tbuckley/cabot-search huggingface dataset:
A cluster analysis of serious adverse event reports after human papillomavirus (HPV) vaccination in Danish girls and young women, September 2009 to August 2017
Authors: Daniel Ward, Nicklas Myrthue Thorsen, Morten Frisch, Palle Valentiner-Branth, Kåre Mølbak, Anders Hviid
Journal: Eurosurveillance (2019)

Background Suspected adverse events (AE) after human papillomavirus (HPV) vaccines include postural orthostatic tachycardia syndrome (POTS), chronic fatigue syndrome (CFS), complex regional pain syndrome (CRPS) and symptoms including headache and orthostatic intolerance. Aim We aimed to identify phenotypes of AEs after HPV vaccination, defined as patterns of AE terms (signs, symptoms, diagnoses), and to evaluate if identified phenotypes reflected previously suspected symptomatology or heightened public concerns over HPV vaccine safety since 1 January 2015. Methods We conducted a retrospective observational study using latent class cluster analysis of all serious AE reports (n = 963) reported by females residing in Denmark between September 2009 and August 2017. Resulting clusters were characterised according to AE terms associated with POTS, CFS and CRPS before (September 2009–December 2014) and during (January 2015–August 2017) a time of heightened media activity regarding HPV vaccines. Results Four clusters of AE reports were distinguished. The most common symptoms were fatigue, dizziness and headache but their frequency varied among clusters. The majority of reports in one cluster were submitted during a period of heightened media activity, including an anomalous spike in submissions in December 2015; a high proportion of these reports included the symptoms cognitive disorder (78%), abdominal pain (77%), dysuria (60%) and sleep disorder (60%). Conclusions Non-specific symptoms including headache, fatigue and dizziness feature prominently in serious AE reports from females in Denmark. Our analysis identified a cluster of reports, likely media stimulated, with a focus on symptoms of CFS and POTS.
Cell Survival and Cytokine Release after Inflammasome Activation Is Regulated by the Toll-IL-1R Protein SARM
Authors: Michael Carty, Jay Kearney, Katharine A. Shanahan, Emily Hams, Ryoichi Sugisawa, Dympna Connolly, Ciara G. Doran, Natalia Muñoz-Wolf, Claudia Gürtler, Katherine A. Fitzgerald, Ed C. Lavelle, Padraic G. Fallon, Andrew G. Bowie
Journal: Immunity (2019)
Abstract ES3-2: Multidisciplinary management of breast cancer brain metastases
Authors: C Tsien
Journal: Cancer Research (2019)

Abstract The management of breast cancer brain metastases requires a multi-disciplinary approach. Local treatment approaches including stereotactic radiosurgery (SRS) and surgery remain an integral component in the management of breast cancer patients. Systemic therapies with better penetration across the blood–brain barrier are currently being investigated. In this session, we will review the role of local therapies in the treatment of brain metastases and considerations on combining these different treatment modalities. We wish to exploit the novel interactions of SRS and systemic agents. We will discuss the evolving role of surgery, stereotactic radiosurgery and whole brain radiotherapy in the treatment of breast cancer brain metastases. We will review recent clinical trial data emphasizing the importance of preserving neurocognitive function in these patients and the general impact on current clinical practice. We will discuss issues regarding the optimal timing of systemic therapies in combination with local therapies and their impact on local control. Overall, there is a changing landscape in the treatment of breast cancer brain metastases with greater emphasis on preserving patients' neurologic function. Clinical trial research continues to be a priority. Ultimately, our goal is a significant paradigm shift in the management of breast cancer brain metastases with the prevention of central nervous system (CNS) metastases. Citation Format: Tsien C. Multidisciplinary management of breast cancer brain metastases [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 ES3-2.
Not just for hippies
Authors: Katherine Bettany
Journal: BMJ (2014)

Some will think of it as a political issue; a Sunday morning talk show issue; a scientific issue; an issue for hippies; but how many think of it as a health issue? The evidence is stacking up, with an increasing number of doctors agreeing that climate change is the biggest threat to global health of the 21st century. It is already killing patients. Something easy to measure is the direct effect of pollution on public health, and according to the World …
Systematic evaluation of C. elegans lincRNAs with CRISPR knockout mutants
Authors: Shuai Wei, He Chen, Emmanuel Enoch Dzakah, Bin Yu, Xiaolin Wang, Tao Fu, Jingxin Li, Lei Liu, Shucheng Fang, Weihong Liu, Ge Shan
Journal: Genome biology (2019)

Long intergenic RNAs (lincRNAs) play critical roles in eukaryotic cells, but systematic analyses of the lincRNAs of an animal for phenotypes are lacking. We generate CRISPR knockout strains for Caenorhabditis elegans lincRNAs and evaluate their phenotypes. C. elegans lincRNAs demonstrate global features such as shorter length and fewer exons than mRNAs. For the systematic evaluation of C. elegans lincRNAs, we produce CRISPR knockout strains for 155 of the total 170 C. elegans lincRNAs. Mutants of 23 lincRNAs show phenotypes in 6 analyzed traits. We investigate these lincRNAs by phenotype for their gene expression patterns and potential functional mechanisms. Some C. elegans lincRNAs play cis roles to modulate the expression of their neighboring genes, and several lincRNAs play trans roles as ceRNAs against microRNAs. We also examine the regulation of lincRNA expression by transcription factors, and we dissect the pathway by which two transcription factors, UNC-30 and UNC-55, together control the expression of linc-73. Furthermore, linc-73 possesses a cis function to modulate the expression of its neighboring kinesin gene unc-104 and thus plays roles in C. elegans locomotion. By using CRISPR/cas9 technology, we generate knockout strains of 155 C. elegans lincRNAs as valuable resources for studies in noncoding RNAs, and we provide biological insights for 23 lincRNAs with the phenotypes identified in this study.
Abstract 225: The first use of a live listeria cancer vaccine in man
Authors: John Rothman
Journal: Cancer Research (2008)

Abstract We report herein on the first in man use of a live Listeria cancer vaccine. 15 women with progressive, recurrent, or advanced cervical cancer who had failed prior chemotherapy, and/or radiotherapy and/or surgery were treated with Lovaxin C (Lm-LLO-E7) in a phase I/II assessment of safety. Lm-LLO-E7 is a living bioengineered strain of Listeria based upon the parent strain 10403S that has been attenuated by the excision of prfA, and modified by plasmid insertion to secrete a fusion protein comprised of the tumor specific antigen HPV-16-E7 fused to a non-hemolytic fragment of the endogenous Listeria protein Listeriolysin O (LLO). This results in a bacterial vector attenuated by approximately 105. Listeria in general, and this vector in specific, has been shown to have numerous effects presumed to be efficacious in the treatment of cancer including; induction of strong innate immunity, strong activation of both CD4+ and CD8+ lymphocytes, stimulated release of a variety of salutary cytokines and chemokines, the upregulation of co-stimulatory molecules, the generation of an inter-tumor environment conducive to tumor cell killing, the stimulation of myelopoesis and maturation of immature myeloid cells, and a lack of T regulatory cell activation. In this study, 5 patients each received two doses of either 1x109, 3.3x109, or 1x1010 cfu separated by 3 weeks. Ampicillin was given 5 days after each dose IV and then orally for 10 days. Follow-up assessments were made at 3 weeks and 3 months subsequent to the second vaccination. Patients had metastatic disease and most were stage IVb at the time of their first vaccination. All 15 treated patients were evaluable for safety analysis and 13 were evaluable in an intent-to-treat analysis of efficacy. Lovaxin C resulted in a flu-like syndrome in all patients comprised of fever, chills, and nausea with or without vomiting. In the 2 lower dose cohorts these symptoms were treated adequately with non-prescription NSAIDs and anti-emetics. At the dose of 1x1010 the same symptoms were observed, however they were dose limiting in severity, with fevers of 40-41oC and associated severe hypotensive diastolic BP. Other side effects observed were likely associated with prior therapies or disease severity. No serum, urine or stool Listeria was detectable. Tumors were assessed by scan using RECIST criteria. At the end of the study 5 patients had progressive disease, 7 patients were stable, and one patient demonstrated a PR by objective criteria. Of the 7 stable patients, 3 demonstrated tumor reductions of approximately 20%. The PR, who was IVb at dosing, was subsequently given 6 courses of chemotherapy and a radical hysterectomy. At the time of this writing she is tumor free, with normal hematology, and all labs WNL. It is concluded that Lovaxin C is safe to use therapeutically.
Abstract ES12-2: Link between BRCA1 and Pol II pausing in mammary gland development and tumorigenesis
Authors: R Li
Journal: Cancer Research (2019)

Abstract Breast cancer risk is significantly elevated for women who carry germ-line mutations in the tumor suppressor gene BRCA1. BRCA1-asociated breast tumors are basal-like, yet they originate from luminal progenitor cells. These precancerous cells of origin are defective in luminal differentiation in BRCA1 mutation carriers before any clinical evidence of cancer. While BRCA1 is best known for its functions in double strand break DNA repair and response to DNA replication stress, it is unclear whether loss of these ubiquitously important functions of BRCA1 is sufficient to account for lineage-specific breast tumor development in BRCA1 mutation-carrying women. Filling this longstanding intellectual disconnect could inform more effective risk assessment and disease prevention. Recent discoveries from others and us challenge the prevailing DNA repair/replication-centric paradigm. First, in vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Using breast tissue of cancer-free BRCA1 mutation-carrying women, we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5' end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1 knockout mouse mammary epithelium. Of note, this BRCA1/COBRA1 interaction occurs in a DSB repair-independent manner. Based on these findings, we suggest that as part of its tumor suppressor activity, BRCA1 promotes luminal epithelial differentiation by mitigating Pol II pausing-dependent transcriptional stress at luminal fate genes. We further propose that accumulation of transcriptional stress in BRCA1-deficient luminal cells redirects luminal transcription and alters luminal homeostasis, which ultimately contributes to lineage-specific BRCA1-associated tumorigenesis. Citation Format: Li R. Link between BRCA1 and Pol II pausing in mammary gland development and tumorigenesis [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 ES12-2.
Abstract P6-02-19: Machine learning based analysis of CT radiomics for the simultaneous indeterminate pulmonary nodules of breast cancer
Authors: Q Xiao, Y Gu, J Wu, Z Wang, Y Huang
Journal: Cancer Research (2019)

Abstract PURPOSE: To investigate texture features of simultaneous indeterminate pulmonary nodules of breast cancer for predicting their potential metastasis. METHODS AND MATERIALS: 150 patients with simultaneous breast cancer diagnosed by biopsy and pulmonary nodules (diameter: 5-20mm) detected by preoperative CT were enrolled in this study. After surgery and breast cancer treatment, the patients were followed up for at least half a year or longer by CT to observe the changes of lung nodules, thereby inferring the potential of metastasis. We classify pulmonary nodules into two groups: the reduced or enlarged pulmonary nodules were defined as highly metastasis possibility (Group 1), and long-term stable pulmonary nodules were defined as low metastasis possibility (Group 2). In addition, pathologic proven primary lung cancer in this study (Group 3) was compared with Group 1. Therefore, we carried out a comparative analysis of the texture features between the groups, and additional statistical were used three regression testing to extract texture features. Finally, we construct a machine learning classifier and calculate the accuracy of cross-validation. RESULTS: We collected 106 features by the texture analysis(TA). There are 18 features with significant differences between Group 1 and the Group 2(p&amp;lt;0.05), and 76 features with significant differences in the Group 1 and Group 3 (p&amp;lt;0.05). We tried to find key features related to pathology in 106 features using three methods: lasso regression, ridge regression and forward stepwise regression. The accuracy in different regressions respectively is 94.5%,94.5%,89.7% using KNN between Group 1 and Group 2. The accuracy in different regressions respectively is 96.2%(KNN),96.2%(Tree),92.3%(Linear Discriminant)in the Group 1 and Group 3. CONCLUDES: The identified radiomics features have the potential to be used as a biomarker for metastasis prediction of simultaneous indeterminate pulmonary nodules in breast cancer patients, and it may contribute to preoperative treatment and postoperative follow-up planning. Citation Format: Xiao Q, Gu Y, Wu J, Wang Z, Huang Y. Machine learning based analysis of CT radiomics for the simultaneous indeterminate pulmonary nodules of 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 P6-02-19.
Abstract P3-08-19: Proteomic tracking of breast cancer metastasis progression
Authors: N Hajjaji, S Aboulouard, YM Robin, D Bertin, I Fournier, J Bonneterre, M Salzet
Journal: Cancer Research (2019)

Abstract Background Metastases from breast cancers have not yet reached curability mainly because of the continuous evolution of cancer cells leading to treatment resistance and tumor progression. Despite the identification of the main genomic drivers of breast cancer resistance, and the development of specific targeted therapies, resistance has not been eradicated. A deeper understanding of tumor biology underlying treatment escape and tumor progression is necessary to find new targets. The aim of this study was to determine whether mass spectrometry based imaging and microproteomics are able to capture changes in protein expression and pathways occurring during metastasis progression. Methods Ten tumor samples from five progressing metastatic breast cancer patients treated at Oscar Lambret Cancer Center (France) were selected based on the availability of paired metastasis biopsy performed at two time points during the evolution of the disease. The proteomic profiles of paired tumor samples were analyzed using MALDI mass spectrometry imaging combined with microproteomics, a spatially resolved proteomic technology. Results Comparison of paired samples showed gain and loss of proteins associated with tumor progression. However, few were shared between patients. The pathways and biological processes mainly represented during tumor progression, and which were found in at least two patients, were those involved in the negative regulation of leukocyte mediated cytotoxicity, the metabolism of carboxilic acid, peptides and nucleosides, in response to stress, oxidation-reduction process, endocytosis, catabolic processes, actin regulation, and extracellular matrix organization. During metastasis evolution, few shared proteins were identified in at least 3 patients such as SRPX2, CILP1, collagen alpha-2(V) chain, Ras-related C3 botulinum toxin substrate 1, filamin-C, PDZ and LIM domain protein 2 and chloride intracellular channel protein 4. The main proteins lost during progression and found in at least 2 patients were cell surface glycoprotein MUC18, collagen alpha-2(IV) chain, polyadenylate-binding protein 2, and latent-transforming growth factor beta-binding protein 4 (LTAGP4). Results from an expanded cohort will be presented at the meeting. Conclusion MALDI mass spectrometry proteomics identified private and shared changes in proteins and biological processes associated with breast cancer metastasis progression. Citation Format: Hajjaji N, Aboulouard S, Robin YM, Bertin D, Fournier I, Bonneterre J, Salzet M. Proteomic tracking of breast cancer metastasis progression [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 P3-08-19.
Business in medicine—part ignored in medical curriculum
Authors: Sarah Ghufran, Ammara Mushtaq
Journal: BMJ (2011)

Medicine seems to be interwoven with business. Healthcare is one of the largest industries and contributes to the gross national product of many countries. Economically, it has created many jobs for people other than health professionals, such as hospital janitors and translators.

Every step taken at a hospital has a business component. From site maintenance, patients’ insurance, drug prescriptions, and surgical facilities to the medical devices available—all require cost management. For years we have debated whether to consider medicine as a business or not. According to a …
Long-Term Exposure to Ambient Ozone and Progression of Subclinical Arterial Disease: The Multi-Ethnic Study of Atherosclerosis and Air Pollution
Authors: Meng Wang, Paul D. Sampson, Lianne E. Sheppard, James H. Stein, Sverre Vedal, Joel D. Kaufman
Journal: Environmental Health Perspectives (2019)

Background: Long-term ozone (O3) exposure is associated with cardiovascular mortality, but little is known about the associations between O3 and subclinical arterial disease. Objectives: We studied the longitudinal association of exposure to O3 and progression of key subclinical arterial markers in adults: intima-media thickness of common carotid artery (IMTCCA), carotid plaque (CP) burden, and coronary artery calcification (CAC). Methods: CAC was measured one to four times at baseline and at follow-up exams (1999–2012) by computed tomography (CT) in 6,619 healthy adults, recruited at age 45–84 y without cardiovascular disease (CVD), over a mean of 6.5 y (standard deviation: 3.5 y). IMTCCA and CP burden were quantified in 3,392 participants using carotid artery ultrasound imaging acquired over a mean of 9 y (1.7 y). Over 91% and 89% participants had at least one follow-up IMTCCA and CAC measurement, respectively. Residence-specific O3 concentrations were estimated by a validated spatiotemporal model spanning from 1999 to 2012. This model relied on comprehensive monitoring data and geographical variables to predict individualized long-term average concentrations since baseline. Linear mixed models and logistic regression model were used to evaluate relationships of long-term average exposure to O3 with longitudinal change in IMTCCA, CAC, and CP formation, respectively. Results: Mean progression rates of IMTCCA and CAC were 12±0.5μm and 25±1.4 Agatston units per year. CP formation was identified in 55% of the subjects. A 3-ppb increase in long-term average O3 exposure was associated with a 5.6-μm [95% confidence interval (CI): 1.4, 9.7] greater increase in IMTCCA over 10 y. A 3-ppb increase in O3 was also associated with new CP formation [odds ratio (OR): 1.2 (95% CI: 1.1, 1.4)] but not CAC progression [−8 Agatston units (95% CI: −18, 2)]. Associations were robust in the analysis with extended covariate adjustment, including copollutants, i.e., nitrogen oxides (NOx) and particulate matter with diameter <2.5μm (PM2.5). Conclusion: Over almost a decade of follow-up, outdoor O3 concentrations were associated with increased rate of carotid wall thickness progression and risk of new plaque formation, suggesting arterial injury in this cohort. https://doi.org/10.1289/EHP3325
GPs in deprived areas face severest pressures, analysis shows
Authors: Gareth Iacobucci
Journal: BMJ (2019)

General practices in deprived areas are being disproportionately affected by “a mounting cycle of pressures” driven by workforce shortages and higher patient volumes, the Health Foundation has found.1

Its analysis concluded that GPs in the most deprived areas faced a higher workload, which was increasing the inequality in healthcare provision.

Meanwhile, a separate analysis by the Nuffield Trust for BBC Two revealed that the number of GPs for each 100 000 people in the UK fell from nearly 65 in 2014 to 60 in 2018, the biggest consecutive fall since the …