tbuckley/cabot-search huggingface dataset:
Optimizing axitinib treatment selection following first-line sunitinib in metastatic renal cell carcinoma.
Authors: Sergio Bracarda, Aristotelis Bamias, Jochen Casper, Sylvie Negrier, Avishay Sella, Michael D. Staehler, Jamal Christo Tarazi, Alessandra Felici, Brad Rosbrook, Monica Jardinaud-Lopez, Bernard Escudier
Journal: Journal of Clinical Oncology (2018)

589 Background: The treatment landscape for metastatic renal cell carcinoma (mRCC) is continuously evolving, with several new first-line (1L) and second-line (2L) treatment options. In the AXIS trial, axitinib resulted in significantly longer progression-free survival (PFS) vs sorafenib in the 2L treatment of mRCC. In these post-hoc exploratory analyses of AXIS, possible key drivers for successful 2L treatment with axitinib after sunitinib were evaluated. Methods: AXIS was an open-label, randomized, phase III trial (NCT00678392) in patients (pts) with mRCC who failed 1 prior systemic therapy. Univariate and multivariate analyses evaluated potential predictive factors for improved PFS (investigator-assessed) and overall survival (OS) with axitinib. PFS (independent review), OS and objective response rate (ORR) for axitinib vs sorafenib according to these predictive factors were assessed. Results: In all, 389 pts received 1L sunitinib: 194 and 195 pts received 2L axitinib and sorafenib, respectively. Based on multivariate analyses of PFS and OS, predictive factors favoring 2L axitinib treatment were identified as: non-bulky disease (sum of the longest diameter &lt; 98 mm), favorable/intermediate (Fav/Int) risk (Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium criteria), no bone and no liver metastases. Thus, pts were grouped according to these factors. In pts with favorable risk factors (n = 86), a significantly longer median (95% confidence interval [CI]) PFS was observed in axitinib (n = 39; 13.9 [7.8–17.7] mo) vs sorafenib pts (n = 47; 4.7 [3.5–6.7] mo; hazard ratio [HR] 0.476 [95% CI 0.263–0.863]; P= 0.0126). Median (95% CI) OS (32.4 [23.8–not evaluable] mo vs 35.0 [23.9–35.0] mo; HR 0.902 [95% CI 0.457–1.780]; P= 0.7661) and ORR (both 12.8%) were similar between the 2 groups. More pts had stable disease ≥20 weeks with axitinib (38.5%) vs sorafenib (21.3%). Conclusions: In the continuously changing treatment landscape for mRCC, axitinib remains a suitable 2L treatment option, particularly in pts with non-bulky disease, Fav/Int risk and no bone nor liver metastases, characterized by an impressive PFS. Clinical trial information: NCT00678392.
Impact of Irradiation on the Protein Content and Microbial Levels of Sesame Seed Flour for use in Oral Immunotherapy
Authors: Anusha Penumarti, Nicole Szczepanski, Janelle Kesselring, Elizabeth Gabel, Jelena Petrovic Berglund, Edwin H. Kim, A. Wesley Burks, Mike D. Kulis
Journal: Journal of Allergy and Clinical Immunology (2018)
Reversing immune checkpoint inhibitor resistance with adenoviral IL-24 and p53 tumor suppressor immune gene therapy.
Authors: Sunil Chada, Dora B Wiederhold, Kerstin Menander, Hyomin Ahn, Eonju Oh, Chae-Ok Yun, Robert E. Sobol
Journal: Journal of Clinical Oncology (2018)

64 Background: Immune checkpoint inhibitors represent an important advance in cancer therapeutics. However, most cancer patients either do not respond or become resistant to this therapy. Methods: We evaluated the ability of tumor suppressors p53 and IL-24, delivered via adenoviral vectors, to reverse immune checkpoint inhibitor resistance and induce abscopal therapeutic effects in the highly immune therapy resistant murine B16F10 melanoma tumor model. To mimic clinical conditions of immune checkpoint inhibitor resistance, animals with established tumors were treated with anti-PD-1 before intra-tumoral delivery of adenoviral vectors encoding tumor suppressors p53 (Ad-p53) or IL-24 (Ad-IL24). Results: Anti-PD-1 had minimal or no therapeutic efficacy when compared to PBS controls. However, there was a reversal of anti-PD-1 resistance in animals treated with Ad-p53, or Ad-IL24, in combination with anti-PD-1. Evaluation of primary tumor growth using ANOVA confirmed synergistic effects of the combination treatments over either agent used as monotherapy (p = 0.0001 for p53, p = 0.002 for IL-24). We also observed statistically significant decreases in contralateral abscopal tumor growth in animals whose primary tumors were treated with either Ad- p53 or Ad-IL24 (p = 0.046, and p = 0.0021, respectively) or in combination with anti-PD-1 (p = 0.02 p53, and p &lt; 0.0001 for IL-24) as compared to animals treated with anti-PD-1 alone. With respect to survival, combined tumor suppressor + anti-PD-1 therapy resulted in a statistically significant increase in survival compared to: a) tumor suppressor therapy alone (p = 0.01 for either Ad-p53 and or IL-24) and b) anti-PD-1 therapy alone (p &lt; 0.001 for p53, and p = x for IL-24). Conclusions: Overall, these results indicate that IL-24 and p53 tumor suppressor immune gene therapy can reverse immune checkpoint inhibitor resistance in primary tumors, and induce abscopal effects inferring the activation of systemic anti-tumor immune responses that reverse resistance to immune checkpoint inhibitor therapy.
A zebrafish live imaging model to study microglia-glioma interactions
Authors: Kelda Chia, Lloyd Hamilton, Julie Mazzolini, Katy Astell, Dirk Sieger
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme is the most common and deadliest form of brain cancer. Gliomas are highly infiltrated by microglia and macrophages, which have been shown to promote tumour growth and invasion. However, due to limitations of existing models it is unclear when exactly microglia respond to gliomas and which signalling mechanism are controlling these early events. We have established a zebrafish in vivo model to study the interactions of macrophages/microglia and early tumours in the living brain in real time. In particular the opportunity to image cellular interactions at high temporal and spatial resolution in the living brain, combined with the possibility of intervening genetically and pharmacologically, make the zebrafish an excellent model. To induce tumour growth we followed a dual strategy, the overexpression of human oncogenes and the xenotransplantation of human glioblastoma cells into the zebrafish brain. The overexpression of human oncogenes led to malignant transformations and glioblastoma growth in the larval zebrafish brain. Importantly, we detected an immediate reaction of the microglial network during the earliest stages of malignant transformations. This response was characterised by increased microglial numbers and a change of their activation status. In vivo imaging revealed intimate interactions between macrophages/microglia and oncogenic cells. This model will allow us to understand the signalling mechanisms underlying the earliest responses of microglia to glioma growth. Transplantation of human glioblastoma cells into larval zebrafish brains showed engraftment and growth of the human cells accompanied by distinct microglial interactions. Importantly, these interactions turned out to be pro-tumoural and transplantation of glioblastoma cells into a zebrafish mutant devoid of microglia showed impaired survival of the human glioblastoma cells. In summary, our data proof the suitability of the zebrafish to study the interplay between microglia and glioma cells. Understanding these interactions on the molecular level is the first step to develop new therapies.
Differential effects of phototherapy, adalimumab and betamethasone-calcipotriol on effector and regulatory T cells in psoriasis
Authors: I.S. Kotb, B.J. Lewis, R.N. Barker, A.D. Ormerod
Journal: British Journal of Dermatology (2018)

Psoriasis is a chronic T-cell-mediated skin disease with marked social and economic burdens. Current treatments are unsatisfactory, with unpredictable remission times and incompletely understood modes of action. Recent advances in our understanding of the pathogenesis of psoriasis have identified the imbalance between CD4+ T effector cells, particularly the T helper (Th)17 subset, and regulatory T cells (Tregs) as key to the development of psoriatic lesions, and therefore a novel therapeutic target.To quantify in patients the effects of three commonly used psoriasis treatment modalities on the Th1, Th2, Th17 and Treg subsets, and to test whether any change correlates with clinical response.Flow cytometry was used to enumerate Th1, Th2, Th17 and Treg subsets in blood and skin of patients with psoriasis before and after receiving any of the following treatments: narrowband ultraviolet B (NB-UVB), adalimumab and topical betamethasone-calcipotriol combination (Dovobet® ) RESULTS: All patients responded clinically to the treatments. NB-UVB significantly increased the numbers of circulating and skin Tregs, while, by contrast, adalimumab reduced Th17 cells in these compartments, and Dovobet had dual effects by both increasing Tregs and reducing Th17 cells.The differential effects reported here for the above-mentioned treatment modalities could be exploited to optimize or design therapeutic strategies to overcome the inflammatory drivers more effectively and restore the Th17-Treg balance in psoriasis.
Development of new endoscopic irreversible electroporation ablation device: Animal experimental study.
Authors: Geeho Min, Hyuk Soon Choi, Woojung Kim, Seong ji Choi, Jung Min Lee, Seung Han Kim, Jae Min Lee, Eun Sun Kim, Bora Keum, Yoon Tae Jeen, Hong Sik Lee, Hoon Jai Chun, Chang Duck Kim
Journal: Journal of Clinical Oncology (2018)

188 Background: Irreversible electroporation (IRE) is a promising novel technique for the ablation of tumors. An advantage of IRE is its mechanism to remove undesired cells by affecting the cell membrane without thermally destructing blood vessels, nerves and the surrounding tissues. Several clinical trials for applying IRE to human organs such as liver, pancreas, and kidney are conducted and studies about IRE ablation for gastrointestinal tumors also have been conducted recently. Here, we developed new endoscopic IRE device, and studied about its effectiveness and feasibility in animal model. Methods: Newly developed endoscopic IRE ablative catheter works with single channel of endoscope. A pair of dipolar electrodes consist of pre-shaped f 0.63mm nitinol wire and the distance between each electrode is 10 mm. The electrodes are loaded within braided tube for stent delivery system then deployed when IRE catheter put in stomach through the endoscope. We performed endoscopy and IRE ablation was done on pig’s stomach mucosa by using endoscopy with newly developed IRE catheter. We divided pig’s stomach into 2 parts(antrum &amp; body), and IRE ablation was applied on each part of the stomach. Pigs were sacrificed after 24hours, and we collected their stomachs with surgical technique. Following fixation, tissues were stained with H&amp;E. Results: Ten male Yorkshire pigs and in vitro stomachs were used in this study. The tissue with H&amp;E stain showed diffuse cell death 24hr after IRE ablation. Consistent with the mechanism of action of IRE on the cell membrane only, there was complete cell death within the IRE lesions without intervening live cells. But there was no difference in histology depending on gastric part in which ablation was applied. During the study, no complication was observed in pigs in 24 hours after ablation. Conclusions: The new endoscopic IRE device, which can perform IRE ablation on gastrointestinal tract using endoscopy showed safe and feasible result.
Association of upregulation of serine and one carbon metabolism genes with shorter recurrence-free and overall survival in urothelial bladder cancer (UBC).
Authors: Michael Lattanzi, Michael Pacold, Arjun Vasant Balar
Journal: Journal of Clinical Oncology (2018)

477 Background: Antimetabolites (e.g. methotrexate and gemcitabine) are not frequently used in the treatment of most solid tumors, but are effective in the treatment of UBC. Rapid cancer cell proliferation relies on an abundance of serine-derived one carbon units to support macromolecule synthesis. Specifically, PHGDH, which encodes a key enzyme of de novo serine synthesis, is amplified in breast cancer and in melanoma, and small molecule inhibitors of enzymes in this pathway are in early clinical development. However, the enzymes of serine and one carbon metabolism have not been widely investigated in UBC. Methods: We conducted an observational analysis of The Cancer Genome Atlas UBC cohort, focusing on gene expression data from a targeted panel indicated by Yang, et al. to be involved in serine and one carbon metabolism. Univariate Cox proportional hazard models were utilized to identify genes impacting OS and RFS, and a subsequent multivariate model was employed to control for inter-gene associations. Results: Expression data from 14 genes were analyzed among 436 UBC patients, of whom complete data were available for 422. At a median follow-up of 17 months, 188 of 422 patients had died. On univariate analysis, 7 of 14 genes were significantly associated with OS: PHGDH, PSPH, MTHFD1, MTHFD2, MTHFD1L, MTHFD2L, and ALDH1L2 (all P &lt; 0.05). Interestingly, overexpression was associated with worse OS for all but one gene, MTHFD2L (HR 0.74), which is known to be underexpressed by cancer cells in favor of MTHFD2 (HR 1.21). In multivariate analysis, overexpression of PHGDH (HR 1.19, P = 0.008), MTHFD1 (HR 1.33, P = 0.041), and ALDH1L2 (HR 1.21, P &lt; 0.001) were independent predictors of poor survival. RFS analysis was limited by missing data; nevertheless, univariate analyses found MTHFD1, MTHFD2, MTHFD1L, MTHFD2L, and ALDH1L2 to be associated with RFS (all P &lt; 0.05). Conclusions: Within the limits of this observational study, these data suggest that serine and one carbon metabolism is important in the progression and prognosis of muscle-invasive bladder cancer. Subsequent in vitro analyses are needed to validate the prognostic and therapeutic significance of these findings.
LEFT ATRIAL APPENDAGE OCCLUSION FOLLOWING LEFT ATRIAL APPENDAGE ISOLATION
Authors: Varuna Gadiyaram, Carola Gianni, Chintan Trivedi, Sanghamitra Mohanty, Domenico Della Rocca, Amin Al-Ahmad, John Burkhardt, G. Gallinghouse, Patrick Hranitzky, Javier Sanchez, Luigi Di Biase, Rodney Horton, Matthew Price, Douglas Gibson, Andrea Natale
Journal: Journal of the American College of Cardiology (2018)
A user's guide to clinical attachments
Authors: Umesh Prabhu
Journal: BMJ (2004)

Cryostat sections of unfixed human breast carcinomas were assayed for oestrogen receptor (ER) content using an isoelectric focusing method to separate the receptor-bound oestradiol. Adjacent sections from the same tissue block were stained so that the tumour content could be estimated by point counting and the ER concentration adjusted to compensate for variations in cellularity. Elastosis was also assessed. The results confirm a positive correlation between ER values and both cellularity and elastosis. The measurement of ER in cryostat sections is relatively simple and rapid, is applicable to small tissue samples, and permits histological identification of the nature and composition of the assayed sample. The method is directly applicable to oestrogen receptor analyses of breast carcinomas in clinical laboratories with facilities for cryostat microtomy.
Impairing L-Threonine Catabolism Promotes Healthspan through Methylglyoxal-Mediated Proteohormesis
Authors: Meenakshi Ravichandran, Steffen Priebe, Giovanna Grigolon, Leonid Rozanov, Marco Groth, Beate Laube, Reinhard Guthke, Matthias Platzer, Kim Zarse, Michael Ristow
Journal: Cell Metabolism (2018)
ENDOTHELIAL FUNCTION PREDICTS ANTHRACYCLINE-INDUCED CARDIOTOXICITY
Authors: Evangelos Oikonomou, Maria Anastasiou, Flora Zagouri, Gerasimos Siasos, Alexios Antonopoulos, Sotirios Tsalamandris, George-Angelo Papamikroulis, Pavlos Papakostas, Theodora Psaltopoulou, Aristotelis Bamias, Meletis Dimopoulos
Journal: Journal of the American College of Cardiology (2018)
I want to become a GP trainer after I've completed my GP training. Do I need to do any special courses or degrees?
Authors: Bill Irish
Journal: BMJ (2005)

Have a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site. <b>www.bmjcareers.com/advicezone</b>
Misunderstanding the goals of animal research
Authors: Eric J Rubin, Sarah M Fortune
Journal: BMJ (2018)

We welcome the application of rigorous standards to preclinical research, but the position expressed by Ritskes-Hoitinga and Wever misses the central value of most animal experimentation.1 Medical research exists on a spectrum from fundamental discovery to clinical validation. Human studies must meet very high levels of proof and, therefore, can generally rigorously test only a single hypothesis. The vast majority …
ANGIOGRAPHIC FRACTIONAL FLOW RESERVE ESTIMATED FROM TWO IMAGE PROJECTIONS ACQUIRED BY A BIPLANE C-ARM SYSTEM: COMPARISON WITH INVASIVE FRACTIONAL FLOW RESERVE
Authors: Jiro Ando, Katharina Otani, Shun Minatsuki, Hironobu Kikuchi, Toshiro Inaba, Arihiro Kiyosue, Satoshi Kodera, Issei Komuro
Journal: Journal of the American College of Cardiology (2018)
GPs—fortunate or unfortunate?
Authors: Patrick Hutt
Journal: BMJ (2005)

Medicine changes rapidly. As we move through our careers, is a feeling of nostalgia inevitable? Does it cloud arguments we might make about medical practice today? This point was made during a seminar celebrating a book written nearly 40 years ago about general practice. Given the sell out crowd, the issues raised, and the strength of opinion expressed, <i>Patrick Hutt</i> decided to report back
How should minimally important change scores for the Patient-Oriented Eczema Measure be interpreted? A validation using varied methods
Authors: L. Howells, S. Ratib, J.R. Chalmers, L. Bradshaw, K.S. Thomas
Journal: British Journal of Dermatology (2018)

The Patient-Oriented Eczema Measure (POEM), scored 0-28, is the core outcome instrument recommended for measuring patient-reported atopic eczema symptoms in clinical trials. To date, two published studies have broadly concurred that the minimally important change (MIC) of the POEM is three points. Further assessment of the MIC of POEM in different populations, and using a variety of methods, will improve interpretability of the POEM in research and clinical practice.To calculate the smallest detectable change in the POEM and estimate the MIC of the POEM using a variety of methods in a trial dataset of children with moderate-to-severe atopic eczema.This study used distribution-based and anchor-based methods to calculate the MIC of the POEM in children with moderate-to-severe eczema.Data were collected from 300 children. The smallest detectable change was 2·13. The MIC estimates were 1·07 (using 0·2 SD of baseline POEM scores) and 2·68 (using 0·5 SD of baseline POEM scores) based on distribution-based methods; were 3·09-6·13 based on patient-/parent-reported anchor-based methods; and were 3·23-5·38 based on investigator-reported anchor-based methods.We recommend the following thresholds be used to interpret changes in POEM scores: ≤ 2, unlikely to be a change beyond measurement error; 2·1-2·9, a small change detected that is likely to be beyond measurement error but may not be clinically important; 3-3·9, probably a clinically important change; ≥ 4, very likely to be a clinically important change.
Health equity, cancer, and social determinants of health
Authors: Michael Marmot
Journal: The Lancet Global Health (2018)

Two facts on non-communicable diseases claim attention: they are global in distribution and, increasingly, show marked social inequalities—the lower the social position, the higher the risk. Inequalities in cancer mortality will, in part, be owing to inequalities in access to high-quality treatment. Cancer Research UK has estimated that worldwide, 30–50% of cancers should be preventable; in the UK alone, four in ten cancers should be preventable. The routes to prevention, in order of importance, are: be smoke-free; maintain a healthy bodyweight; consume adequate fruit and vegetables; limit alcohol consumption; be sun-smart; eat less processed and red meat; eat a high-fibre diet; be active; and eat less salt. Prevention of cancer will not be achieved simply by exhorting people to behave better but will depend on action on the social determinants of health. In middle-income and high-income countries, smoking and obesity follow the social gradient—the lower the social position, the higher the risk. Although alcohol consumption is typically higher in people of high social status, alcohol-associated harm goes the other way—it increases as the social gradient is descended. In the UK, as in some other countries, the lower the social position, the lower the consumption of fruit and vegetables. Quite apart from other potential causes of inequalities in the occurrence of cancer, action on the identified behaviours will mean action on the social determinants of health inequities. In the WHO Commission on Social Determinants of Health,1WHOClosing the gap in a generation. Health equity through action on the social determinants of health. World Health Organization, Geneva2008Google Scholar we pointed to inequities in the conditions of daily life that, in turn, are driven by inequities in power, money, and resources. In my English review of health inequalities,2Marmot M Strategic review of health inequalities in England post-2010: fair society, health lives. University College London, London2010Google Scholar I described six domains of recommendations for reducing inequalities in health within one country: (1) the best start in life for every child; (2) education and life-long learning; (3) employment and working conditions; (4) sufficient income for a healthy life; (5) healthy and sustainable environments in which to live and work; and (6) the social determinants approach to prevention of ill health. Action in these six domains will necessitate action across government, not only from health ministries or from those of us working in the health sector. The potential is great: it is to reduce inequalities in the occurrence of cancer and other non-communicable diseases and to advance the cause of health equity. I declare no competing interests.