignment.
A baby with a cough
Authors: Helen Gbinigie, Jeewan Rawal, Tiffani Mccartthy
Journal: BMJ (2011)

A 12 week old baby boy of South East Asian ethnicity was admitted in winter with a three day history of cough, coryza, rapid breathing, and reduced feeding. The initial diagnosis was bronchiolitis. He deteriorated on the second day after admission with worsening respiratory distress.

Testing for respiratory syncytial virus in his nasopharyngeal aspirate was negative, and he had normal inflammatory markers and white blood cell count. A chest radiograph was taken (fig 1⇓). He was started on intravenous amoxicillin because pneumonia was suspected.



Fig 1 Day 1



Two days later he developed high grade fever and needed oxygen. While taking a history from his parents, they explained that the boy’s grandmother, who had looked after him since the first week of life, was visiting from Pakistan and was being investigated for chronic cough.



(1) Fig 1⇑ shows an anteroposterior chest radiograph. The abnormalities are a …
Abstract P3-11-13: On-treatment biomarkers can improve prediction of response to neoadjuvant chemotherapy in breast cancer
Authors: RJ Bownes, AK Turnbull, D Cameron, AH Sims, O Oikonomidou
Journal: Cancer Research (2019)

Abstract Purpose: Neo-Adjuvant chemotherapy treatment is increasingly being used in breast cancer to preoperatively shrink tumour volumes and facilitate surgical plans. These datasets however, are still scarce, making it difficult to assess the relative value of multiple time point biopsies compared to diagnostic only sampling. This study aims to identify sequential samplings intrinsic value. Method: A total of 97 samples from a cohort of 50 neoadjuvant chemotherapy treated primary breast cancer patients (aged 29-76 at diagnosis, Allred status 47:53% +/-, Her2 status 80:20% +/-, mixed grade and menopausal status) taken pre- treatment, at 2 weeks on-treatment, mid chemotherapy and at resection were sequenced with Ion Ampliseq transcriptome yielding expression values for 12,635 genes. Differential expression analysis was performed across response groups (16 Responders, 34 Non-Responders) as defined by Pathological Complete Response and over treatment time to identify significantly differentially expressed genes, pathways and markers indicative of response status. Results: An on-treatment marker for response was identified (AAGAB), which resulted in a testing accuracy of 100% and a validation accuracy of 78% in the I-SPY 1 Trial. AAGAB was predictive of long term survival (p = 0.048 testing, p = 0.031 validation) in both chemotherapy cohorts at the same expression level as defined for treatment response. The single gene on-treatment biomarker, AAGAB proves more performant than established prognostic tests, Mammaprint (Edinburgh NEO trial, pre-treatment 61%, on-treatment 63%. I-SPY 1 trial, pre-treatment 60%, on-treatment 66%) and Pam50 RORS (neo trial pre-treatment 50%, on treatment 58%, Magbanua trial pre-treatment 56%, on-treatment 64%) Conclusion: Changes in gene expression of on-treatment chemotherapy breast cancer resulted in the identification of a novel gene marker that was as effective in predicting prognostic status as established prognostic tests. These results support the use of on-treatment testing in breast cancer to improve the accuracy of tumour response prediction. Citation Format: Bownes RJ, Turnbull AK, Cameron D, Sims AH, Oikonomidou O. On-treatment biomarkers can improve prediction of response to neoadjuvant chemotherapy in breast cancer [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 P3-11-13.
How to make the most of your paediatrics placement
Authors: Emma Alexander, Charlotte Burford, Vandana Jain
Journal: BMJ (2018)

An overview of the different settings in paediatrics and what skills you should aim to practise Paediatrics is different from adult medicine, with a new set of challenges. Although a placement in paediatrics can be an exciting prospect, students often approach it with trepidation. During your placement it is common to rotate between several subspecialties, including neonatal intensive care, the paediatric emergency department, inpatients, and community paediatrics. This article gives an overview of what you should aim to achieve in each of these settings to get the most out of your placement and to help you prepare for objective structured clinical examinations. #### Box 1: Skills to observe and practise on a placement in paediatrics* #### Box 3: How to take a paediatric history ##### Prenatal history ##### Birth history ##### Neonatal period
Women’s views on overdiagnosis in breast cancer screening: a qualitative study
Authors: Karsten Juhl Jørgensen
Journal: BMJ (2013)

The paper

Abstract

Objective —To elicit women’s responses to information about the nature and extent of overdiagnosis in mammography screening (detecting disease that would not present clinically during the woman’s lifetime) and explore how awareness of overdiagnosis might influence attitudes and intentions about screening.

Design —Qualitative study using focus groups that included a presentation explaining overdiagnosis, incorporating different published estimates of its rate (1-10%, 30%, 50%) and information on the mortality benefit of screening, with guided group discussions

Setting —Sydney, Australia.

Participants —Fifty women aged 40-79 years with no personal history of breast cancer and with varying levels of education and participation in screening.

Results —Previous awareness of breast cancer overdiagnosis was minimal. Women generally reacted with surprise, but most came to understand the issue. Responses to overdiagnosis and the different estimates of its magnitude were diverse. The highest estimate (50%) made some women perceive a need for more careful personal decision making about screening. In contrast, the lower and intermediate estimates (1-10% and 30%) had limited impact on attitudes and intentions, with many women remaining committed to screening. For some women, the information raised concerns, not about whether to screen but whether to treat a screen detected cancer or consider alternative approaches (such as watchful waiting). Information preferences varied: many women considered it important to take overdiagnosis into account and make informed choices about whether to have screening, but many wanted to be encouraged to be screened.

Conclusions —Women from a range of socioeconomic backgrounds could comprehend the issue of overdiagnosis in mammography screening, and they generally valued information about it. Effects on screening intentions might depend heavily on the rate of overdiagnosis. Overdiagnosis —Will be new and …
TGF-β type 2 receptor–mediated modulation of the IL-36 family can be therapeutically targeted in osteoarthritis
Authors: Tieshi Li, Susan Chubinskaya, Alessandra Esposito, Xin Jin, Lidia Tagliafierro, Richard Loeser, Arnavaz A. Hakimiyan, Lara Longobardi, Huseyin Ozkan, Anna Spagnoli
Journal: Science Translational Medicine (2019)

Mechanisms that govern the shift from joint homeostasis to osteoarthritis (OA) remain unknown. Here, we identify a pathway used for joint development and homeostasis, and its role in OA. Using a combination of transgenic, pharmacological, and surgical conditions in mouse and human tissues, we found that TGF-β signaling promotes joint homeostasis through regulation of the IL-36 family. We identified IL-36 receptor antagonist (IL-36 in mice and IL-36RN in humans) as a potential disease-modifying OA drug. Specifically, OA development was associated with IL-36α up-regulation and IL-36Ra down-regulation in mice with tissue-specific postnatally induced ablation of Tgfbr2, mice treated with a TGF-β signaling inhibitor, mice with posttraumatic OA, and aging mice with naturally occurring OA. In human cartilage, OA severity was associated with decreased TGFBR2 and IL-36RN, whereas IL-36α increased. Functionally, intra-articular treatment with IL-36Ra attenuated OA development in mice, and IL-36RN reduced MMP13 in human OA chondrocytes. These findings highlight the relevance of TGFBR2-IL-36 interplay in joint homeostasis and IL-36RN as a potential therapeutic agent for OA.