tbuckley/cabot-search huggingface dataset:
Comparing survival of patients with single or multiple primary melanoma in the Netherlands: 1994–2009
Authors: L.M. Pardo, R.J.T. Leest, E. Vries, I. Soerjomataram, T. Nijsten, L.M. Hollestein
Journal: British Journal of Dermatology (2016)

In the Netherlands the incidence of melanoma has been increasing whilst melanoma survival has improved significantly in the last 20 years1. As a result, there is an increasing number of melanoma survivors, who are at increased risk of developing new melanomas2.

There is limited and conflicting literature concerning the survival of patients with multiple melanomas compared with a single melanoma3-5.

This article is protected by copyright. All rights reserved.
Association of Abnormal Postoperative Left Ventricular Global Longitudinal Strain With Outcomes in Severe Aortic Stenosis Following Aortic Valve Replacement
Authors: Rami Kafa, Kenya Kusunose, Andrew L. Goodman, Lars G. Svensson, Joseph F. Sabik, Brian P. Griffin, Milind Y. Desai
Journal: JAMA Cardiology (2016)

This study examines the effect of aortic valve replacement on postoperative left ventricular global longitudinal strain in patients with severe aortic stenosis and preserved left ventricular ejection fraction.
Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients
Authors: Jonathan Chung‐Fai Leung, Thomson Chi‐Wang Loong, Jeremy Lok Wei, Grace Lai‐Hung Wong, Anthony Wing‐Hung Chan, Paul Cheung‐Lung Choi, Sally She‐Ting Shu, Angel Mei‐Ling Chim, Henry Lik‐Yuen Chan, Vincent Wai‐Sun Wong
Journal: Hepatology (2016)

Although nonalcoholic fatty liver disease (NAFLD) is closely linked to obesity, around 10%-20% of nonobese Americans and Asians still develop NAFLD. Data on this special group are limited. We therefore studied the severity and clinical outcomes of nonobese NAFLD patients. Consecutive NAFLD patients who underwent liver biopsy were prospectively recruited. We used the NASH Clinical Research Network system to score the histology. The Asian body mass index cutoff of 25 kg/m2 was used to define nonobese NAFLD. Among 307 recruited NAFLD patients, 72 (23.5%) were nonobese. Compared to obese patients, nonobese patients had lower NAFLD activity score (3.3 ± 1.3 vs. 3.8 ± 1.2; P = 0.019), mainly contributed by steatosis (1.7 ± 0.8 vs. 2.0 ± 0.8; P = 0.014) and presence of hepatocyte ballooning (60.9% vs. 73.4%; P = 0.045). Similarly, nonobese patients had lower fibrosis stage (1.3 ± 1.5 vs. 1.7 ± 1.4; P = 0.004), serum cytokeratin-18 fragments (283 vs. 404 U/L; P < 0.001) and liver stiffness measurement by transient elastography (6.3 vs. 8.6 kilopascals; P < 0.001). By multivariate analysis in nonobese patients, only elevated serum triglyceride level was independently associated with higher NAFLD activity score (adjusted odds ratio [OR], 1.644; P = 0.021), whereas elevated creatinine level was the only factor associated with advanced fibrosis (adjusted OR, 1.044; P = 0.025). After a median follow-up of 49 months, 6 patients died, 2 developed hepatocellular carcinoma, and 1 had liver failure, all of whom were in the obese group. Conclusion: Nonobese NAFLD patients tend to have less-severe disease and may have a better prognosis than obese patients. Hypertriglyceridemia and higher creatinine are the key factors associated with advanced liver disease in nonobese patients. (Hepatology 2017;65:54-64)
Targeting the human double minute (HDM)-2 ubiquitin ligase as a strategy against non-Hodgkin’s lymphoma
Authors: R. J. Jones, L. Leopold, D. Yang, R. Z. Orlowski
Journal: Journal of Clinical Oncology (2007)

14016 Background: The ubiquitin-proteasome pathway has been validated as a target for non-Hodgkin lymphoma (NHL) with the recent approval of bortezomib for mantle cell lymphoma (MCL). In addition to anti-tumor activity, however, proteasome inhibitors have pleiotropic effects, including activation of an anti-apoptotic heat shock protein response, and their use clinically is complicated by toxicities such as peripheral neuropathy. By targeting E3 ubiquitin ligases, which are involved in ubiquitination of only a small subset of cellular proteins, it may be possible to achieve more specific anti-tumor effects with a better therapeutic index. One attractive target is HDM-2, which is responsible for ubiquitination of the p53 tumor suppressor. Methods: To evaluate the therapeutic potential of agents targeting HDM-2, we studied the impact of the small molecule MI-63, an inhibitor of the HDM-2-p53 interaction, in both p53 wild-type and -mutant cell line models. Results: Treatment of wild-type p53 MCL, NHL, and acute lymphocytic leukemia (ALL) cell lines with MI-63 induced a dose- and time- dependent inhibition of proliferation, with an IC50 in the 1.0–5.0 μM range. This was associated with G1/S cell cycle arrest , and apoptosis mediated by caspase-3. MI-63 induced accumulation and phopshorylation of p53 and also enhanced MDM-2 levels. Multiple p53 target genes were induced, including p21Cip1 and p53-upregulated modulator of apoptosis (PUMA), resulting in cleavage of poly-ADP-ribose-polymerase (PARP). Cell lines expressing certain p53 mutants were sensitive to the effects of MI-63, resulting in activation of caspases 3, 8, 9 and apoptosis. Cells without p53 expression were resistant to MI-63, but at higher drug concentrations proliferation was still inhibited, indicating a possible impact on HDM-2-mediated but p53-independent cell death pathways. Combinations of MI-63 with other anti-tumor agents showed enhanced anti-proliferative effects that met the criteria for synergistic interactions. Conclusions: Inhibition of the HDM-2-p53 interaction is a promising approach both by itself, and in combination with currently used chemotherapeutics, against lymphoid malignancies, providing a rational for translation of this agent into the clinic. No significant financial relationships to disclose.
Remissions of Multiple Myeloma during a First-in-Humans Clinical Trial of T Cells Expressing an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor
Authors: Syed Abbas Ali, Victoria Shi, Michael Wang, David Stroncek, Irina Maric, Jennifer N Brudno, Maryalice Stetler-Stevenson, Jeremy J. Rose, Steven Feldman, Brenna Hansen, Frances T. Hakim, Ronald E. Gress, James N. Kochenderfer
Journal: Blood (2015)
Mitotic Poisoning by 4-Aminostilbenes&lt;xref ref-type="fn" rid="fn1"&gt;2&lt;/xref&gt;
Authors: Peo C. Koller
Journal: JNCI Journal of the National Cancer Institute (1955)

Mitotic Poisoning by 4-Aminostilbenes Get access Peo C. Koller Peo C. Koller Chester Beatty Research Institute, Instiute of Cancer Research, Royal Cancer Hospital, London, England Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 15, Issue 5, April 1955, Pages 1237–1265, https://doi.org/10.1093/jnci/15.5.1237 Published: 01 April 1955 Article history Received: 13 August 1954 Published: 01 April 1955
Ultrasound Molecular Imaging of the Breast Cancer Neovasculature using Engineered Fibronectin Scaffold Ligands: A Novel Class of Targeted Contrast Ultrasound Agent
Authors: Lotfi Abou-Elkacem, Katheryne E. Wilson, Sadie M. Johnson, Sayan M. Chowdhury, Sunitha Bachawal, Benjamin J. Hackel, Lu Tian, Jürgen K. Willmann
Journal: Theranostics (2016)

Molecularly-targeted microbubbles (MBs) are increasingly being recognized as promising contrast agents for oncological molecular imaging with ultrasound.With the detection and validation of new molecular imaging targets, novel binding ligands are needed that bind to molecular imaging targets with high affinity and specificity.In this study we assessed a novel class of potentially clinically translatable MBs using an engineered 10 th type III domain of human-fibronectin (MB-FN3VEGFR2) scaffold-ligand to image VEGFR2 on the neovasculature of cancer.The in vitro binding of MB-FN3VEGFR2 to a soluble VEGFR2 was assessed by flow-cytometry (FACS) and binding to VEGFR2-expressing cells was assessed by flow-chamber cell attachment studies under flow shear stress conditions.In vivo binding of MB-FN3VEGFR2 was tested in a transgenic mouse model (FVB/N Tg(MMTV/PyMT634Mul) of breast cancer and control litter mates with normal mammary glands.In vitro FACS and flow-chamber cell attachment studies showed significantly (P<0.01)higher binding to VEGFR2 using MB-FN3VEGFR2 than control agents.In vivo ultrasound molecular imaging (USMI) studies using MB-FN3VEGFR2 demonstrated specific binding to VEGFR2 and was significantly higher (P<0.01) in breast cancer compared to normal breast tissue.Ex vivo immunofluorescence-analysis showed significantly (P<0.01)increased VEGFR2-expression in breast cancer compared to normal mammary tissue.Our results suggest that MBs coupled to FN3-scaffolds can be designed and used for USMI of breast cancer neoangiogenesis.Due to their small size, stability, solubility, the lack of glycosylation and disulfide bonds, FN3-scaffolds can be recombinantly produced with the advantage of generating small, high affinity ligands in a cost efficient way for USMI.
Adaptive and pathogenic aspects of sex-role stereotypes: implications for parenting and psychotherapy
Authors: H E Lerner
Journal: American Journal of Psychiatry (1978)

There has been considerable controversy concerning adaptive versus pathogenic effects of sex-role stereotypes on individual development. The author evaluates both the positive and negative consequences of sex-role stereotypes without regard for any particular sociocultural definition of masculinity or feminity. She hypothesizes that the degree to which sex-role stereotypes are adaptive and facilitative (as opposed to restrictive and pathogenic) is inversely related to the degree to which an individual has consolidated a comfortable and stable gender is identity. Implications for parenting and treatment are elaborated.
Abstract 14315: New Insights Into the Mechanisms of Sepsis: The Role of Proprotein Convertase Subtilisin/kexin Type 9 as a Key Regulator of Pathogen Toxin Clearance
Authors: Elena Topchiy, Yingjin Wang, John Boyd, Keith R Walley
Journal: Circulation (2015)

Background: To prevent severe inflammation during infection, the patient must quickly clear bacterial endotoxins from the circulation before they accumulate and are able to interact with immune cells and vascular endothelium, and induce inflammatory organ failure. Bacterial endotoxins are carried within lipoprotein particles. Thus, one mechanism of action for sepsis treatments could be acceleration of lipoprotein clearance by adipocytes and hepatocytes. Proprotein convertase subtilisin/kexin type 9 (PCSK9) decreases the rate of lipoprotein clearance. We have recently reported that reduced function of PCSK9 improves outcome and prevents cardiovascular complications associated with sepsis. Hypothesis: PCSK9 inhibits LDL associated LPS clearance through hepatic LDLR and VLDL associated LPS clearance through adipose VLDLR. Methods and Results: Using siRNA against the LDLR in HepG2 hepatocytes decreased uptake of fluorescently labeled LPS (fLPS) after 48 hours by 1.50±0.10 fold (n=3, p&lt;0.05). Addition of recombinant PCSK9 in the absence of LDLR did not alter uptake of LPS. We confirmed that hepatic uptake of LPS is exclusively via the LDLR by fluorescent microscopy of ex vivo LPS treated primary hepatocytes isolated from LDLR -/- mice. To address the importance of the LDLR upon clearance of LPS from plasma, we injected fLPS into the portal vein of LDLR-/-, PCSK9-/- and wild type mice (WT). Compared to WT, LDLR-/- mice had 36±13% (n=9, p&lt;0.001) increase in plasma LPS after 1 hour, whereas PCSK9-/- show a significant decrease (28±4%, n=9, p&lt;0.001) in plasma LPS. LDLR-/-, but not PCSK9-/- mice showed 46±7% decrease (n=10, p&lt;0.05) in hepatic uptake. On the other hand, compared to the WT PCSK9-/- mice had 200±35% (n=8, p&lt;0.001) increase in LPS uptake by visceral adipose tissue whereas LDLR-/- had no effect compared to WT mice. To further investigate LPS uptake by adipose tissue we injected flLPS into the tail vein of VLDLR-/- and WT mice. VLDLR-/- mice had 33±6% (n=10, p&lt;0.001) decrease in visceral adipose tissue uptake, with no significant change in hepatic uptake. Conclusions: Expression of hepatic LDLR and adipose VLDLR is mainly regulated by PCSK9 and both play important role in clearing LPS from circulation.
The Peptidome of Behçet's Disease–Associated HLA–B*51:01 Includes Two Subpeptidomes Differentially Shaped by Endoplasmic Reticulum Aminopeptidase 1
Authors: Pablo Guasp, Carlos Alvarez‐Navarro, Patricia Gomez‐Molina, Adrian Martín‐Esteban, Miguel Marcilla, Eilon Barnea, Arie Admon, José A. López de Castro
Journal: Arthritis & Rheumatology (2015)

Objective To characterize the peptidome of the Behçet's disease–associated HLA–B*51:01 allotype as well as the differential features of major peptide subsets and their distinct endoplasmic reticulum aminopeptidase 1 (ERAP‐1)–mediated processing. Methods The endogenous B*51:01‐bound peptidome was characterized from 721.221 transfectant cells, after affinity chromatography and acid extraction, by tandem mass spectrometry. Recombinant ERAP‐1 variants were used to digest synthetic B*51:01 ligands. HLA and transporter associated with antigen processing (TAP) binding affinities of peptide ligands were calculated with well‐established algorithms. ERAP‐1 and ERAP‐2 from 721.221 cells were characterized by genomic sequencing and Western blotting. Results The B*51:01 peptidome consisted of 29.5% octamers, 61.7% nonamers, 4.8% decamers, and 4.0% longer peptides. The major peptide motif consisted of Pro and Ala at position 2, aliphatic/aromatic position 3 residues, and Val and Ile at the C‐terminal position. The ligands with Pro or Ala at position 2 constituted 2 distinct subpeptidomes. Peptides with Pro at position 2 showed higher affinity for B*51:01 and lower affinity for TAP than those with Ala at position 2. Most important, both peptide subsets differed drastically in the susceptibility of their position 1 residues to ERAP‐1, revealing a distinct influence of this enzyme on both subpeptidomes, which may alter their balance, affecting the global affinity of B*51:01–peptide complexes. Conclusion ERAP‐1 has a significant influence on the B*51:01 peptidome and its affinity. This influence is based on very distinct effects on the 2 subpeptidomes, whereby only peptides in the subpeptidome with Ala at position 2 are extensively destroyed, except when their position 1 residues are ERAP‐1 resistant. This pattern provides a mechanism for the epistatic association of ERAP‐1 and B*51:01 in Behçet's disease.
The FinXX trial: Safety results in 600 patients (pts) randomized to either docetaxel (T) followed by cyclophosphamide (C) + epirubicin (E) + 5-FU (F) (CEF) or T + capecitabine (X) followed by CEX as adjuvant therapy for early breast cancer (BC)
Authors: H. Joensuu, A. Hemminki, R. Huovinen, M. Tanner, R. Kokko, R. Asola, A. Jukkola-Vuorinen, S. Lahtela, H. Lindman, P. Kellokumpu-Lehtinen
Journal: Journal of Clinical Oncology (2007)

11035 Background: Adding X to T extends survival in pts with metastatic BC. The primary objective of the FinXX trial is to compare recurrence-free survival with XT→CEX vs T→CEF as adjuvant therapy in pts with early stage BC. Secondary objectives were comparison of safety and overall survival. Methods: Between Jan 2004 and May 2005, 600 of a planned 1,500 pts were randomized to receive T x 3 → CEF x 3 (T 80 mg/m 2 d1 → C 600 mg/m 2 d1, E 75 mg/m 2 d1, F 600 mg/m 2 d1) or TX x 3 → CEX x 3 (T 60 mg/m 2 d1 + X 900 mg/m 2 bid d1–15 → C 600 mg/m 2 d1, E 75 mg/m 2 d1, X 900 mg/m 2 bid d1–15) q3 wks. Results: Grade 3/4 toxicities (CTCAE, v3) in &gt;5% of pts are shown below. 62 pts required G-CSF. Nos. of cycles with G-CSF were: T 34; XT 15; CEF 17; CEX 15. Adverse events (AEs) led to interruption of T in 7 pts (2%) and XT in 50 pts (16%). Median dose intensities at cycle 3 were T: 95%; XT: 84/97%; CEF: 98/97/98%; CEX: 98/98/84%. T dose reductions of =20% in cycle 3 were needed in 18% and 8% of pts receiving T and XT, respectively. 4 pts died during treatment: pulmonary embolism (n=1) with T and suicide, sudden death and colitis/sepsis (each n=1) with XT. Conclusions: XT→CEX is generally well tolerated. Treatment interruptions were more common with XT→CEX, but were effective in reducing development of grade 3/4 AEs. Neutropenic infections were less frequent with XT vs T and infrequent with XT, CEF and CEX. Rates of grade 3/4 diarrhea and HFS were acceptable with XT and minimal with CEX. Accrual is nearly complete; efficacy data are expected in 2009. [Table: see text] [Table: see text]
Prevalence and Outcomes of Anemia and Hematinic Deficiencies in Patients With Chronic Heart Failure
Authors: John G. F. Cleland, Jufen Zhang, Pierpaolo Pellicori, Ben Dicken, Riet Dierckx, Ahmad Shoaib, Kenneth Wong, Alan Rigby, Kevin Goode, Andrew L. Clark
Journal: JAMA Cardiology (2016)

<h3>Importance</h3> Detailed information on the prevalence, associations, and consequences of anemia and iron deficiency in epidemiologically representative outpatients with chronic heart failure (HF) is lacking. <h3>Objective</h3> To investigate the epidemiology of anemia and iron deficiency in a broad range of patients referred to a cardiology clinic with suspected HF. <h3>Design, Setting, and Participants</h3> We collected clinical data, including hemoglobin, serum iron, transferrin saturation, and serum ferritin concentrations, on consecutive patients referred with suspected HF to a single outpatient clinic serving a local community from January 1, 2001, through December 31, 2010. Follow-up data were censored on December 13, 2011. Patients underwent phenotyping by echocardiography and plasma N-terminal pro–brain natriuretic peptide measurement and were followed for up to 10 years. <h3>Main Outcome Measures</h3> Prevalences of anemia and iron deficiency and their interrelationship, all-cause mortality, and cardiovascular mortality. <h3>Results</h3> Of 4456 patients enrolled in the study, the median (interquartile range) age was 73 (65-79) years, 2696 (60.5%) were men, and 1791 (40.2%) had left ventricular systolic dysfunction (LVSD). Of those without LVSD, plasma N-terminal pro–brain natriuretic peptide concentration was greater than 400 pg/mL in 1172 (26.3%), less than 400 pg/mL in 841 (18.9%), and not measured in 652 (14.6%). Overall, 1237 patients (27.8%) had anemia, with a higher prevalence (987 [33.3%]) in patients who met the criteria for HF with or without LVSD. Depending on the definition applied, iron deficiency was present in 270 (43.2%) to 425 (68.0%) of patients with and 260 (14.7%) to 624 (35.3%) of patients without anemia. Lower hemoglobin (hazard ratio 0.92; 95% CI, 0.89-0.95;<i>P</i>&lt; .001) and serum iron (hazard ratio 0.98; 95% CI, 0.97-0.99;<i>P</i>= .007) concentrations were independently associated with higher all-cause and cardiovascular mortality in multivariable analyses. <h3>Conclusions and Relevance</h3> Anemia is common in patients with HF and often associated with iron deficiency. Both anemia and iron deficiency are associated with an increase in all-cause and cardiovascular mortality and might both be therapeutic targets in this population.
Development Of a Disease Specific Quality Of Life Questionnaire For Patients With Aplastic Anemia and/Or Paroxysmal Nocturnal Hemoglobinuria (QLQ-AA/PNH)
Authors: Martha Groth, Susanne Singer, Cathrin Niedeggen, Andrea Petermann-Meyer, Alexander Roeth, Hubert Schrezenmeier, Britta Höchsmann, Tim H. Brümmendorf, Jens Panse
Journal: Blood (2013)
Evidence-Based Versus Personalized Prostate Cancer Screening: Using Baseline Prostate-Specific Antigen Measurements to Individualize Screening
Authors: Stacy Loeb
Journal: Journal of Clinical Oncology (2016)

the need for prostate biopsy. These trials include the US Prostate, Lung, Colorectal, andOvarian Cancer ScreeningTrialthatrandomly assigned 76,685 men age 55 to 74 years to annual screening versus usual care and recommended aprostate biopsy for aPSA.4ng/mL or suspicious digital rectal examination. This study found no difference in prostate cancer mortality between the screening and usual care groups. 9 However, these results are not surprising, given that approximately 90% of men in the usual care arm had PSA testing (more than in the screening arm). 10 Therefore, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial is not informative regarding the efficacy of screening versus no screening. The European Randomized Study of Screening for Prostate Cancer randomly assigned 162,388 menage55 to69yearstoscreening and control arms. 11 This study reported a significant reduction in metastatic disease and prostate cancer death with PSA screening at 2to 4-year intervals, primarily using a PSA threshold of 3 ng/mL. The Goteborg population-based randomized trial in Sweden randomly assigned 20,000 men to PSA screening every 2 years beginning at age 50 years and found the greatest overall reduction in prostate cancer mortality reported to date. 12 This may imply that more frequent screening in younger men accounts for the better results observed in this population compared with the rest of the European trial. Indeed, a recent study comparing men age 50 to 54 years from this trial to age-matched Swedish men from the pre-PSA era found that screening in this age group was associated with a large reduction in metastatic disease (incidence rate ratio, 0.43; 95% CI, 0.22 to 0.79) and prostate cancer death (incidence rate ratio, 0.29; 95% CI, 0.11 to 0.67). 13 However, since the time of these randomized trials, numerous studies suggest offering screening at an even earlier age. In a large prospective US screening study, our group reported that men with a baseline PSA level in their 40s above the age-specific median of 0.7 ng/mL had a significantly higher risk of future prostate cancer diagnosis and aggressive disease. 14 Conversely, among men with a baseline PSA level below the age-specific median in their 40s, only 0.3% reached the PSAthreshold for biopsy of 2.5 ng/mLwithin the next 5 years, and only one was diagnosed with prostate cancer before age 50 years. 15
The Joint Commission looks to the future
Authors: D. S. O'Leary
Journal: JAMA (1987)

Since early in this century, the medical profession has provided firm leadership in promoting high-quality patient care in the nation's hospitals. During the past two decades, this effort has steadily spread to involve a wide spectrum of organized health care settings. In this issue of the<i>Journal</i>, Roberts and colleagues<sup>1</sup>describe the historical evolution of the Joint Commission on Accreditation of Hospitals and its role in effecting this professional mandate. While the achievements of the Joint Commission are note-worthy, there is little basis for self-satisfaction in the current health care climate. In today's altered environment for patient care, resource limitation, changing and sometimes perverse reimbursement incentives, the professional liability crisis, and increased competition for patients have led to the elevation of quality of care to the status of a major public policy issue in this country. Public and professional concerns about the potential adverse impacts of these forces on