tbuckley/cabot-search huggingface dataset:
Characteristics and Public Availability of Results of Clinical Trials on Rare Diseases Registered at Clinicaltrials.gov
Authors: Agnes Dechartres, Carolina Riveros, Michael Harroch, Timor Faber, Philippe Ravaud
Journal: JAMA Internal Medicine (2016)

1% (P < .001).Euthanasia and ending of life without the patient's explicit request also increased, but the number of studied cases of the 2 categories was small, at 8 and 15 cases in 2001, and at 11 and 25 cases in 2013, respectively, and the increases, from 0.2% to 0.3% for euthanasia and from 0.5% to 0.8% for ending of life without the patient's explicit request, were not significant.The greatest increase was in the use of continuous deep sedation until death, which rose from 4.7% of all deaths in 2001 to 17.5% in 2013 (P < .001).Sedation was combined with forgoing life-prolonging treatment, alleviation of pain and symptoms, or physician-assisted death in 62%, 28%, and 3% of cases, respectively.Discussion | In Switzerland in 2013, more than 4 of 5 nonsudden deaths, corresponding to 58.7% of all deaths, were preceded by at least 1 specific end-of-life practice in 2013 compared with 52.0% in 2001.Similar increases in medical end-of-life practices were reported in the Netherlands, from 43.8% in 2001 to 57.8% in 2010, and in Belgium, from 38.4% in 2001 to 47.8% in 2013. 2,3orgoing life-prolonging treatment and intensified alleviation of pain and symptoms constitute the vast majority of medical end-of-life practices.In Switzerland, an increase in the percentage of deaths in which life-prolonging treatment was forgone predominated among medical end-of-life practices.This trend contrasts with the situation in the Netherlands, where forgoing life-prolonging treatment decreased slightly, from 20.2% in 2001 to 18.2% in 2010, and intensified alleviation of symptoms increased from 20.1% in 2001 to 36.4% in 2010. 2 In Switzerland, physician-assisted death occurs mainly as assisted suicide.We were unable to establish how many such deaths involved foreigners without permanent residence in Switzerland. 5The trends in euthanasia and ending of life without the patient's explicit request, both of which are illegal in Switzerland, reflected small absolute differences in numbers for these 2 practices from 2001 to 2013 and are difficult to interpret.In our study population, the substantial increase in the use of continuous deep sedation until death, from 4.7% of all deaths in 2001 to 17.5% in 2013, is noteworthy; this practice was therefore more common in Switzerland than in either Belgium (12.0% in 2013) or the Netherlands (12.3% in 2010). 2,3In 2005, the Swiss Association of Palliative Care released specific guidelines on palliative sedation. 6These guidelines may have stimulated both awareness of palliative sedation and the practice itself.
Primary Mediastinal Large B-Cell Lymphoma: Investigation On The Role Of Rituximab and PET During Treatment
Authors: Pier Luigi Zinzani, Cinzia Pellegrini, Beatrice Casadei, Enrico Derenzini, Alessandro Broccoli, Letizia Gandolfi, Federica Quirini, Lisa Argnani, Vittorio Stefoni
Journal: Blood (2013)
Activated c-Met[pY1003]: A potential marker of intrinsic resistance and therapy target to restore sensitivity to gefitinib
Authors: P. A. Zucali, M. Gallegos Ruiz, E. Giovannetti, A. Destro, K. Floor, G. L. Ceresoli, J. A. Rodriguez, M. Roncalli, A. Santoro, G. Giaccone
Journal: Journal of Clinical Oncology (2007)

7624 Background: Epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) show anti-tumor activity in only 10% of Caucasian non-small cell lung cancer (NSCLC) patients. Aim of this study was to evaluate several biological parameters potentially related to EGFR, including c-Met activation, as potential markers of intrinsic resistance to EGFR-TKIs in NSCLC. Methods: P-Akt, p-Erk, c-Src, E-Cadherin, c-Met[pY1003] and c-Met[pY1230/1234/1235] status was immunohistochemically determined on a tissue micro-array of tumor samples from 51 NSCLC patients treated with gefitinib. EGFR, k-ras, and c-Met mutation analysis was also carried out. A panel of NSCLC cell lines expressing c-Met[pY1003] were treated with gefitinib (0.01–100μ M) alone or in combination with hepatocyte growth factor (40 ng/ml) and the c-Met-agonistic antibody DN-30 (80 μg/ml) for 72 hours in 0.5% FCS medium. Drug interaction between gefitinib and DN-30 was assessed, at a non-constant concentration ratio, using the combination index (CI) method. Results: There was no association between p-Erk, c-Src, E-Cadherin, c-Met[pY1230/1234/1235], and k-ras status and response or survival. EGFR exon 19 deletion and p-Akt nuclear staining were significantly associated with response (P&lt;0.0001; Fisher's exact test) and longer time to progression (TTP) (P=0.007; log-rank test), respectively. High c-Met[pY1003] membrane staining was significantly associated with progressive disease (P=0.019; Fisher's exact test) and shorter TTP (P=0.0416; log-rank test), but not with survival. Multivariate analysis confirmed a significant relationship between c-Met[pY1003] and increased risk of disease progression (HR=2.464, 95% CI 1.293–4.696, P=0.006). No c-Met mutations were found. In vitro, the combination with DN- 30 synergistically (CI&lt;1) enhanced gefitinib-induced growth inhibition in all c-Met[pY1003]-expressing NSCLC cells studied (H460, SW1573, A549 and H292). Conclusions: Activation of c-MET may be a biological marker of intrinsic resistance to gefitinib in NSCLC patients, and combined inhibition of c-Met and EGFR may be a suitable therapeutic approach in patients with activated c-Met[pY1003] tumors. No significant financial relationships to disclose.
Abstract 18726: Thrombin-Inhibiting Nanoparticles Prevent Growth of Fibrin Clots by Inhibiting and Adhering to Clot-Bound Thrombin
Authors: Jacob W Myerson, Rohun U Palekar, Samuel A Wickline
Journal: Circulation (2013)

Introduction: Sustained and localized prevention of clotting via thrombin inhibition could provide efficient care without significant bleeding effects for clinical scenarios including angioplasty, myocardial infarction, microangiopathy, and acute kidney injury. Thrombin-inhibiting perfluorocarbon nanoparticles (PFC NPs) carrying the direct inhibitors bivalirudin (BVR) and PPACK have demonstrated minimal bleeding effects with inhibition of and binding at sites of acute thrombosis in mouse and rabbit models. Here, we demonstrate that thrombin-inhibiting PFC NPs inhibit clot-bound thrombin and seal clots against further growth when exposed to plasma. Methods and Results: In solution, BVR, PPACK, BVR NPs, and PPACK NPs demonstrated concentration-dependent inhibition of Fibrinopeptide A (FPA) production by thrombin, as evaluated by ELISA. FPA ELISA for human plasma exposed to human fibrin clots demonstrated that BVR, PPACK, BVR NPs, and PPACK NPs inhibited thrombin bound in fibrin clots to the same extent as in solution. Fibrin clots were incubated with non-targeted NPs, BVR NPs, or PPACK NPs. 19F MRI at 12T demonstrated that BVR and PPACK NPs specifically bind to clots (figure 1A). Clots treated with BVR, PPACK, BVR NPs, PPACK NPs, or saline, were submerged in human plasma and imaged sequentially over one hour in T2-weighted 1H MRI at 12T. Clots treated with saline, BVR, or PPACK grew in volume when exposed to plasma, adding loose fibrin gel. Clots treated with BVR or PPACK NPs did not grow significantly (figure 1B-E). Conclusions: Thrombin-inhibiting PFC NPs have previously been shown to specifically bind to sites of acute thrombotic injury. Data presented herein show that PPACK and BVR NPs inhibit activity of clot-bound thrombin and specifically bind to fibrin clots derived from human plasma. PPACK and BVR NPs bound on the surface of fibrin clots prevent further clot growth on exposure to plasma.
New therapeutic approach for brain tumors: Intranasal administration of Ras inhibitor perillyl alcohol.
Authors: C. O. Fonseca
Journal: Journal of Clinical Oncology (2010)

2098 Background: Historically, recurrent glioblastoma (GBM) has a median survival of three to six months. Since active Ras contribute to malignant phenotype of these brain tumors we are conducting a phase I/II study to evaluate the antitumoral activity of intranasal administration of a Ras inhibitor, perillyl alcohol (POH), in a 4× daily schedule in patients with recurrent malignant gliomas. Methods: It was included 89 adults with recurrent GBM receiving daily intranasal administration of 440 mg POH and 52 matched GBM patients as historical control group. Results: Six month free survival (stable disease) was 48.3% for POH-treated patients with significant (p = 0.0001) survival advantage compared with historical control untreated group. Median survival rate of secondary GBM was 11.2 months, longer (p = 0.0002) than primary GBM (5.9 months). Age adjustment multivariate analysis showed significant difference (p = 0.0002) in the survival rate between primary and secondary GBM. Patients with tumors localized in deep regions (thalamus, basal ganglia) survived longer (p = 0.0083) than those with tumors in lobar regions. Radiographic improvement and reduction of corticosteroid dosage (36 %) further associated with a delay towards progression. Conclusions: Intranasal administration of POH increased the overall survival of patients with recurrent GBM in comparison with historical controls, but especially patients with secondary GBM and those with tumor localized in deep regions of the brain without clinical evidence of side effects for over a year. No significant financial relationships to disclose.
Introduction and overview of the special issue “Brain imaging and aging”: The new era of neuroimaging in aging research
Authors: Katsutoshi Furukawa, Aiko Ishiki, Naoki Tomita, Yuta Onaka, Haruka Saito, Tomoko Nakamichi, Kazunari Hara, Yusuke Kusano, Masamune Ebara, Yuki Arata, Miku Sakota, Isabelle Miyazawa, Tomoko Totsune, Shoji Okinaga, Nobuyuki Okamura, Yukitsuka Kudo, Hiroyuki Arai
Journal: Ageing Research Reviews (2016)
Primary care management of patients after weight loss surgery
Authors: Michael Moore, James Hopkins, Patrick Wainwright
Journal: BMJ (2016)

#### What you need to know

Bariatric surgery is the most effective treatment for sustained weight loss in people with complex obesity,1 2 and reports from large UK and international registries highlight its overall safety.3 4 The overall mortality of 0.07% and composite complication rate of less than 4% for gastric bypass are similar to those for laparoscopic cholecystectomy.4 After surgery, short hospital stays are the norm (median one day for gastric band and two days for a sleeve gastrectomy or gastric bypass).2 General practitioners thus need to recognise early, as well as late, postoperative complications, monitor long term nutrition, and provide support. General practitioners may also need to assess patients who have had bariatric surgery abroad (sometimes with non-standard procedures), without any follow-up planned. Useful resources for patients include BOSPA (http://www.bospauk.org) and WLSinfo (http://www.wlsinfo.org.uk).

Box 1 describes the three most common procedures performed in the United Kingdom. More than 95% are done laparoscopically.3 5

#### Box 1: Most common bariatric surgery procedures in UK (fig 1⇓)

##### Laparoscopic adjustable gastric banding

An adjustable band is placed around the top of the stomach, forming a small gastric pouch above it. The band is adjusted by injecting saline into a port positioned under the skin to achieve the sensation of fullness after a small amount of food.

##### Roux-en-Y gastric bypass

The most common operation for weight loss in the UK NHS (60%), involving creation of a small gastric pouch by stapling. A classical Roux-en-Y reconstruction is then fashioned with …
CXCL12 promotes glycolytic reprogramming in acute myeloid leukemia cells via the CXCR4/mTOR axis
Authors: M Braun, M Qorraj, M Büttner, F A Klein, D Saul, M Aigner, W Huber, A Mackensen, R Jitschin, D Mougiakakos
Journal: Leukemia (2016)
Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia
Authors: Zizhen Feng, Yuan Yao, Chao Zhou, Fengju Chen, Fangrui Wu, Liping Wei, Wei Liu, Shuo Dong, Michele Redell, Qianxing Mo, Yongcheng Song
Journal: Journal of Hematology & Oncology (2016)

Mixed lineage leukemia (MLL) gene translocations are found in ~75 % infant and 10 % adult acute leukemia, showing a poor prognosis. Lysine-specific demethylase 1 (LSD1) has recently been implicated to be a drug target for this subtype of leukemia. More studies using potent LSD1 inhibitors against MLL-rearranged leukemia are needed. LSD1 inhibitors were examined for their biochemical and biological activities against LSD1 and MLL-rearranged leukemia as well as other cancer cells. Potent LSD1 inhibitors with biochemical IC50 values of 9.8–77 nM were found to strongly inhibit proliferation of MLL-rearranged leukemia cells with EC50 of 10–320 nM, while these compounds are generally non-cytotoxic to several other tumor cells. LSD1 inhibition increased histone H3 lysine 4 (H3K4) methylation, downregulated expression of several leukemia-relevant genes, induced apoptosis and differentiation, and inhibited self-renewal of stem-like leukemia cells. Moreover, LSD1 inhibitors worked synergistically with inhibition of DOT1L, a histone H3 lysine 79 (H3K79) methyltransferase, against MLL-rearranged leukemia. The most potent LSD1 inhibitor showed significant in vivo activity in a systemic mouse model of MLL-rearranged leukemia without overt toxicities. Mechanistically, LSD1 inhibitors caused significant upregulation of several pathways that promote hematopoietic differentiation and apoptosis. LSD1 is a drug target for MLL-rearranged leukemia, and LSD1 inhibitors are potential therapeutics for the malignancy.
Asymptomatic People May Contribute to Dengue Transmission
Authors: M. J. Friedrich
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Progression-free survival as surrogate end point for overall survival in clinical trials of HER2-targeted agents in HER2-positive metastatic breast cancer
Authors: S. Michiels, L. Pugliano, S. Marguet, D. Grun, J. Barinoff, D. Cameron, M. Cobleigh, A. Di Leo, S. Johnston, G. Gasparini, B. Kaufman, M. Marty, V. Nekljudova, S. Paluch-Shimon, F. Penault-Llorca, D. Slamon, C. Vogel, G. von Minckwitz, M. Buyse, M. Piccart
Journal: Annals of Oncology (2016)
Unilateral facial flushing precipitated by eating
Authors: Ella Daniels, Richard Watchorn
Journal: BMJ (2016)

A healthy 7 year old girl born by forceps delivery presented with a lifelong history of unilateral facial flushing precipitated by eating (fig 1). What diagnosis correlates with these clinical findings?



Frey’s syndrome. This occurs after injury (during forceps delivery in this case) to auriculotemporal nerve fibres, which regenerate and erroneously stimulate the sweat glands or blood vessels …
Tumor-necrosis factor impairs CD4+ T cell–mediated immunological control in chronic viral infection
Authors: Marc Beyer, Zeinab Abdullah, Jens M Chemnitz, Daniela Maisel, Jil Sander, Clara Lehmann, Yasser Thabet, Prashant V Shinde, Lisa Schmidleithner, Maren Köhne, Jonel Trebicka, Robert Schierwagen, Andrea Hofmann, Alexey Popov, Karl S Lang, Annette Oxenius, Thorsten Buch, Christian Kurts, Mathias Heikenwalder, Gerd Fätkenheuer, Philipp A Lang, Pia Hartmann, Percy A Knolle, Joachim L Schultze
Journal: Nature Immunology (2016)
Historic Images in Nuclear Medicine
Authors: Søren Hess, Poul Flemming Høilund-Carlsen, Abass Alavi
Journal: Clinical Nuclear Medicine (2014)

In 1976, 2 major molecular imaging events coincidentally took place: Clinical Nuclear Medicine was first published in June, and in August researchers at the Hospital of the University of Pennsylvania created the first images in humans with 18F-FDG. FDG was initially developed as part of an evolution set in motion by fundamental research studies with positron-emitting tracers in the 1950s by Michel Ter-Pegossian and coworkers at the Washington University. Today, Clinical Nuclear Medicine is a valued scientific contributor to the molecular imaging community, and FDG PET is considered the backbone of this evolving and exciting discipline.
Analyzing the Role of MicroRNAs in Schizophrenia in the Context of Common Genetic Risk Variants
Authors: Mads Engel Hauberg, Panos Roussos, Jakob Grove, Anders Dupont Børglum, Manuel Mattheisen
Journal: JAMA Psychiatry (2016)

The recent implication of 108 genomic loci in schizophrenia marked a great advancement in our understanding of the disease. Against the background of its polygenic nature there is a necessity to identify how schizophrenia risk genes interplay. As regulators of gene expression, microRNAs (miRNAs) have repeatedly been implicated in schizophrenia etiology. It is therefore of interest to establish their role in the regulation of schizophrenia risk genes in disease-relevant biological processes.To examine the role of miRNAs in schizophrenia in the context of disease-associated genetic variation.The basis of this study was summary statistics from the largest schizophrenia genome-wide association study meta-analysis to date (83 550 individuals in a meta-analysis of 52 genome-wide association studies) completed in 2014 along with publicly available data for predicted miRNA targets. We examined whether schizophrenia risk genes were more likely to be regulated by miRNA. Further, we used gene set analyses to identify miRNAs that are regulators of schizophrenia risk genes.Results from association tests for miRNA targetomes and related analyses.In line with previous studies, we found that similar to other complex traits, schizophrenia risk genes were more likely to be regulated by miRNAs (P < 2 × 10-16). Further, the gene set analyses revealed several miRNAs regulating schizophrenia risk genes, with the strongest enrichment for targets of miR-9-5p (P = .0056 for enrichment among the top 1% most-associated single-nucleotide polymorphisms, corrected for multiple testing). It is further of note that MIR9-2 is located in a genomic region showing strong evidence for association with schizophrenia (P = 7.1 × 10-8). The second and third strongest gene set signals were seen for the targets of miR-485-5p and miR-137, respectively.This study provides evidence for a role of miR-9-5p in the etiology of schizophrenia. Its implication is of particular interest as the functions of this neurodevelopmental miRNA tie in with established disease biology: it has a regulatory loop with the fragile X mental retardation homologue FXR1 and regulates dopamine D2 receptor density.
Is Estradiol Monitoring Necessary in Women Receiving Ovarian Suppression for Breast Cancer?
Authors: Antroula Papakonstantinou, Theodoros Foukakis, Kenny A. Rodriguez-Wallberg, Jonas Bergh
Journal: Journal of Clinical Oncology (2016)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 36-year-old premenopausal woman had been diagnosed with stage III breast cancer. After an initial biopsy confirmed breast cancer, she underwent mastectomy and axillary node dissection for a left-sided breast cancer, measuring 7 cm. The tumor had lobular histology and was considered grade 2 of 3. Metastatic carcinoma was identified in 10 of 13 axillary nodes. Immunohistochemical studies showed that the tumor was strongly positive for estrogen and progesterone receptor expression and had a Ki-67 score of 15% (&gt; 20% is considered high according to a Swedish quality control study and the St Gallen Expert Consensus). 1 , 2 There was no amplification of the HER2/neu gene. Staging scans were negative for metastatic disease. In the adjuvant setting, she received three cycles of anthracycline-cyclophosphamide combination chemotherapy followed by three cycles of taxane chemotherapy and then locoregional radiotherapy. After completion of chemotherapy, she developed amenorrhea. As adjuvant endocrine therapy, she began monthly goserelin administration to achieve ovarian function suppression (OFS), in combination with the aromatase inhibitor (AI) exemestane. She experienced menopausal symptoms including hot flashes, vaginal dryness, and sexual dysfunction. After two monthly treatments with goserelin and exemestane, a sensitive assay for serum estradiol was checked and returned at 16 pg/mL (61 pmol/L); postmenopausal range for sensitive assay is less than 15 pg/mL (&lt; 50 pmol/L). The patient has now been referred to our unit to discuss further management.
Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells
Authors: Chih-Hang Anthony Tang, Joseph A. Zundell, Sujeewa Ranatunga, Cindy Lin, Yulia Nefedova, Juan R. Del Valle, Chih-Chi Andrew Hu
Journal: Cancer Research (2016)

Abstract Endoplasmic reticulum (ER) stress responses through the IRE-1/XBP-1 pathway are required for the function of STING (TMEM173), an ER-resident transmembrane protein critical for cytoplasmic DNA sensing, IFN production, and cancer control. Here we show that the IRE-1/XBP-1 pathway functions downstream of STING and that STING agonists selectively trigger mitochondria-mediated apoptosis in normal and malignant B cells. Upon stimulation, STING was degraded less efficiently in B cells, implying that prolonged activation of STING can lead to apoptosis. Transient activation of the IRE-1/XBP-1 pathway partially protected agonist-stimulated malignant B cells from undergoing apoptosis. In Eμ-TCL1 mice with chronic lymphocytic leukemia, injection of the STING agonist 3′3′-cGAMP induced apoptosis and tumor regression. Similarly efficacious effects were elicited by 3′3′-cGAMP injection in syngeneic or immunodeficient mice grafted with multiple myeloma. Thus, in addition to their established ability to boost antitumoral immune responses, STING agonists can also directly eradicate malignant B cells. Cancer Res; 76(8); 2137–52. ©2016 AACR.