tbuckley/cabot-search huggingface dataset:
Combined regimen of Irinotecan (Iri), Fluorouracil (FU), Leucovorin (LV) with Oxaliplatin (Oxa), FU/LV, in elderly patients with metastatic colorectal cancer (MCRC) treated in second line therapy
Authors: H. G. Botto
Journal: Journal of Clinical Oncology (2006)

13583 Background: In previous trials in elderly patients (pts) with MCRC, treated with Iri-FU/LV combination in first line therapy (1 st line therapy), we reported: Overall Response Rate (ORR) of 38%, (ASCO 343,2004) and with Oxa-FU/LV combination in 1 st line therapy: ORR of 34%, (ASCO 3743,2005). The purpose of this trial was to study the feasibility, toxicity and response, with the combined regimen of Iri-FU/LV with Oxa-FU/LV in elderly pts with MCRC, treated in second line therapy (2 nd line therapy), all of them recurrent after the 1 st line therapies mentioned before. Methods: Sixteen pts with MCRC; M/9, F/7; PS: 0=9, 1=5, 2=2; median age 74,5 years (65–84 y), with normal hematological, cardiac and renal functions. Sites of disease: hepatic, 9 pts; locoregional, 7 pts. After the employment of Iri-FU/LV combination in 9 pts, and Oxa-FU/LV combination in 7pts, they have all shown recurrent disease. Treatment: Iri, 100 mg/m 2 , FU 350 mg/m 2 , LV 20 mg/m 2 , iv, day 1º and Oxa 75 mg/m 2 and increases dosis of FU 550 mg/m 2 , LV 50 mg/m 2 , iv, day 8°, every 28 days. Pts evaluation was performed every two cycles, the median number of cycles was 5 (range 3–8), the total number of cycles was 84. All pts were examined for response, toxicity and survival. Results: PR: 31.2%; SD: 31.2%; PD: 37.5%. ORR: 31.2% (hepatic metastasis 19% and locoregional disease 12.2%). Toxicity: Gr 2/3, neutropenia 43.7%; anemia 37.5%; thrombocitopenia 12.5%; diarrea 12.5%; paresthesia 6.25%. The median time to progression was 6 months (range 2–12 m), the median survival time was 14 months (range 7–25 m). Conclusions: The combined regimen of Iri-FU/LV with Oxa-FU/LV, following this shedule in second line therapy, in elderly pts with recurrent MCRC proved feasibility, good activity, acceptable toxicity and good survival time. No significant financial relationships to disclose.
Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration
Authors: Amit U. Joshi, Paras S. Minhas, Shane A. Liddelow, Bereketeab Haileselassie, Katrin I. Andreasson, Gerald W. Dorn, Daria Mochly-Rosen
Journal: Nature Neuroscience (2019)
Abstract 16422: Defining New Strategies for Therapy in Ampk Mutations and Hypertrophic Cardiomyopathy: Implications for Personalised Medicine in Inherited Cardiac Disorders
Authors: Rameen Shakur, Robert Lowe, richard white, derek stemple, dalia Bensadek, Angus Lamond, Ludovic Vallier
Journal: Circulation (2018)

Introduction: AMPK cardiomyopathy is an autosomal dominant inherited metabolic heart muscle disease often characterized by left ventricular hypertrophy (LVH), progressive conducting abnormalities a...
Clinical phenotypes and outcomes of precapillary pulmonary hypertension of sickle cell disease
Authors: Laurent Savale, Anoosha Habibi, François Lionnet, Bernard Maitre, Vincent Cottin, Xavier Jais, Ari Chaouat, Elise Artaud-Macari, Matthieu Canuet, Grégoire Prevot, Christelle Chantalat-Auger, David Montani, Olivier Sitbon, Fréderic Galacteros, Gérald Simonneau, Florence Parent, Pablo Bartolucci, Marc Humbert
Journal: European Respiratory Journal (2019)

Rationale Precapillary pulmonary hypertension (PH) is a devastating complication of sickle cell disease (SCD). Little is known about the influence of the SCD genotype on PH characteristics. Objectives To describe clinical phenotypes and outcomes of precapillary PH due to SCD according to disease genotype. Methods A nationwide multicentre retrospective study including all patients with SCD-related precapillary PH from the French PH Registry was conducted. Clinical characteristics and outcomes according to SCD genotype were analysed. Results 58 consecutive SCD patients with precapillary PH were identified, of whom 41 had homozygous for haemoglobin S (SS) SCD, three had S-β 0 thalassaemia (S-β 0 thal) and 14 had haemoglobin SC disease (SC). Compared to SC patients, SS/S-β 0 thal patients were characterised by lower 6-min walk distance (p=0.01) and lower pulmonary vascular resistance (p=0.04). Mismatched segmental perfusion defects on lung scintigraphy were detected in 85% of SC patients and 9% of SS/S-β 0 thal patients, respectively, and 50% of SS/S-β 0 thal patients had heterogeneous lung perfusion without segmental defects. After PH diagnosis, 31 patients (53%) received medical therapies approved for pulmonary arterial hypertension, and chronic red blood cell exchange was initiated in 23 patients (40%). Four patients were managed for chronic thromboembolic PH by pulmonary endarterectomy (n=1) or balloon pulmonary angioplasty (n=3). Overall survival was 91%, 80% and 60% at 1, 3 and 5 years, respectively, without influence of genotype on prognosis. Conclusions Patients with precapillary PH related to SCD have a poor prognosis. Thrombotic lesions appear as a major component of PH related to SCD, more frequently in SC patients.
Composite mesh design for delivery of autologous mesenchymal stem cells influences mesh integration, exposure and biocompatibility in an ovine model of pelvic organ prolapse
Authors: S. Emmerson, S. Mukherjee, J. Melendez-Munoz, F. Cousins, S.L. Edwards, P. Karjalainen, M. Ng, K.S. Tan, S. Darzi, K. Bhakoo, A. Rosamilia, J.A. Werkmeister, C.E. Gargett
Journal: Biomaterials (2019)
The Genome of the Endangered Dryas Monkey Provides New Insights into the Evolutionary History of the Vervets
Authors: Tom van der Valk, Catalina M Gonda, Henri Silegowa, Sandra Almanza, Itzel Sifuentes-Romero, Terese B Hart, John A Hart, Kate M Detwiler, Katerina Guschanski
Journal: Molecular Biology and Evolution (2019)

Genomic data can be a powerful tool for inferring ecology, behavior, and conservation needs of highly elusive species, particularly, when other sources of information are hard to come by. Here, we focus on the Dryas monkey (Cercopithecus dryas), an endangered primate endemic to the Congo Basin with cryptic behavior and possibly <250 remaining adult individuals. Using whole-genome sequencing data, we show that the Dryas monkey represents a sister lineage to the vervets (Chlorocebus sp.) and has diverged from them ∼1.4 Ma with additional bidirectional gene flow ∼750,000-∼500,000 years ago that has likely involved the crossing of the Congo River. Together with evidence of gene flow across the Congo River in bonobos and okapis, our results suggest that the fluvial topology of the Congo River might have been more dynamic than previously recognized. Despite the presence of several homozygous loss-of-function mutations in genes associated with sperm mobility and immunity, we find high genetic diversity and low levels of inbreeding and genetic load in the studied Dryas monkey individual. This suggests that the current population carries sufficient genetic variability for long-term survival and might be larger than currently recognized. We thus provide an example of how genomic data can directly improve our understanding of highly elusive species.
Modification of primary amines to higher order amines reduces in vivo hematological and immunotoxicity of cationic nanocarriers through TLR4 and complement pathways
Authors: Randall Toy, Pallab Pradhan, Vijayeetha Ramesh, Nelson C. Di Paolo, Blake Lash, Jiaying Liu, Emmeline L. Blanchard, Christopher J. Pinelli, Philip J. Santangelo, Dmitry M. Shayakhmetov, Krishnendu Roy
Journal: Biomaterials (2019)
Incorporating Intimate Partner Violence Interventions in Nurse Home Visitation Programs—Reply
Authors: Susan M. Jack, David L. Olds, Harriet L. MacMillan
Journal: JAMA (2019)

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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
Targeting interferon signaling and CTLA-4 enhance the therapeutic efficacy of anti-PD-1 immunotherapy in preclinical model of HPV+ oral cancer
Authors: Stephanie Dorta-Estremera, Venkatesh L. Hegde, Ravaen B. Slay, Rachel Sun, Ananta V. Yanamandra, Courtney Nicholas, Sita Nookala, Gloria Sierra, Michael A. Curran, K. Jagannadha Sastry
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> The US is experiencing an epidemic of HPV<sup>+</sup> oropharyngeal cancers (OPC), the rates and burden of which now exceed that for cervical cancer. Immunotherapy targeting programmed death 1 (PD-1) on tumor-infiltrating lymphocytes and/or its ligand PD-L1 on tumor cells, which was effective in several cancers has however, showed efficacy in only less than 15% of patients. <h3>Methods</h3> We used a preclinical HPV<sup>+</sup> oral tumor model, mEER, consisting of mouse tonsil derived epithelial cells expressing HPV-16 E6 and E7 genes, along with the H-ras oncogene to test strategies for enhancing the efficacy of anti-PD-1 therapy. <h3>Results</h3> Monotherapy with PD-1 blocking antibody was ineffective against flank-implanted tumors, but induced regression in 54% of mice bearing orthotopic tongue tumors that correlated with higher CD8 T cell responses. Since the CD8<sup>+</sup> T cells derived from tongue tumors also showed high levels of the immune checkpoint inhibitory receptor CTLA-4, we tested combination immunotherapy targeting both CTLA-4 and PD-1 together and observed 93.3% survival of mice bearing tumors in the tongue for the duration of our 100-day study. Protective immunity correlated with a significant decrease in immunosuppressive lymphoid and myeloid populations within the tumor microenvironment. Consistent with the reported capacity of interferon-driven PD-L1/PD-1 pathway induction to serve as a biomarker of response to PD-1 blockade, we observed elevated interferon signaling and significantly higher levels of PD-1/PD-L1 in tongue-implanted mEER tumors compared to those growing on the flank correlating with their preferential responsiveness to PD-1 blockade. More importantly, in a pseudometastasic mouse model bearing both flank and tongue tumors to represent metastatic disease, delivery of Stimulator of Interferon Induced Genes (STING) agonist into the flank tumors combined with systemic treatment with α-PD-1 and α-CTLA-4 antibodies resulted in sustained tumor regression in 71% of mice. In this case, productive abscopal anti-tumor immunity was associated with robust increases in the ratios of cytotoxic CD8<sup>+</sup> T cells (CTL) versus regulatory T cells (Treg) and versus functional myeloid-derived suppressor cells (MDSC). <h3>Conclusions</h3> These results support combining α-PD-1 therapy with induction of IFN-α/β signaling via provision of STING agonist and/or through CTLA-4 blockade as potential treatment option for HNSCC patients, especially, those not responding to α-PD-1 monotherapy.
Therapeutic Targeting of TGFβ Ligands in Glioblastoma Using Novel Antisense Oligonucleotides Reduces the Growth of Experimental Gliomas
Authors: Alexandros Papachristodoulou, Manuela Silginer, Michael Weller, Hannah Schneider, Kathy Hasenbach, Michel Janicot, Patrick Roth
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Transforming growth factor (TGF)-β is expressed at high levels by glioma cells and contributes to the malignant phenotype of glioblastoma. However, its therapeutic targeting remains challenging. Here, we examined an alternative therapeutic approach of TGFβ inhibition using two novel phosphorothioate-locked nucleic acid (LNA)-modified antisense oligonucleotide gapmers, ISTH1047 and ISTH0047, which specifically target TGFβ1 and TGFβ2. Experimental Design: We characterized the effects of ISTH1047 and ISTH0047 on TGFβ1/2 expression, downstream signaling and growth of human LN-308, LN-229, and ZH-161 cells as well as murine SMA-560 glioma cells in vitro. Furthermore, we assessed their target inhibition and effects on survival in orthotopic xenogeneic and syngeneic rodent glioma models in vivo. Results: Both antisense oligonucleotides specifically silenced their corresponding target and abrogated SMAD2 phosphorylation in several glioma cell lines. Moreover, inhibition of TGFβ1 or TGFβ2 expression by ISTH1047 or ISTH0047 reduced the migration and invasiveness of LN-308 and SMA-560 glioma cells. Systemic antisense oligonucleotide administration to glioma-bearing mice suppressed TGFβ1 or TGFβ2 mRNA expression as well as the expression of the downstream target PAI-1 in orthotopic gliomas. Glioma-bearing mice had significantly prolonged survival upon systemic treatment with ISTH1047 or ISTH0047, which was associated with a reduction of intratumoral SMAD2 phosphorylation and, in a fully immunocompetent model, with increased immune cell infiltration. Conclusions: Targeting TGFβ expression with the novel LNA antisense oligonucleotides ISTH1047 or ISTH0047 results in strong antiglioma activity in vitro and in vivo, which may represent a promising approach to be examined in human patients with glioma.
Abstract 249: Improving Care for in-Hospital Cardiac Arrest Patients — The Rock Study
Authors: David Fredman, Leif Svensson, Mårten Rosenqvist
Journal: Circulation (2010)

Background: Cardiac arrest is a race against time. Every minute counts. Guidelines stipulate defibrillation within 3 minutes in the hospital setting. In 2004 the average time between cardiac arrest...
Antimalarial pantothenamide metabolites target acetyl–coenzyme A biosynthesis in <i>Plasmodium falciparum</i>
Authors: Joost Schalkwijk, Erik L. Allman, Patrick A. M. Jansen, Laura E. de Vries, Julie M. J. Verhoef, Suzanne Jackowski, Peter N. M. Botman, Christien A. Beuckens-Schortinghuis, Karin M. J. Koolen, Judith M. Bolscher, Martijn W. Vos, Karen Miller, Stacy A. Reeves, Helmi Pett, Graham Trevitt, Sergio Wittlin, Christian Scheurer, Sibylle Sax, Christoph Fischli, Iñigo Angulo-Barturen, Mariá Belén Jiménez-Diaz, Gabrielle Josling, Taco W. A. Kooij, Roger Bonnert, Brice Campo, Richard H. Blaauw, Floris P. J. T. Rutjes, Robert W. Sauerwein, Manuel Llinás, Pedro H. H. Hermkens, Koen J. Dechering
Journal: Science Translational Medicine (2019)

Malaria eradication is critically dependent on new therapeutics that target resistant Plasmodium parasites and block transmission of the disease. Here, we report that pantothenamide bioisosteres were active against blood-stage Plasmodium falciparum parasites and also blocked transmission of sexual stages to the mosquito vector. These compounds were resistant to degradation by serum pantetheinases, showed favorable pharmacokinetic properties, and cleared parasites in a humanized mouse model of P. falciparum infection. Metabolomics revealed that coenzyme A biosynthetic enzymes converted pantothenamides into coenzyme A analogs that interfered with parasite acetyl-coenzyme A anabolism. Resistant parasites generated in vitro showed mutations in acetyl-coenzyme A synthetase and acyl-coenzyme A synthetase 11. Introduction and reversion of these mutations in P. falciparum using CRISPR-Cas9 gene editing confirmed the roles of these enzymes in the sensitivity of the malaria parasites to pantothenamides. These pantothenamide compounds with a new mode of action may have potential as drugs against malaria parasites.
Abstract 16237: Hypertrophic Cardiomyopathy in the Geisinger Population: Genetic Architecture and Phenotype
Authors: Prashant Patel, Sarath B Krishnamurthy, Sowmya Pinnamaneni, Amy Kolinovsky, Syed Hussain, Jeffrey Ruhl, H L Kirchner, David J Carey, David H Ledbetter, Frederick E Dewey, Michael F Murray, Marc S Williams, Raghu P Metpally, Vishal C Mehra
Journal: Circulation (2017)

Background: Hypertrophic cardiomyopathy (HCM) is traditionally thought to have a prevalence of 0.2% in the American population. However, the prevalence of genetic variants associated with the disea...
Pathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability Homeostasis
Authors: Peter Dongmin Sohn, Cindy Tzu-Ling Huang, Rui Yan, Li Fan, Tara E. Tracy, Carolina M. Camargo, Kelly M. Montgomery, Taylor Arhar, Sue-Ann Mok, Rebecca Freilich, Justin Baik, Manni He, Shiaoching Gong, Erik D. Roberson, Celeste M. Karch, Jason E. Gestwicki, Ke Xu, Kenneth S. Kosik, Li Gan
Journal: Neuron (2019)
Of What Remains
Authors: Athalia Rachel Pyzer
Journal: Annals of Internal Medicine (2019)

On Being a Doctor17 September 2019Of What RemainsAthalia Rachel Pyzer, MD, PhDAthalia Rachel Pyzer, MD, PhDThe University of Chicago Medicine, Chicago, Illinois (A.R.P.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M19-1606 Audio Reading - “Of What Remains” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “Of What Remains” by Athalia Rachel Pyzer, MD, PhD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail “The patient was an army surgeon in his youth, you know,” the resident dolefully offered as I turned away, her afterthought lingering in the air behind me. Pausing in the doorway of the hospital room, I hovered, wondering whether she expected an answer. I must have been a medical student at the time, sent to draw the blood sample. Enough time has passed that I couldn't tell you the service I was working on or even the name of the hospital; however, if you gave me a number 2 pencil and a glass of courage, I could draw you his ... Author, Article, and Disclosure InformationAffiliations: The University of Chicago Medicine, Chicago, Illinois (A.R.P.)Corresponding Author: Athalia Rachel Pyzer, MD, PhD, The University of Chicago Medicine, 5841 South Maryland Avenue, Chicago, IL 60637; e-mail, athalia.[email protected]edu. PreviousarticleNextarticle Advertisement Audio Reading - “Of What Remains” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “Of What Remains” by Athalia Rachel Pyzer, MD, PhD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 17 September 2019Volume 171, Issue 6Page: 437KeywordsBloodDementiaMemoryNeuronsPotassiumRibsSurgeonsUreaVeinsWalking ePublished: 17 September 2019 Issue Published: 17 September 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Mitochondrial ATP-Sensitive Potassium Channels Inhibit Apoptosis Induced by Oxidative Stress in Cardiac Cells
Authors: MasaharuAkao, AndreasOhler, BrianO’Rourke, EduardoMarbán
Journal: Circulation Research (2001)

Abstract—Mitochondria can either enhance or suppress cell death. Cytochrome c release from mitochondria and depolarization of the mitochondrial membrane potential (ΔΨ) are crucial events in triggering apoptosis. In contrast, activation of mitochondrial ATP-sensitive potassium (mitoKATP) channels prevents lethal ischemic injury in vivo, implicating these channels as key players in the process of ischemic preconditioning. We probed the relationship between mitoKATP channels and apoptosis in cultured neonatal rat cardiac ventricular myocytes. Incubation with 200 μmol/L hydrogen peroxide induced TUNEL positivity, cytochrome c translocation, caspase-3 activation, poly(ADP-ribose) polymerase cleavage, and dissipation of ΔΨ. Pharmacological opening of mitoKATP channels by diazoxide (100 μmol/L) preserved mitochondrial integrity and suppressed all markers of apoptosis. Diazoxide prevented ΔΨ depolarization in a concentration-dependent manner (EC50 ≈40 μmol/L, with saturation by 100 μmol/L), as shown by both flow ...
Localization of Mutant Calreticulin in the Golgi Apparatus Is Required for Its Oncogenic Capacity
Authors: Nami Masubuchi, Marito Araki, Erina Hayashi, Yinjie Yang, Misa Imai, Yoshihiko Kihara, Yoshihisa Mizukami, Yumi Hironaka, Hiraku Takei, Yoko Edahiro, Akimichi Ohsaka, Norio Komatsu
Journal: Blood (2017)
Promoting physical activity to patients
Authors: Christine Haseler, Ranulf Crooke, Tobias Haseler
Journal: BMJ (2019)

### What you need to know

The health benefits of physical activity are proved and wide ranging, exceeding that of any drug. The Academy of Medical Royal Colleges has described physical activity as a “miracle cure.”1 Meanwhile, inactivity contributes to as many deaths in the UK as smoking2 and is the fourth leading risk factor for mortality worldwide.3 More than 25% of adults in the UK are inactive, doing less than 30 minutes of physical activity a week.2 Clinicians are uniquely placed to help their patients to become more physically active, and even a brief discussion within a consultation can lead to change.

This article offers a practical guide to help clinicians discuss physical activity within a consultation, including how to address concerns patients may have about becoming more active and how to help them overcome barriers to change.6

### What do we mean by “physical activity”?

Although exercise and physical activity are sometimes used interchangeably, they have distinct meanings. In practice, although exercise may be a more familiar term to people, it can also be off putting to some: you don’t need to be doing exercise to be active.

Physical activity, defined by the World Health Organization, is “any body movement performed by skeletal muscles that expends energy,” whereas exercise is “physical activity with the primary purpose of improving or maintaining physical fitness or performance.7” Moderate intensity physical activity “requires a moderate amount of effort and noticeably accelerates the heart rate,5” leads to faster breathing and feeling warmer, …