tbuckley/cabot-search huggingface dataset:
Personalized and Conscientious Medical Imaging
Authors: Jun Deng
Journal: JAMA Oncology (2016)

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Abstract 3310: Riboflavin targets autofluorescent-positive breast cancer stem cells upon light exposure
Authors: Shamileh Fouladdel, Tahra Luther, Kaitlin Harvey, Rachel Martin-Trevino, Jill Granger, Ebrahim Azizi, Max S. Wicha
Journal: Cancer Research (2016)

Abstract Most tumors are hierarchically organized and driven by a population of cells that display stem cell properties. These cancer stem cells (CSCs) have been characterized by in vitro assays such as sphere formation and in vivo by tumor initiation. In addition cell surface markers have been utilized to enrich for CSC populations. More recently a subtype of CSCs have been reported to display autofluorescence (AF), a property mediated by cellular uptake and concentration of riboflavin. In order to characterize the molecular heterogeneity of CSCs, we studied AF positive sorted single cells in different subtypes of breast cancer cell lines and also patient derived xenograft (PDX) breast tumor cells. Exposure of cell lines and PDXs to riboflavin significantly increased the percentage of AF+ cells 3-5 fold. These sorted AF+ cells were enriched for tumorsphere forming capacity in vitro. Flow cytometry analysis revealed partial overlap of AF+ cells with the previously characterized EMT-CSC phenotype CD44+/CD24- cells. We also utilized the microfluidic C1 and BioMark HD instruments to determine the expression patterns of 96 target genes using TaqMan assays in a multiplex RT-qPCR setting at single cell resolution. Single cell gene expression data showed a distinct signature in AF+ cells with high expression levels of MKI67, PCNA, ABCG2, BRCA1, Jag2, EZH2, and MMP9 genes. Since AF is mediated by specific cellular uptake and concentration of riboflavin, and the report that riboflavin is capable of generating cytotoxic free radicals upon light exposure, we determined whether this property could be exploited to selectively target CSCs. The AF+ cells were cultured in the presence and absence of riboflavin, exposed to visible light and analyzed by MTT cytotoxicity assay. Data revealed significant cytotoxicity of riboflavin on AF+ cells that were exposed to visible light. In conclusion, AF+ cells show distinct cancer stem cell features and are sensitive to light-activated riboflavin. These findings will help better understanding of tumor biology to identify new target therapies for treatment of cancer patients. Citation Format: Shamileh Fouladdel, Tahra Luther, Kaitlin Harvey, Rachel Martin-Trevino, Jill Granger, Ebrahim Azizi, Max S. Wicha. Riboflavin targets autofluorescent-positive breast cancer stem cells upon light exposure. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3310.
Abstract SY09-01: The tumor immunity continuum as a framework for rational combinations
Authors: Priti S. Hegde
Journal: Cancer Research (2016)

Abstract The PD-L1/PD-1 pathway is emerging as a central axis for immune-based therapeutic strategies in the treatment of multiple cancers. While these therapies are defined by durable responses extending to impressive overall survival improvement, this clinical benefit is limited to a few. We utilized gene signature analysis of cell subsets associated with the TME and molecular classification of disease using whole transcriptome analysis, PD-L1 IHC, CD8 IHC and tumor mutational load to identify signatures associated with immune response to atezolizumab (ati-PDL1) therapy from large Phase II trials and describe signatures associated with immune escape. Namely, we demonstrate that a preexisting immune response associated with inflamed tumors is highly predictive of clinical benefit to checkpoint inhibition. In addition, we describe both histological and molecular phenotypes associated with immune escape. The biological drivers of PD-L1 expression on tumor cells and tumor infiltrating immune cells will be presented. Using the lessons learned from human tumor immunology, we propose the concept of the tumor immunity continuum as a framework to expand the patient pool that derive long-term clinical benefit by harnessing their immune system. Citation Format: Priti S. Hegde. The tumor immunity continuum as a framework for rational combinations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY09-01.
Dacarbazine (DTIC) plus bevacizumab (B) combination therapy in chemotherapy (CTh)-naïve advanced melanoma (MM) patients (pts): A phase II study.
Authors: A. di Pietro, P. Ferrucci, E. Munzone, M. Mosconi, S. Gandini, C. Pari, F. Cataldo, F. Verrecchia, F. Nole, A. Testori
Journal: Journal of Clinical Oncology (2010)

8536 Background: Advanced MM pts' poor prognosis is not improved by the neither of the 2 FDA approved agents, DTIC and IL-2 (median survival-time < 9 month [mo]; 5-yr survival-rate < 5%). Single-agent DTIC has average response-rate of 10% and median response-duration of 5-6 mo, being poly-CTh never proven to be superior. To improve such sober results, different DTIC- combinations have been proposed. MM in vitro models showed VEGF transcription up-regulation by DTIC, suggesting DTIC/anti-VEGF combination as an intriguing exploiting path. Methods: Between July 2006-September 2009, at IEO, Milan, 40 CTh-naïve advanced MM pts underwent CTh with DTIC (800 mg/mq q4w) + B (10 mg/kg q2w), being disease evaluated at each access by physical examination and every 3 cycles by whole-body (wb) CT-scan, according to RECIST criteria. Response rate, median TTP and safety were analyzed. Results: 36/40 pts were evaluated at the analysis-time, with 4 screening failures (3 pts: brain metastasis detection at the pre-study wb CT-scan; 1pts: bleeding risk). Male/Female = 23/13; median age was 57 yr. PS 0/1 = 32/4. 6 pts (16.6%) developed partial response (PR), 13 (36.1%) stable disease (SD ≥ 24w = 10 pts, 25.6%); 17 (47.2%) progressive disease (PD; 8 pts: RECIST-criteria PD at the first CT-scan evaluation; 9 pts: early clinical PD). PR pts were on average older (65.7 yrs; range 46.3-74.1) than both SD (57.2 yrs; range 33.1-78.5) and PD pts (51.4 yrs; range 31.6-76.3). Median TTP was 6 mo (95% CI 2.8-12.6). Furthermore, exploratory data analysis interestingly shows 42.2% clinical benefit (defined as PR+SD ≥ 24w) and 16.5 mo (95% CI 5-31.5) median survival. Treatment was well tolerated (mild hypertension and mucositis [8/36], easily controlled by symptomatics); 3 SAEs were recorded: 2 major cardiac events and 1 allergic reaction to B at the first administration. Conclusions: Long-lasting response obtained in both SD and PR pts and mild side effects support DTIC/B as a promising combination in advanced MM pts. We are currently investigating whether the molecular pattern and gene profiling of each patient can predict responders vs. nonresponders to the DTIC/B combination. No significant financial relationships to disclose.
Abstract 1623: CITED2 modulates metastatic ability through effects on IKK-alpha in breast cancer cells
Authors: Swaathi Jayaraman, Michele Doucet, Wen M. Lau, Scott L. Kominsky
Journal: Cancer Research (2016)

Abstract Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain-2 (CITED2) is a member of the CITED family of non-DNA binding transcriptional co-activators. Previously, we identified CITED2 as a novel facilitator of bone metastasis in murine mammary cancer. Extending these initial studies to human breast cancer, CITED2 mRNA expression was significantly elevated in patient samples of metastatic breast cancer relative to primary tumors, with highest levels in bone metastasis. To explore the functional impact of CITED2 in breast cancer metastasis, we stably reduced CITED2 expression in the human breast cancer cell lines MDA-MB-231 and MDA-MB-468 cells, which are metastatic in animal models. While CITED2 knockdown had no effect on cell proliferation, it significantly reduced tumor migration and invasion in vitro and metastasis following intra-cardiac administration in athymic nude mice in vivo. To explore the mechanism responsible for these effects, we examined the impact of CITED2 knockdown on gene expression in MDA-MB-231 cells by microarray analysis. As confirmed at the mRNA and protein levels in both MDA-MB-231 and MDA-MB-468 cells, expression of the NF-κB regulator IKKα was significantly reduced along with several downstream targets of the NF-κB pathway (OPN, MMP9, uPA, SPARC, IL11 and IL-1β). In line with the reduced expression of IKKα, both canonical and non-canonical NF-κB signaling was inhibited following CITED2 knockdown. By ChIP assay, CITED2 was recruited to the promoters of IKKα, as well as the NF-κB targets OPN, MMP9, and SPARC. Finally, restoration of IKKα expression in MDA-MB-231 and MDA-MB-468 cells following CITED2 knockdown rescued their invasive ability. Collectively, these results suggest that CITED2 exerts its pro-metastatic effects in breast cancer cells via regulating IKKα. Citation Format: Swaathi Jayaraman, Michele Doucet, Wen M. Lau, Scott L. Kominsky. CITED2 modulates metastatic ability through effects on IKK-alpha in breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1623.
Abstract 1109: AAGUGC-microRNAs are an integral part of an oncogenic signaling network driving non-small cell lung cancer proliferation
Authors: Yan Zhou, Oliver Frings, Erik Fredlund, Jorrit Boekel, Rui M. Branca, Lukas M. Orre
Journal: Cancer Research (2016)

Abstract microRNA dysregulation is a common feature of cancer cells, but the complex roles of microRNAs in cancer are not fully elucidated. Here we used functional genomics to identify oncogenic microRNAs in non-small cell lung cancer (NSCLC) and to evaluate their impact on response to EGFR targeting therapy. Our data demonstrates that microRNAs with an AAGUGC-motif in their seed-sequence increase both cancer cell proliferation and sensitivity to EGFR inhibitors. Using miR-372 as a prototypic AAGUGC-miRNA we set out to identify target mRNAs and an explanation to the discovered phenotype. Global transcriptomics, proteomics and target prediction, resulted in the identification of more than 500 candidate target mRNAs, including several tumor suppressors involved in the G1/S transition. The clinical relevance of our findings were evaluated by analysis of public domain data of NSCLC patients, revealing that almost 200 of the candidate target mRNAs showed a negative correlation to AAGUGC-miRNAs. In addition, the analysis of NSCLC clinical data supported the link between this microRNA seed-family and cancer cell proliferation and indicated that high expression of this type of microRNAs is associated with shorter relapse free survival. Expanding the analysis to include additional types of cancer revealed large differences in expression of AAGUGC-miRNA both within and between cancer types. In general the results from the analysis of NSCLC was replicated in other cancer types, where expression of AAGUGC-miRNAs was associated with decreased mRNA levels of tumor suppressor targets and increased expression of genes involved in proliferation. In conclusion we propose that AAGUGC-microRNAs are an integral part of an oncogenic signaling network, and that these findings have potential therapeutic implications, especially in selecting patients for EGFR-targeting therapy. Citation Format: Yan Zhou, Oliver Frings, Erik Fredlund, Jorrit Boekel, Rui M. Branca, Lukas M. Orre. AAGUGC-microRNAs are an integral part of an oncogenic signaling network driving non-small cell lung cancer proliferation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1109.
Pulmonary arterial hypertension and the Enigma code of smouldering inflammation
Authors: Jose Gomez-Arroyo, Antonio Abbate, Norbert F. Voelkel
Journal: European Respiratory Journal (2016)

"What causes fever?" was the question that prompted the work that led to the discovery of the "leukocyte pyrogen", eventually named interleukin (IL)-1, in the late 1970s [1]. However, despite the rapid understanding of innate and adaptive immune responses and inflammation during the 1980s, it was not until 1995 that Humbert et al. [2] reported that both IL-1 and IL-6 levels were increased in the plasma of patients with idiopathic pulmonary arterial hypertension (PAH), thus revealing an inflammatory component in the pathogenesis of severe PAH. Ever since the first report by Humbert et al. [2], the role of inflammation as a cause or consequence of PAH has remained controversial [3] and this ongoing debate has perhaps prevented the pragmatism to design clinical trials to test novel anti-inflammatory therapies in patients with PAH. Anti-interleukin-1 treatment for pulmonary arterial hypertension: are we there yet? <http://ow.ly/8irv300EXoo> The authors wish to thank Charles A. Dinarello (University of Colorado, Denver, CO, USA) for his critical reading of this manuscript.
P1001 : Carotid-femoral pulse wave velocity (CF-PWV) as a surrogate marker of advanced liver fibrosis in type-2 diabetic (T2DM) patients evaluated by transient hepatic elastography
Authors: N.C. Leite, M.T. Ferreira, G. Salles, C.R. Cardoso, C.A. Villela- Nogueira
Journal: Journal of Hepatology (2015)
Lung Function Abnormalities in Smokers with Ischemic Heart Disease
Authors: Frits M. E. Franssen, Joan B. Soriano, Nicolas Roche, Paul H. Bloomfield, Guy Brusselle, Leonardo M. Fabbri, Francisco García-Rio, Mark T. Kearney, Namhee Kwon, Bo Lundbäck, Klaus F. Rabe, Alice Raillard, Hana Muellerova, John R. Cockcroft
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

The aim of the ALICE (Airflow Limitation in Cardiac Diseases in Europe) study was to investigate the prevalence of airflow limitation in patients with ischemic heart disease and the effects on quality of life, healthcare use, and future health risk.To examine prebronchodilator and post-bronchodilator spirometry in outpatients aged greater than or equal to 40 years with clinically documented ischemic heart disease who were current or former smokers.This multicenter, cross-sectional study was conducted in 15 cardiovascular outpatient clinics in nine European countries. Airflow limitation was defined as post-bronchodilator FEV1/FVC less than 0.70.Among the 3,103 patients with ischemic heart disease who were recruited, lung function was defined for 2,730 patients. Airflow limitation was observed in 30.5% of patients with ischemic heart disease: 11.3% had mild airflow limitation, 15.8% moderate airflow limitation, 3.3% severe airflow limitation, and 0.1% very severe airflow limitation. Most patients with airflow limitation (70.6%) had no previous spirometry testing or diagnosed pulmonary disease. Airflow limitation was associated with greater respiratory symptomatology, impaired health status, and more frequent emergency room visits (P < 0.05).Airflow limitation compatible with chronic obstructive pulmonary disease affects almost one-third of patients with ischemic heart disease. Although airflow limitation is associated with additional morbidity and societal burden, it is largely undiagnosed and untreated. Clinical trial registered with www.clinicaltrials.gov (NCT 01485159).
Thrombotic microangiopathy during carfilzomib use: case series in Singapore
Authors: Y Chen, M Ooi, S F Lim, A Lin, J Lee, C Nagarajan, C Phipps, Y S Lee, N F Grigoropoulos, Z Lao, S Surendran, E M Teh, Y T Goh, W J Chng, S K Gopalakrishnan
Journal: Blood Cancer Journal (2016)

Carfilzomib is an irreversible proteasome inhibitor and is an effective treatment for multiple myeloma (MM). 1,2It received US Food and Drug Administration approval based on a single-arm multicenter trial of carfilzomib monotherapy in 266 patients with relapsed MM following at least two prior lines of treatment including bortezomib and immunomodulators. 1,3Safety analyses from four phase II carfilzomib trials (N = 526) that included heavily pre-treated MM patients suggested a favorable risk-benefit profile with no specific signal of thrombotic microangiopathy (TMA) reported.However, serious adverse events of anemia, thrombocytopenia and increased serum creatinine comprised 1.3%, 1.1% and 1.3%, respectively. 4Over 350 subjects have been enrolled in randomized phase III trials in Asian countries.Herein, we report four cases of TMA related to carfilzomib use among 24 patients from 2 tertiary hospitals in Singapore (Table 1).All patients who started carfilzomib had a creatinine clearance 430 ml/min and platelet counts450 × 10 9 /l at the start of treatment.Patients 1 (70/Chinese/Male) and 2 (66/Chinese/Female) had newly diagnosed MM and were treated in an institutional review board-approved investigator-initiated study (IIS) using carfilzomib in combination with cyclophosphamide and dexamethasone as frontline therapy for high-risk MM (SGHMM1, NCT02217163).Within this trial, carfilzomib is given at 20 mg/m 2 in cycle (C) 1, days (D) 1 and 2 followed by 56 mg/m 2 for all subsequent doses as tolerated.Patient 1 had reported fever and flu-like symptoms on C2D2.The carfilzomib dose on C2D2 was postponed to C2D3 after fever resolved.He developed grade 1 diarrhea the day after, and on C2D6 hemoglobin declined from 7.5 to 5.3 g/dl and platelets dropped from 105 × 10 9 to 5 × 10 9 /l.This was accompanied by emergence of schistocytes on the blood film and an acute rise in serum creatinine (209 μmol/l from 97 μmol/l).Hemolytic screen was positive (LDH 1833 U/l, bilirubin 24 μmol/l, reticulocyte index 2.6, haptoglobin o 0.1 g/l) with a negative Coomb's reaction.Prothrombin time (PT) was 11.7 s and activated partial thromboplastin time (APTT) was 27.2 s.The diagnosis of TMA was made, Named patient program (Cd)Cycle 1 D1, 2, 8, 9, 15, 16 (of 28 day cycle)-IV 20 mg/m 2 Subsequent cycles D1, 2, 8, 9, 15, 16 (of 28 day cycles)-IV 27 mg/m 2
The MEDCAR study : Clinical evidence of recovery from atrial electrical remodeling after cardioversion of persistent atrial fibrillation
Authors: RG Tieleman, H Bosker, van Isabelle Gelder, T Kingma, Aam Wilde, CH Kirchhof, JH Bennekers, FA Bracke, MA Allessie, HJ Crijns
Journal: Circulation (2000)
What is the best way to manage neurogenic bowel dysfunction?
Authors: Doreen McClurg, Christine Norton
Journal: BMJ (2016)

#### What you need to know

A single episode of faecal incontinence can precipitate a fear of repetition and may lead to reduced social activity and isolation. Bowel dysfunction, faecal incontinence, and constipation have a prevalence of around 70% in people with central neurological disease such as Parkinson’s disease, stroke, multiple sclerosis, or spinal cord injury. Tools such as the Bristol Stool Chart have been developed to aid conversation about bowel dysfunction (fig 1). Constipation may lead to difficult evacuation, abdominal pain and bloating, haemorrhoids, anal fissures, rectal bleeding, prolapse, and autonomic dysreflexia. Hospital admission for impaction occurs more than twice as frequently as in healthy people. Management to ameliorate either incontinence or constipation risks precipitating the other. The condition is time consuming and arduous and causes anxiety to the patient and care givers.



Fig 1  Bristol Stool Chart



Various approaches have been tried for faecal incontinence and constipation in these patients, but limited …
Cytomegalovirus Reactivation Prophylaxis With Low Dose Valgancyclovir After Hematopoietic Stem Cell Transplantation
Authors: Bianca Serio, Luca Pezzullo, Raffaele Fontana, Silvana Annunziata, Rosa Rosamilio, Idalucia Ferrara, Monia Rocco, Valentina Giudice, Mariarosaria Sessa, Ciro De Luca, Carmine Selleri
Journal: Blood (2013)
Case 23-1973
Authors: Richard C. Cabot, Benjamin Castleman, Robert E. Scully, Betty U. McNeely, Robert H. Schapiro, James J. Galdabini
Journal: New England Journal of Medicine (1973)

Presentation of CaseA 73-year-old man was admitted to the hospital because of abdominal pain.Ten years previously he underwent endarterectomy of the abdominal aorta because of severe occlusive disease; at the operation the gallbladder was noted to be surrounded by adhesions, but no stones were felt, and the liver appeared normal. Four months later hepatitis occurred and was ascribed to multiple transfusions of whole blood and plasma. During the next year he entered the hospital on several occasions because of persistent liver disease. A liver biopsy disclosed subacute hepatitis. Prednisone was given. Diabetes mellitus developed and was treated with . . .
Zero to 50,000 — The 20th Anniversary of the Hospitalist
Authors: Robert M. Wachter, Lee Goldman
Journal: New England Journal of Medicine (2016)

In the past 20 years, the number of hospitalists in the United States has grown from a few hundred to more than 50,000. Although challenges remain, many stars have aligned to enable the model to thrive and contribute to high-quality, efficient inpatient care.