tbuckley/cabot-search huggingface dataset:
A phase I dose-escalation and pharmacokinetic (PK) study of a novel spectrum selective kinase inhibitor, XL647, in patients with advanced solid malignancies (ASM)
Authors: H. A. Wakelee, A. A. Adjei, J. Halsey, J. L. Lensing, J. D. Dugay, L. J. Hanson, J. M. Reid, J. R. Piens, B. I. Sikic
Journal: Journal of Clinical Oncology (2006)

3044 Background: XL647 is an orally bioavailable small molecule inhibitor of multiple receptor tyrosine kinases involved in tumor cell growth, angiogenesis, and metastasis, including EGFR (erbB1), erbB2, VEGFR2/KDR, and EphB4. Methods: Patients (pts) with ASM were enrolled in successive cohorts to receive XL647 orally as a single dose on day 1 with PK sampling, followed by 5 continuous daily doses starting on day 4 with additional PK sampling. Pts then continued to receive XL647 for 5 consecutive days, followed by a break, with cycles repeating every 14 days. Tumor imaging was conducted at baseline, after the first 3 or 4 cycles, and then after every 4 cycles. Pts were allowed to stay on-study in the absence of unacceptable toxicity until evidence of disease progression. Results: A total of 37 pts have been treated across 9 dose levels to date: 0.06, 0.12, 0.19, 0.28, 0.39, 0.78, 1.56, 3.12, 4.68, and 7.0 mg/kg. One pt at 3.12 mg/kg had a dose limiting toxicity (DLT) of asymptomatic QTc prolongation on electrocardiogram, resulting in expansion of that cohort. The first two pts who received 7.0 mg/kg experienced DLTs of grade 3 diarrhea, requiring dose reduction. Both pts from the 7.0 mg/kg cohort tolerated 4.68 mg/kg well. Expansion of the 4.68 mg/kg cohort to 6 pts occurred without further DLTs and this is considered the maximum tolerated dose (MTD). One serious adverse event, grade 4 pulmonary embolism, was considered possibly related to study treatment in a pt dosed at 0.28 mg/kg. PK analysis indicates that XL647 shows approximately dose-proportional exposure, a mean time to maximal concentration (tmax) of 6–9 hours and an elimination half-life of 50–70 hours. To date, 1 pt (non-small cell lung cancer [NSCLC]) from cohort 1 had a partial response and 7 others (NSCLC [2], chordoma [2], adenoid cystic carcinoma, adrenocortical carcinoma, colorectal) have had prolonged stable disease (&gt;3 months). Conclusions: XL647 has been well tolerated. An MTD of 4.68 mg/kg oral dosing for 5 consecutive days every 14 days has been established. Exploration of additional dosing schedules is ongoing, including continuous daily dosing. [Table: see text]
Use of Vaccinia Virus Smallpox Vaccine in Laboratory and Health Care Personnel at Risk for Occupational Exposure to Orthopoxviruses — Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2015
Authors: Brett W. Petersen, Tiara J. Harms, Mary G. Reynolds, Lee H. Harrison
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

On June 25, 2015, the Advisory Committee on Immunization Practices (ACIP) recommended routine vaccination with live smallpox (vaccinia) vaccine (ACAM2000) for laboratory personnel who directly handle 1) cultures or 2) animals contaminated or infected with replication-competent vaccinia virus, recombinant vaccinia viruses derived from replication-competent vaccinia strains (i.e., those that are capable of causing clinical infection and producing infectious virus in humans), or other orthopoxviruses that infect humans (e.g., monkeypox, cowpox, and variola) (recommendation category: A, evidence type 2 [Box]). Health care personnel (e.g., physicians and nurses) who currently treat or anticipate treating patients with vaccinia virus infections and whose contact with replication-competent vaccinia viruses is limited to contaminated materials (e.g., dressings) and persons administering ACAM2000 smallpox vaccine who adhere to appropriate infection prevention measures can be offered vaccination with ACAM2000 (recommendation category: B, evidence type 2 [Box]). These revised recommendations update the previous ACIP recommendations for nonemergency use of vaccinia virus smallpox vaccine for laboratory and health care personnel at risk for occupational exposure to orthopoxviruses (1). Since 2001, when the previous ACIP recommendations were developed, ACAM2000 has replaced Dryvax as the only smallpox vaccine licensed by the U.S. Food and Drug Administration (FDA) and available for use in the United States (2). These recommendations contain information on ACAM2000 and its use in laboratory and health care personnel at risk for occupational exposure to orthopoxviruses.
Sinus Node Responses to Various Factors The Effects of pH, Antiarrhythmic Drugs, Stimulation Sites, etc. : Symposium on Sinus Node Function and Its Abnormality
Authors: Iwao Yamaguchi, Hirokazu Hayakawa
Journal: Circulation (1980)

The role of two divisions of autonomic nervous system was investigated and the variations of the sinus cycle length after autonomic blockade (the intrinsic cycle length, ICL) and the sinus node recovery time (SNRT) were tested in 26 patients with symptomatic sinus bradycardia. Three groups of patients were recognized from the responses of sinus rate to autonomic blocking with propranolol followed by atropine, comparing with the healthy controls. In 9 patients (group A) with normal responses to cholinergic and beta-adrenergic blockades, reactions to the autonomic stimulations with barorefiexe and Valsalva maneuver and to isoproterenol were all normal. Reduced automaticity of sinus node and normal autonomic regulation are conceivable in these patients. In some of this group, sinoatrial disease was evident from abnormal ICL. In other I 7 patients with reduced response to atropine, reactions to the autonomic stimulations and to isoproterenol were blunted. With propranolol, enhanced prolongation of sinus cycle length was observed in 7 patients (group BI) and normal or reduced response in 10 (group BII). Severe clinical symptoms were more prevalent in group BI and BII patients than group A and SNRT and ICL was abnormal in most of Group B. Sinoatrial disease is evident in these patients, and reduced cholinergic control and partial beta-adrenergic compensation in group BI and disturbed regulation by both of cholinergic and beta-adrenergic system in group BII are suggested. Difference between ICL at 4 pm and O am was more than 200 msec in 8 and exceeded 300 msec in 5 of I 7 patients whose ICL were determined twice. Measurement of SNRT was repeated more than three times at O, 6 and 10 am and 4 and 10 pm in I 8 patients. SNRT fluctuated more than 2 seconds in 10 and the ratio of the longest SNRT to the shortest was 2 or more in 7 patients. We conclude that different and altered autonomic mechanisms exist in the patients with the sick sinus syndrome. Sinus node automaticity free from autonomic influence is fluctuating and the clinical parameters of sinus node function are non-reproducible in some of the sick sinus patients.
Irinotecan versus best supportive care (BSC) as second-line therapy in gastric cancer: A randomized phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)
Authors: P. C. Thuss-Patience, A. Kretzschmar, T. Deist, A. Hinke, D. Bichev, B. Lebedinzew, G. Schumacher, B. Gebauer, V. Maier, P. Reichardt
Journal: Journal of Clinical Oncology (2009)

4540 Background: Up to now the value of 2 nd -line therapy for metastatic gastric cancer is unclear. So far there are no randomized phase III data comparing 2 nd -line chemotherapy to BSC. Irinotecan has proven activity in 1 st -line therapy. In this randomized phase III study we compared irinotecan to BSC to evaluate the value of 2 nd - line chemotherapy for gastric cancer. Methods: Prospective multicenter randomized phase III study, open label. Eligibility: Metastatic or locally advanced gastro-esophageal junction or gastric adenocarcinoma. Objective tumor progession (PD) within 6 months after 1 st - line chemotherapy. ECOG PS 0–2. Statistics: Primary endpoint: Overall survival (OS). Hypothesis: H1: OS(Irinotecan)&gt;OS(BSC). Calculated number of pts needed (power 80%, alpha error 5%): 60 pts per arm. Stratification for a) PD less versus (vs) more than 3 months after 1 st line chemotherapy, b) ECOG PS 0/1 vs 2. Treatment: Arm A: Irinotecan 250mg/m 2 q3w (1 st cycle) to be increased to 350 mg/m 2 , depending on toxicity. Arm B: BSC Results: Between Oct 2002 and Dec 2006 40 pts were randomized. The study was closed prematurely due to poor accrual. Arm A:21 pts, arm B 19 pts. Median age A: 58 yrs (43–73), B: 55 yrs (35–72); PD less vs more than 3 months after 1 st -line chemotherapy: A: 18 / 3, B: 17 / 2pts. ECOG PS 0/1 vs 2: A: 17/ 4, B: 14/ 5pts. Pre-treatment with cisplatin: A: 21, B:19 pts. Arm A: 68 cycles administered in 21 pts. Toxicity: (main CTC grade 3/ 4): Nausea 1 pt, vomiting 1 pt, diarrhoea: 5 pts, neutropenic fever: 2 pts, data incomplete 6 pts. In 37% of 19 evaluable pts irinotecan dose was escalated to 350mg/m 2 . Response (19 pts evaluable): No objective responses, SD 58%, PD 42%. Improvement of tumor related symptoms: 44% of pts in arm A, 5% in arm B. Survival: (evaluable pts arm A 21, arm B 18): median survival arm A: 123 days (95%CI 95–216), arm B 72.5 days (95%CI 41–106); OS: HR=2.85 (95%CI 1.41–5.79), Logrank test (two-sided): p=0.0027. Conclusions: To our knowledge this is the first randomized phase III study investigating 2 nd - line chemotherapy in gastric cancer. Irinotecan as 2 nd -line chemotherapy significantly prolongs overall survival compared to BSC. 2 nd -line chemotherapy can now be considered as a proven option in gastric cancer. [Table: see text]
Association of Erp29 Genetic Polymorphism with Breast Cancer Risk and Prognosis
Authors: G.J. Lourenço, C.B.M. Oliveira, C. Cardoso-Filho, L.S. Bossi, C. Oliveira, L.O.Z. Sarian, M.S. Costa-Gurgel, C.S.P. Lima
Journal: Annals of Oncology (2014)
Fundamentals of magnetic resonance imaging
Authors: H.G. Jacobson
Journal: JAMA (1987)

Medical imaging methods traditionally have depicted variations in one or two simple physical variables in tissues, e.g., physical density, atomic number, acoustic velocity, and radioactivity concentration. Magnetic resonance images reveal differences in several variables, with the prominent variables reflecting complex energy transfer mechanisms that occur at the atomic and nuclear levels. Furthermore, the relative contributions of these variables to the image are readily altered by changing the pulse sequence and the pulsing times within the sequence. These changes dramatically affect the image and its characterization of normal anatomy. Hence, magnetic resonance images and their contributions to diagnostic medicine can be properly appreciated only if one has some understanding of the procedures by which they are produced.
RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation
Authors: Jayanth Kumar Palanichamy, Tiffany M. Tran, Jonathan M. Howard, Jorge R. Contreras, Thilini R. Fernando, Timothy Sterne-Weiler, Sol Katzman, Masoud Toloue, Weihong Yan, Giuseppe Basso, Martina Pigazzi, Jeremy R. Sanford, Dinesh S. Rao
Journal: Journal of Clinical Investigation (2016)

Posttranscriptional control of gene expression is important for defining both normal and pathological cellular phenotypes. In vitro, RNA-binding proteins (RBPs) have recently been shown to play important roles in posttranscriptional regulation; however, the contribution of RBPs to cell specification is not well understood. Here, we determined that the RBP insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is specifically overexpressed in mixed lineage leukemia-rearranged (MLL-rearranged) B-acute lymphoblastic leukemia (B-ALL), which constitutes a subtype of this malignancy associated with poor prognosis and high risk of relapse. IGF2BP3 was required for the survival of B-ALL cell lines, as knockdown led to decreased proliferation and increased apoptosis. Enforced expression of IGF2BP3 provided murine BM cells with a strong survival advantage, led to proliferation of hematopoietic stem and progenitor cells, and skewed hematopoietic development to the B cell/myeloid lineage. Cross-link immunoprecipitation and high throughput sequencing uncovered the IGF2BP3-regulated transcriptome, which includes oncogenes MYC and CDK6 as direct targets. IGF2BP3 regulated transcripts via targeting elements within 3' untranslated regions (3'UTR), and enforced IGF2BP3 expression in mice resulted in enhanced expression of Myc and Cdk6 in BM. Together, our data suggest that IGF2BP3-mediated targeting of oncogenic transcripts may represent a critical pathogenetic mechanism in MLL-rearranged B-ALL and support IGF2BP3 and its cognate RNA-binding partners as potential therapeutic targets in this disease.
Clinical Evaluation and Cone Alterations in Choroideremia
Authors: Nicolas Nabholz, Marie-Céline Lorenzini, Béatrice Bocquet, Annie Lacroux, Valérie Faugère, Anne-Françoise Roux, Vasiliki Kalatzis, Isabelle Meunier, Christian P. Hamel
Journal: Ophthalmology (2016)
Cardiac Fibrosis
Authors: Joshua G. Travers, Fadia A. Kamal, Jeffrey Robbins, Katherine E. Yutzey, Burns C. Blaxall
Journal: Circulation Research (2016)

Myocardial fibrosis is a significant global health problem associated with nearly all forms of heart disease. Cardiac fibroblasts comprise an essential cell type in the heart that is responsible for the homeostasis of the extracellular matrix; however, upon injury, these cells transform to a myofibroblast phenotype and contribute to cardiac fibrosis. This remodeling involves pathological changes that include chamber dilation, cardiomyocyte hypertrophy and apoptosis, and ultimately leads to the progression to heart failure. Despite the critical importance of fibrosis in cardiovascular disease, our limited understanding of the cardiac fibroblast impedes the development of potential therapies that effectively target this cell type and its pathological contribution to disease progression. This review summarizes current knowledge regarding the origins and roles of fibroblasts, mediators and signaling pathways known to influence fibroblast function after myocardial injury, as well as novel therapeutic strategies under investigation to attenuate cardiac fibrosis.
Predicting the 10-year risk of hip and major osteoporotic fracture in rheumatoid arthritis and in the general population: an independent validation and update of UK FRAX without bone mineral density
Authors: Corinne Klop, Frank de Vries, Johannes W J Bijlsma, Hubert G M Leufkens, Paco M J Welsing
Journal: Annals of the Rheumatic Diseases (2016)

Objectives FRAX incorporates rheumatoid arthritis (RA) as a dichotomous predictor for predicting the 10-year risk of hip and major osteoporotic fracture (MOF). However, fracture risk may deviate with disease severity, duration or treatment. Aims were to validate, and if needed to update, UK FRAX for patients with RA and to compare predictive performance with the general population (GP). Methods Cohort study within UK Clinical Practice Research Datalink (CPRD) (RA: n=11 582, GP: n=38 755), also linked to hospital admissions for hip fracture (CPRD-Hospital Episode Statistics, HES) (RA: n=7221, GP: n=24 227). Predictive performance of UK FRAX without bone mineral density was assessed by discrimination and calibration. Updating methods included recalibration and extension. Differences in predictive performance were assessed by the C-statistic and Net Reclassification Improvement (NRI) using the UK National Osteoporosis Guideline Group intervention thresholds. Results UK FRAX significantly overestimated fracture risk in patients with RA, both for MOF (mean predicted vs observed 10-year risk: 13.3% vs 8.4%) and hip fracture (CPRD: 5.5% vs 3.1%, CPRD-HES: 5.5% vs 4.1%). Calibration was good for hip fracture in the GP (CPRD-HES: 2.7% vs 2.4%). Discrimination was good for hip fracture (RA: 0.78, GP: 0.83) and moderate for MOF (RA: 0.69, GP: 0.71). Extension of the recalibrated UK FRAX using CPRD-HES with duration of RA disease, glucocorticoids (&gt;7.5 mg/day) and secondary osteoporosis did not improve the NRI (0.01, 95% CI −0.04 to 0.05) or C-statistic (0.78). Conclusions UK FRAX overestimated fracture risk in RA, but performed well for hip fracture in the GP after linkage to hospitalisations. Extension of the recalibrated UK FRAX did not improve predictive performance.
Meeting the Organ Donor
Authors: Louise Wen
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 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
Long-term follow-up of paclitaxel and topotecan plus rituximab (TTR) for patients with relapsed and refractory B-cell non-Hodgkin’s lymphoma
Authors: G. K. Suh, P. McLaughlin, J. E. Romaguera, F. B. Hagemeister, B. Pro, I. F. Khouri, F. Samaniego, M. A. Rodriguez, L. E. Fayad, L. Feng, A. Younes
Journal: Journal of Clinical Oncology (2008)

8599 Background: The goal of salvage chemotherapy in patients with relapsed or primary refractory B-cell non- Hodgkin’s lymphoma (NHL) is to optimize remission status prior to autologous stem cell transplant (ASCT). This study evaluated the efficacy and safety of Paclitaxel (Taxol [T]) and Topotecan plus Rituximab (TTR) as a novel salvage therapy in NHL patients. Methods: 72 eligible patients (pts) with up to 2 previous treatments not containing rituximab, taxane, or topotecan were enrolled. Rituximab 375mg/m2 IV was given on day 1, paclitaxel 200mg/m2 IV on day 2, and topotecan 1mg/m2/day IV on days 2–6 in 3-week cycles with G-CSF support. After 2 to 6 cycles, responding pts were offered ASCT. This single-arm phase II study assessed 70 pts for treatment response and toxicity. 32 (45%) pts were primary refractory, and 20 pts (28%) had received prior platinum-based regimen. Primary endpoints were overall survival (OS) and event- free survival (EFS). Results: Of 70 evaluable pts, 31 (44%) received ASCT. 21 pts (30%) responded but did not receive ASCT. Non-responders were offered additional salvage therapy as tolerated. Initial intent-to-treat analysis was performed in 2003. Median follow- up for current analysis is 70 months (mos). Overall response rate was 70% with 42% complete response (CR). Response was 45% and 80% for pts with and without prior platinum therapy, respectively. EFS for all pts was 16.1 mos (95%CI 7.4, 29.2). EFS was 3.5 mos (CI 2.8, 5.9) for all pts in non-ASCT group; 7.4 mos (CI 5.0, 30.3) for responders. EFS for ASCT group was not reached (NR). OS for all pts was 38.7 mos (CI 19.5, NR). OS was 13.6 mos (CI 10.3, 21.9) for all pts in non-ASCT group; 21.7 mos (CI 13.6, NR) for responders. OS for ASCT group was not reached. The differences in EFS and OS between ASCT and non-ASCT groups were statistically significant (p<0.0001). Grade 3/4 toxicities were neutropenia (62%), thrombocytopenia (53%), and neutropenic fever (30%). Conclusions: Salvage therapy with TTR had significant response rate, even among pts who failed prior platinum-based therapy. This regimen when combined with ASCT is highly effective, as median EFS and OS were not reached in a median follow-up of 70 mos. Hematologic suppression was the most significant toxicity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Berlex Oncology, Millennium Cogenix, Co-Med Communications, Genentech™ BioOncology, Health Sciences Communications, Physicians Education Resource Bayer, Berlex Oncology, BioGen IDEC, Bristol-Myers Squibb, Genentech™ BioOncology, GlaxoSmithKline, Integrated Therapeutics, Millennium, OSI Oncology, Schering-Plough
Anatomy and Surgery of Hernia
Journal: JAMA (1968)

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
IL15 Agonists Overcome the Immunosuppressive Effects of MEK Inhibitors
Authors: Michael J. Allegrezza, Melanie R. Rutkowski, Tom L. Stephen, Nikolaos Svoronos, Amelia J. Tesone, Alfredo Perales-Puchalt, Jenny M. Nguyen, Fahmida Sarmin, Mee R. Sheen, Emily K. Jeng, Julia Tchou, Hing C. Wong, Steven N. Fiering, Jose R. Conejo-Garcia
Journal: Cancer Research (2016)

Abstract Many signal transduction inhibitors are being developed for cancer therapy target pathways that are also important for the proper function of antitumor lymphocytes, possibly weakening their therapeutic effects. Here we show that most inhibitors targeting multiple signaling pathways have especially strong negative effects on T-cell activation at their active doses on cancer cells. In particular, we found that recently approved MEK inhibitors displayed potent suppressive effects on T cells in vitro. However, these effects could be attenuated by certain cytokines that can be administered to cancer patients. Among them, clinically available IL15 superagonists, which can activate PI3K selectively in T lymphocytes, synergized with MEK inhibitors in vivo to elicit potent and durable antitumor responses, including by a vaccine-like effect that generated resistance to tumor rechallenge. Our work identifies a clinically actionable approach to overcome the T-cell–suppressive effects of MEK inhibitors and illustrates how to reconcile the deficiencies of signal transduction inhibitors, which impede desired immunologic effects in vivo. Cancer Res; 76(9); 2561–72. ©2016 AACR.