tbuckley/cabot-search huggingface dataset:
Selinexor, a selective inhibitor of nuclear export (SINE), shows enhanced activity in combination with PD-1/PD-L1 blockade in syngeneic murine models of colon cancer and melanoma
Authors: Matthew R Farren, Reena Shakya, Rebecca Hennessey, Thomas Mace, Jennifer Yang, Omar Elnaggar, Gregory Young, Yosef Landesman, Robert Carlson, Sivan Elloul, Marsha Crochiere, Christin Burd, Gregory Lesinski
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Exportin-1 (XPO1) is a nuclear export protein with >220 cargo proteins, including tumor suppressors and cell cycle modulators. Selinexor is a SINE (Selective Inhibitor of Nuclear Export) compound that has been administered to >900 cancer patients in Phase I and II trials to date,
Continuous Combined Estrogen Plus Progestin and Endometrial Cancer: The Women’s Health Initiative Randomized Trial
Authors: R. T. Chlebowski, G. L. Anderson, G. E. Sarto, R. Haque, C. D. Runowicz, A. K. Aragaki, C. A. Thomson, B. V. Howard, J. Wactawski-Wende, C. Chen, T. E. Rohan, M. S. Simon, S. D. Reed, J. E. Manson
Journal: JNCI Journal of the National Cancer Institute (2015)

Background:While progestin addition to estrogen mitigates endometrial cancer risk, the magnitude of the effect on incidence, specific endometrial cancer histologies, and endometrial cancer mortality remains unsettled. These issues were assessed by analyses after extended follow-up of the Women's Health Initiative (WHI) randomized clinical trial evaluating continuous combined estrogen plus progestin use.
Identification of resolvin D2 receptor mediating resolution of infections and organ protection
Authors: Nan Chiang, Jesmond Dalli, Romain A. Colas, Charles N. Serhan
Journal: The Journal of Experimental Medicine (2015)

Endogenous mechanisms that orchestrate resolution of acute inflammation are essential in host defense and the return to homeostasis. Resolvin (Rv)D2 is a potent immunoresolvent biosynthesized during active resolution that stereoselectively stimulates resolution of acute inflammation. Here, using an unbiased G protein–coupled receptor-β-arrestin–based screening and functional sensing systems, we identified a receptor for RvD2, namely GPR18, that is expressed on human leukocytes, including polymorphonuclear neutrophils (PMN), monocytes, and macrophages (MΦ). In human MΦ, RvD2-stimulated intracellular cyclic AMP was dependent on GPR18. RvD2-stimulated phagocytosis of Escherichia coli and apoptotic PMN (efferocytosis) were enhanced with GPR18 overexpression and significantly reduced by shRNA knockdown. Specific binding of RvD2 to recombinant GPR18 was confirmed using a synthetic 3H-labeled-RvD2. Scatchard analysis gave a Kd of ∼10 nM consistent with RvD2 bioactive concentration range. In both E. coli and Staphylococcus aureus infections, RvD2 limited PMN infiltration, enhanced phagocyte clearance of bacteria, and accelerated resolution. These actions were lost in GPR18-deficient mice. During PMN-mediated second organ injury, RvD2’s protective actions were also significantly diminished in GPR18-deficient mice. Together, these results provide evidence for a novel RvD2–GPR18 resolution axis that stimulates human and mouse phagocyte functions to control bacterial infections and promote organ protection.
Indian girls born in states with sex selection are less malnourished, finds study
Authors: Nigel Hawkes
Journal: BMJ (2015)

Girls born in Indian states where prenatal sex selection is common show better health in childhood than do those born in other states, research published in the Economic Journal has found.

The implication is that simply banning prenatal sex selection might not improve girls’ overall wellbeing, the authors said. Discrimination would still occur, but after birth rather than before it. They think that the better health of girls in these states was because they were born to families who really wanted them.

Sex selection has left some parts of India with a skewed sex ratio. …
Abstract P126: Influence of CIMT as a Motivator for Health Behavior Change in a Heart Health Program
Authors: Elaine Walizer, Marina Vernalis, Randolph Modlin
Journal: Circulation (2014)

Introduction: Carotid intima media thickness (CIMT) ultrasound is a known surrogate marker of atherosclerosis but few studies examine its influence on patient behavior. Motivation and self-efficacy (SE) are known predictors of health behavior change. This randomized, double-blind trial examined 1) use of CIMT images plus associated CVD risk to motivate adherence, and 2) the predictive ability of motivation and SE on adherence change. Methods: Patients with ≥ 2 cardiovascular disease (CVD) risk factors and subclinical atherosclerosis were assigned to either the intervention group [receive results weekly (R-CIMT)] or control group [withhold results (W-CIMT)]. All patients received a 12-week lifestyle program (Mediterranean diet, aerobic exercise, group support). Overall change in adherence from baseline to week 12 was determined using an ANCOVA model where % adherence was a composite measure of diet and exercise adherence. Initial motivation plus exercise and nutrition SE were assessed to determine their predictive ability of adherence in a standard regression model. Results: 166 patients randomized; 161 (R-CIMT n=81; W-CIMT n=80) eligible for intention-to-treat analysis. Patients were middle age (mean age = 54 ± 11 yrs), 62% (100 or 161) women, 48% (77 of 161) black. Baseline group differences: W-CIMT group was younger (52 vs 55 yrs; p=0.05), had a lower systolic blood pressure (120 vs 125; p=0.01), lower % family history of CVD (49 vs 65; p=0.03). In comparing R-CIMT vs W-CIMT groups, no difference was detected in overall % adherence change (16.4 ± 25.6 vs 19.8 ± 25.4; p=0.39). Initial motivation and SE measures were not predictive of change in adherence when added to group assignment (see Table). Conclusions: CIMT evidence of subclinical atherosclerosis increased participant CVD risk awareness but did not translate into actionable healthy behavior changes beyond those in the control group. Neither exercise nor dietary adherence was affected by initial motivation or self-efficacy when added to CIMT risk awareness.
Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation
Authors: Jian Yu, Liguang Chen, Bing Cui, George F. Widhopf, Zhouxin Shen, Rongrong Wu, Ling Zhang, Suping Zhang, Steven P. Briggs, Thomas J. Kipps
Journal: Journal of Clinical Investigation (2015)

Evolutionarily conserved receptor tyrosine kinase–like orphan receptor-1 and -2 (ROR1/2) are considered distinct receptors for Wnt5a and are implicated in noncanonical Wnt signaling in organogenesis and cancer metastasis. We found that Wnt5a enhanced proliferation and migration of chronic lymphocytic leukemia (CLL) cells and that these effects were blocked by the humanized anti-ROR1 mAb cirmtuzumab (UC-961). Treatment of CLL cells with Wnt5a induced ROR1 to oligomerize with ROR2 and recruit guanine exchange factors (GEFs), which activated Rac1 and RhoA; siRNA-mediated silencing of either ROR1 or ROR2 or treatment with UC-961 inhibited these effects. Using the ROR1-deficient CLL cell line MEC1, we demonstrated that ectopic ROR1 expression induced ROR1/ROR2 heterooligomers, which recruited GEFs, and enhanced proliferation, cytokine-directed migration, and engraftment potential of MEC1 cells in immune-deficient mice. Notably, treatment with UC-961 inhibited engraftment of ROR1+ leukemia cells in immune-competent ROR1-transgenic mice. Molecular analysis revealed that the extracellular Kringle domain is required for ROR1/ROR2 heterooligomerization and the cysteine-rich domain or intracellular proline-rich domain is required for Wnt5a-induced recruitment of GEFs to ROR1/ROR2. This study identifies an interaction between ROR1 and ROR2 that is required for Wnt5a signaling that promotes leukemia chemotaxis and proliferation.
Health-related quality of life (HRQL) impact of idelalisib (IDELA) in patients (pts) with relapsed chronic lymphocytic leukemia (CLL): Phase 3 results.
Authors: Paolo Ghia, Susan Mary O'Brien, Peter Hillmen, Richard R. Furman, Steven E. Coutre, Jeff Porter Sharman, Bruce D. Cheson, John M. Pagel, Jacqueline Claudia Barrientos, Andrew David Zelenetz, Thomas J. Kipps, Ian Flinn, Herbert Aaron Eradat, Nicole Lamanna, Michael J. Hallek, Bertrand Coiffier, Andrew Pettitt, Wei Ye, Thomas Michael Jahn, Lynne I. Wagner
Journal: Journal of Clinical Oncology (2014)

7099 Background: Pt-reported outcomes (PROs) evaluated HRQL among CLL pts randomized to IDELA + rituximab (R) (n=110) vs double-blind placebo + R (n=110). Methods: The 44-item Functional Assessment of Cancer Therapy–Leukemia (FACT-Leu) scale measured Physical (PWB), Functional (FWB), Social (SWB) and Emotional (EWB) Well-being and leukemia-specific concerns (LeuS). The FACT-Leu Total score is the sum of subscales; Trial Outcome Index (TOI) is the sum of PWB, FWB and LeuS. Higher scores reflect better HRQL. Repeated measures mixed-effects models assessed change from baseline within and between-arms. Results: IDELA + R was superior for OS: HR=0.28 (0.09, 0.86), p=0.018. In the mixed-effects model analysis, PWB (p=0.015), FWB (p= 0.014), LeuS (p=0.001), TOI (p=0.002), and FACT-Leu Total (p=0.006) scores were significantly higher for IDELA + R. EWB/SWB scores did not change significantly over time. Repeated measure mixed-effects model results are shown in the table. Conclusions: In this frail CLL population, IDELA + R had superior efficacy, clinically significant improvements in HRQL, and superior symptom control occurring by 8 weeks compared to R + placebo. Clinical trial information: NCT01539512. Week PWB FWB LeuS TOI FACT-Leu total 2 -0.1 (0.65) 0.6 (0.80) 0.4 (1.31) 1.3 (2.38) 1.1 (2.96) 4 0.8 (0.66) 1.0 (0.81) 2.5 (1.33) 4.0 (2.41) 4.0 (3.01) 6 0.1 (0.68) 1.0 (0.84) 2.2 (1.37) 2.9 (2.48) 3.9 (3.09) 8 0.6 (0.71) 0.7 (0.87) 3.5 (1.43)* 4.6 (2.57) 5.2 (3.2) 12 1.1 (0.75) 1.5 (0.92) 4.7 (1.51 ** 7.0 (2.72)** 6.5 (3.39) 16 1.9 (0.83)* 1.3 (1.01) 5.3 (1.66)** 8.4 (2.99)** 9.2 (3.72)** 20 1.6 (0.91) 1.4 (1.13) 5.4 (1.85)** 9.0 (3.33)** 9.0 (4.14)** 24 1.8 (1.02) 1.9 (1.26) 5.0 (2.06)** 9.1 (3.69)** 10.0 (4.58)** 30 2.1 (1.14) 2.6 (1.41) 3.0 (2.32) 7.7 (4.13) 9.6 (5.13) 36 1.5 (1.26) 2.8 (1.56) 5.1 (2.54)** 8.2 (4.59) 9.1 (5.69) 42 2.1 (1.57) 2.8 (1.93) 3.9 (3.16) 8.1 (5.57) 9.1 (6.92) 48 3.6 (1.79)** 3.6 (2.20) 5.5 (3.60) 12.4 (6.32)** 13.1 (7.85) * p< 0.05; ** p<0.05 and exceeded established minimally important difference (MID) change scores of 2, 4, 5 and 6 points for PWB, LeuS, TOI and FACT-Leu total, respectively, between arms.
Response of Malignant Mammary Cell Lines to a Growth Inhibitor Partially Purified From Plasma-Derived Human Serum2
Authors: Marie L. Dell'Aquila, Edwin V. Gaffney
Journal: JNCI Journal of the National Cancer Institute (1984)

The specificity and mode of action of a growth inhibitory factor (GIF) isolated from human plasma-derived serum (PDS) was examined with cell lines established from malignant and nonmalignant human tissues. The mammary cell line, MCF-7, was used in previous work to monitor purification of GIF from serum. The current study showed that, of 9 mammary cell lines, 5 (MDA-MB-415, BT-474, MCF-7, T47D, ZR-75) were inhibited by GIF partially purified from a single serum source. The degree of cell line sensitivity to DEAE-purified GIF was directly related to the amount of inhibition observed with unfractionated PDS. The growth of cells established from other malignancies (lung, colon, melanoma, cervix) and normal diploid fibroblasts was not inhibited. MCF-7 cell growth inhibition was fully reversible following 3 days incubation in GIF but was not reversible after 5 days. Inhibition represented a cytostatic effect. Among the macromolecular synthetic events assayed, DNA and RNA remained unaffected by GIF whereas protein synthesis per cell was markedly elevated. Fluorescence-activated cell sorter analysis of treated and control populations showed no differences in G1, S-, and G2 phase distributions.
Proteomic analysis of the airway inflammation in work related asthma
Authors: Hille Suojalehto, Irmeli Lindström, Niina Ahonen, Anne Puustinen
Journal: European Respiratory Journal (2014)

Aim Upper airway reactions in subjects with work related asthma were investigated by proteomic analysis.

Methods Altogether 195 subjects participated the study. Four groups (8 subjects/ group) were formed for 2D-DIGE analysis of nasal brush specimens: healthy controls, asthmatics with symptoms related to protein allergens, isocyanates or welding fumes. Unsupervised clustering (DeCyder 2-D Differential Analysis Software) and protein network (Ingenuity System's database) analyses were performed after gel spot protein identifications by MS/MS (nanoLC-QExactive).

Results On average 2500 spots per DIGE gel were detected; 218 protein spots were picked for identification yielding 125 different proteins. Exposure to protein allergens had the largest effects on the proteome. Hierarchical clustering revealed that subjects with symptoms to protein allergens and isocyanates have similar profiles, whereas subjects exposed to welding fumes differed from these groups. The highly overrepresented functional categories were defense response, protease inhibitor activity, immunity, response to inflammation and wounding, complement activation and cellular response to oxidative stress. Substantial down-regulations of Annexin A1 and A2 proteoforms and oxidative stress defense proteins (GST, SOD and PRXs) are associated with the exposure to protein allergens and isocyanates.

Conclusions Subjects exposed to protein allergens and isocyanates elicit similar nasal proteome responses, even though no IgE-mediated sensitization was detected to isosyanates. Identified changes in protein expressions reveal biological activities related to airway inflammation, oxidation-reduction, tissue matrix turnover and immunity.
Increased Submacular Choroidal Thickness in Active, Isolated, Extramacular Toxoplasmosis
Authors: Clovis Arcoverde Freitas-Neto, Jennifer H. Cao, Juliana L. Oréfice, Rogério A. Costa, Fernando Oréfice, Joan Lee, Abhishek Payal, C. Stephen Foster
Journal: Ophthalmology (2015)
Contrast-Enhanced CMR Overestimates Early Myocardial Infarct Size
Authors: Robert Jablonowski, Henrik Engblom, Mikael Kanski, David Nordlund, Sasha Koul, Jesper van der Pals, Elisabet Englund, Einar Heiberg, David Erlinge, Marcus Carlsson, Håkan Arheden
Journal: JACC. Cardiovascular imaging (2015)

This study aimed to investigate whether an overestimation of infarct size on cardiac magnetic resonance (CMR) versus triphenyltetrazolium chloride (TTC) exists acutely and whether it remains after 7 days in an experimental pig model and to elucidate possible mechanisms. Overestimation of infarct size (IS) on late gadolinium enhancement CMR early after acute myocardial infarction has been debated. Pigs were subjected to 40 min of left anterior descending artery occlusion and 6 h (n = 9) or 7 days (n = 9) reperfusion. IS by in vivo and ex vivo CMR was compared with TTC staining. Extracellular volume (ECV) was obtained from biopsies using technetium 99m diethylenetriamine pentaacetic acid (99mTc-DTPA) and light microscopy. TTC slices were rescanned on CMR enabling slice-by-slice comparison. IS did not differ between in vivo and ex vivo CMR (p = 0.77). IS was overestimated by 27.3% with ex vivo CMR compared with TTC (p = 0.008) acutely with no significant difference at 7 days (p = 0.39). Slice-by-slice comparison showed similar results. A significant decrease in ECV was seen in biopsies of myocardium at risk (MaR) close to the infarct (sometimes referred to as the peri-infarction zone) over 7 days (48.3 ± 4.4% vs. 29.2 ± 2.4%; p = 0.0025). The ECV differed between biopsies of MaR close to the infarct and the rest of the salvaged MaR acutely (48.3 ± 4.4% vs. 32.4 ± 3.2%; p = 0.013) but not at 7 days (29.2 ± 2.4% vs 25.7 ± 1.4%; p = 0.23). CMR overestimates IS compared with TTC acutely but not at 7 days. This difference may be explained by higher ECV in MaR closest to the infarct acutely that decreases during 7 days to the same level as the rest of the salvaged MaR. The increased ECV in the MaR closest to the infarct day 1 could be due to severe edema or an admixture of infarcted and salvaged myocardium (partial volume) or both. Nonetheless, this could not be reproduced at 7 days. These results have implications for timing of magnetic resonance infarct imaging early after acute myocardial infarction.
<i>PARKIN</i>Inactivation Links Parkinson’s Disease to Melanoma
Authors: Hui-Han Hu, Caroline Kannengiesser, Suzanne Lesage, Jocelyne André, Samia Mourah, Laurence Michel, Vincent Descamps, Nicole Basset-Seguin, Martine Bagot, Armand Bensussan, Céleste Lebbé, Lydia Deschamps, Philippe Saiag, Marie-Thérèse Leccia, Brigitte Bressac-de-Paillerets, Amel Tsalamlal, Rajiv Kumar, Stephan Klebe, Bernard Grandchamp, Nathalie Andrieu-Abadie, Luc Thomas, Alexis Brice, Nicolas Dumaz, Nadem Soufir
Journal: JNCI Journal of the National Cancer Institute (2015)

Melanoma incidence is higher in patients affected by Parkinson's disease (PD) and vice versa, but the genetic link shared by both diseases is unknown. As PARK2 is both a tumor suppressor gene and frequently mutated in young onset PD, we evaluated the role of PARK2 in melanoma predisposition and progression.An in-depth PARK2 gene dosage analysis and sequencing was performed on 512 French case patients and 562 healthy control patients, as well as sporadic tumors and melanoma cell lines. The frequency of genetic alterations was compared between case patients and control patients using two-sided Fisher's exact tests and odds ratio (OR) calculations. We used western blotting to determine PARKIN expression in melanocytes and melanoma cell lines and transfection followed by clonogenic assays to evaluate the effect of PARKIN expression on cellular proliferation. All statistical tests were two-sided.Germline PARK2 mutations (including copy number variations, splicing, and putative deleterious missense mutations) were present in 25 case patients but only four control patients (OR = 3.95, 95% confidence interval = 1.34 to 15.75). Copy number variations (CNVs) and loss of heterozygosity were present in 60% and 74%, respectively, of primary tumors. PARKIN protein was expressed in melanocytes but not in most melanoma cell lines, and its expression decreased following melanocyte transformation by oncogenic NRAS. Re-expression of PARKIN in melanoma cell lines resulted in a drastic reduction of cell proliferation and inhibition of PARKIN in melanocytes stimulated their proliferation.Our results show an important role for PARK2 as a tumor suppressor both in melanoma predisposition and progression, which could explain the epidemiological association of these diseases.
Do’s and don’ts in evaluation of endoscopic screening for gastrointestinal cancers
Authors: Michael Bretthauer, Mette Kalager, Hans-Olov Adami
Journal: Endoscopy (2015)

Endoscopic screening for cancers of the esophagus, stomach, and colon has been introduced in many countries of the world. Endoscopic screening has the potential to reduce incidence and mortality of the target diseases, but may also be harmful and have unwanted side effects. Precise estimates of the magnitude of benefits and harms of endoscopic screening for cancer are a prerequisite for informed decision making for or against participation in screening for individuals in the target population. This paper outlines the most common pitfalls in the evaluation of screening and offers some recommendations for future studies.
Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): Update of Cancer and Leukemia Group B (CALGB) protocol 9633
Authors: G. M. Strauss, J. E. Herndon, M. A. Maddaus, D. W. Johnstone, E. A. Johnson, D. M. Watson, D. J. Sugarbaker, R. A. Schilsky, E. E. Vokes, M. R. Green
Journal: Journal of Clinical Oncology (2006)

7007 Background: In 2004, preliminary results of CALGB 9633 demonstrated statistically significant evidence that adjuvant chemotherapy with paclitaxel and carboplatin (PC) improved disease-free (DFS) and overall survival (OS) in resected stage IB NSCLC. Indeed, the study was closed early by the DSMB after a planned interim analysis demonstrated a p value for OS less than a prespecified stopping boundary. However, two larger trials, NCIC-JBR10 and ANITA, have shown significant OS advantages with adjuvant chemo, but failed to demonstrate improved survival in the stage IB subset. This report provides more mature data from CALGB 9633. Methods: InCALGB 9633, stage IB patients (pts) were randomized following resection to paclitaxel 200 mg/m 2 and carboplatin AUC 6 q3wks ×4 cycles or to observation. While initially planned to accrue 500 pts, the accrual rate was &lt;50% of expected. Because slow accrual allowed longer observation times for each pt, the accrual target was reduced to 384 pts. OS is the primary endpoint. The redesigned study had 80% power to detect a hazard ratio (HR) of 0.67 after 150 observed deaths using a 1-tailed logrank test conducted at the 0.05 level of significance. Results: Between 9/15/96 and 11/26/03, 344 pts were randomized. Median follow-up is 54 mo. Demographics and toxicity has been previously reported (JCO Sup, 22:621a, 2004). The current intent-to-treat analysis shows a significant improvement in DFS favoring adjuvant chemo (HR=0.74; 90% 2-sided CI: 0.57–0.96; p=0.027). There is a trend toward improvement in OS that is not significant (HR=0.80; 90% CI: 0.60–1.07; p=0.10). There is, however, a significant advantage in 3-yr survival (79% vs. 70%; p=0.045). Five-yr survival is not different (60% vs. 57%; p=0.32), although median follow-up is &lt;5 yrs and CIs are wide. Continued follow-up is planned since only 131 of 150 deaths required for final analysis have been observed. Conclusions: This updated but “preliminary” analysis no longer shows a significant OS advantage for adjuvant chemotherapy in stage IB NSCLC. However, the re-designed study does not have adequate power to detect small differences in OS that may be clinically significant. Advantages in DFS and 3-yr survival support continued consideration of adjuvant PC in stage IB NSCLC. [Table: see text]
Patient Decision Aids for Discouraging Low-Value Health Care Procedures
Authors: Judith J. Prochaska, Ashley Sanders-Jackson
Journal: JAMA Internal Medicine (2015)

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 Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast 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 Internal Medicine journal