tbuckley/cabot-search huggingface dataset:
Use of a mathematical model of serum-free light chain decline to identify a kinetic predictive marker of survival in patients with newly diagnosed multiple myeloma treated with bortezomib plus dexamethasone and autologous stem cell transplantation.
Authors: Heiblig Mael, Lachenal Florence, Olivier Colomban, Lionel Karlin, Benoit You
Journal: Journal of Clinical Oncology (2013)

e19515 Background: According to 2011 International Myeloma Working Group recommandations, serum-free light chain (sFLC) assessment is indicated in non secretory Multiple Myeloma (MM). sFLC monitoring is now routinely used for diagnosis and early response treatment assessment but its actual prognosis values regarding survival is not clear. Based on mathematical modeling, this study aimed at evaluate the predictive value on progression free survival (PFS) of modeled sFLC kinetics during frontline treatment. Methods: Model-based analysis of sFLC kinetics from 28 newly diagnosed MM patients treated at a single institution with 4 cycles of bortezomib and dexamethasone plus autologous stem cell transplantation (ASCT). MONOLIX program was used to fit Box-Cox transformed [sFLC] concentration-time profiles to the equation : [sFLC(t) = [sFLC1*exp(-KDEC1*t)]+[sFLC2*exp(-KDEC2*t)]+[sFLC3*exp(KPROD*t)] ] where KDEC1 and KDEC2 represent the decline rates of sFLC while KPROD is the involved light chain production rate observed after the end of the decrease. The predictive values of the modeled kinetic parameters , regarding PFS were tested using logistic regression, and survival analysis. Results: Median PFS was 17.9 months . Three modeled kinetic parameters categorized by their medians had strong predictive values regarding PFS using univariate tests: sFLC decline rate KDEC1 (median PFS = 38.6 months if KDEC1 ≥ median vs 14 months if KDEC1 &lt; median, P=0.01); light chain production rate KPROD (median PFS = 24.9 months if KPROD &lt; median vs 7.8 months if KPROD ≥ median, p=0.01); and initial SFLC production slope sFLC3 (median PFS = 24.9 months if sFLC3 &lt; median vs 14 months if sFLC3 ≥ median, p=0.03). The same kinetic model for M-protein decline was not significant (p=0.53). Using multivariate analysis, the only remaining significant predictive factor of PFS was: KDEC 1 (HR, 0.11; 95% CI 0.01-0.88; P=0.04). Conclusions: The modeled kinetic parameter of sFLC decline KDEC1, may be easily used as an early predictor of survival after frontline ASCT in MM. Validation in larger studies is warranted.
Abstract 18445: Embryonic Origins of Vascular Progenitors in the Adult Murine Aorta
Authors: Sarah K Steinbach, Martha H Carruthers, David Smyth, Freda D Miller, Clinton S Robbins, Mansoor Husain
Journal: Circulation (2013)

Background: The vasculature is derived from many different sources during embryonic development, including neural crest, and mesoderm of splanchnic, pharyngeal and somitic origin. Vascular smooth muscle cells (VSMC) of the aorta are similarly derived from several embryonic sources, however the developmental and phenotypic heterogeneity of their progenitors is poorly understood. Methods &amp; Results: Using specialized Cre mice which irreversibly mark cells of specific embryonic origin, we isolated distinct subsets of progenitors from the aorta that are derived from neural crest (Wnt1), somite (Myf5) and another (Brachyury; T) mesoderm source. Intriguingly, a population of lineage-marked cells that express high levels of the reporter tdTomato (tdT-hi) is uniquely expressed in the aorta, and not found in blood, bone marrow or spleen. In Myf5- and T-marked lineages, this tdT-hi population gave rise to clonally-derived spheres that differentiated into VSMC, adipocytes, S100β-positive neural cell and macrophage in vitro. Consistent with the observed progenitor activity of the tdT-hi population, a subset of these cells co-express Sox2 and Sca1, known adult stem/progenitor cell markers. Further evidence of progenitor activity was demonstrated in an in vitro CFU assay where tdT-hi cells gave rise to Mac3+Ly6C+ macrophage and Ly6G+ neutrophils. As experimental cell culture is prone to artifact, and differentiated cell types may not be represented in vivo, we conducted complementary analyses in mice. Leukocytes such as macrophage, B-cells and T-cells from Myf5-Cre mice were found to be lineage-marked cells with lower levels of tdT expression (tdT-lo), suggesting derivation from somitic mesoderm and differentiation from the tdT-hi aortic progenitor. Indeed, somite-derived leukocytes were enriched over 6-fold in the arch of the aorta vs. the blood, bone marrow and spleen of these mice. Summary: These data support the existence of an aorta-resident Myf5 lineage-marked (i.e. somitic mesoderm-derived) progenitor capable of contributing to both VSMC and blood compartments. How these neural crest vs. somite- and other mesoderm-derived aortic-resident progenitors and their progeny participate in vascular pathogenesis is not yet known.
Abstract 16529: Molecular and Functional Characterization of an Ultra Rare Frame-shift Mutation in CALR-encoded Calreticulin as a Probable Long QT Syndrome-susceptibility Variant
Authors: Christopher M Gibbs
Journal: Circulation (2015)

Introduction: Long QT syndrome (LQTS) is the most common, autosomal dominant, sudden death predisposing cardiac channelopathy. Although 17 LQTS genes have been discovered, 20% of LQTS remains genetically elusive. Whole exome sequencing (WES) followed by a strategic, knowledge-based variant filtration approach may elucidate novel LQTS-susceptibility genes. Methods: A LQTS family with multiple sudden deaths was referred for genetic evaluation. The index case was a 21-year-old male who died suddenly but had a pre-mortem ECG with marked QT prolongation. The decedent’s mother also showed QT prolongation. Only paraffin embedded tissue (PET) was available from the decedent, so the mother’s DNA was analyzed by WES. Following WES, variants were filtered using Ingenuity Variant Analysis (IVA) software. Only non-synonymous variants with a quality score &gt;20, read-depth &gt;10, and absent in ExAC were considered. Further filtration was performed using IVA’s biological context pathway analysis set to capture genes most likely related to LQTS. Electrophysiological studies were performed on the variant with highest probability of pathogenicity. Results: Following WES and variant filtration, only a CALR frame-shift variant (R376fs/10) remained as a probable LQTS mutation. No radical CALR variants reside in ExAC’s 60,000+ exomes. The mutation was confirmed in the decedent’s PET-derived DNA. CALR-encoded calreticulin (CRT) is a Ca2+ binding chaperone of the endoplasmic reticulum. Both knockout and over-expression of CRT exert extreme effects on the murine cardiac system, including sudden death. Recently, CRT has been linked with altered L-type calcium (LTCC) ion channel activity. Wild-type (WT)-CALR reduced Cav1.2 peak current density by 43.1%. In contrast, CALR-R376fs/10 mutation reversed this Cav1.2 inhibition and caused a net gain-of-function of Cav1.2 channel current compared with CALR-WT co-expression (64.2% increase). No pathogenic variants in CALR were identified in 25 additional, unrelated, genetically elusive LQTS cases. Conclusion: Mutations in CALR-encoded calreticulin may be a rare cause of autosomal dominant LQTS precipitated in part by an accentuation of the LTCC, thereby potentially mimicking CACNA1C-mediated LQTS.
Spiraling Out of Control
Authors: Sara Mixter, R. Sedighi Manesh, Sara C. Keller, Laura Platt, Harry Hollander
Journal: New England Journal of Medicine (2017)

A 22-year-old man presented to the emergency department with a 5-day history of myalgias, cough, dyspnea, nonbilious emesis, and nonbloody diarrhea.
An appeal against the item's death sentence: Accounting for diagnostic data patterns with an item-based model of visual search
Authors: Rani Moran, Heinrich René Liesefeld, Marius Usher, Hermann J. Müller
Journal: Behavioral and Brain Sciences (2017)

Abstract We show that our item-based model, competitive guided search, accounts for the empirical patterns that Hulleman &amp; Olivers (H&amp;O) invoke against item-based models, and we highlight recently reported diagnostic data that challenge their approach. We advise against “forsaking the item” unless and until a full fixation-based model is shown to be superior to extant item-based models.
Abstract 12468: Follow-up Coronary Angiography at Chronic Phase is Beneficial in Patients With Acute Myocardial Infarction
Authors: Naoki Abe, Takumi Higuma, Syunta Tateyama, Tomohide Endeo, Kenji Hanada, Syuji Shibutani, Hiroaki Yokoyama, Masahiro Yamada, Hirofumi Tomita, Hiroyuki Hanada, Tomohiro Osanai, Ken Okumura
Journal: Circulation (2013)

Backgrounds:  Follow-up coronary angiography (FCA) after acute myocardial infarction (AMI) may be useful in detecting asymptomatic coronary artery lesions. It is unknown whether routine FCA is beneficial in patients with AMI.   Methods and Results:  Five hundred and eighty-one patients with AMI undergoing percutaneous coronary intervention (PCI) at the acute phase and who survived for >one year after AMI were included in this study. Routine FCA was performed in 469 (81%) within one year after AMI, and not in the other 112 (19%). We examined the subsequent mortality after one year between FCA and non-FCA group (mean follow-up period, 3.8 years). Severity of AMI expressed by the anterior AMI, left ventricular ejection fraction, number of vessels with significant stenotic lesion, and maximal creatine kinase level were similar between the two groups. There was no procedure-related complication in FCA group. Patients in non-FCA group were significantly older than those in FCA (72±13 vs. 64±12; p≤0.001). Estimated glomerular filtration rate (eGFR (ml/min/1.73m2)) level was significantly lower in non-FCA group than in FCA (65±27 vs. 76±43; p≤0.05). In 153 of FCA patients (33%), PCI was done against new or restenotic lesion after FCA. Kaplan-Meier analysis showed that all-cause mortality after one year was significantly lower in FCA group than in non-FCA (4.9% vs. 19.8%; p≤0.001 by Log-rank test). Cardiac mortality after one year was also significantly lower in FCA group than in non-FCA (0.9% vs. 4.5%; p=0.004 by Log-rank test). AMI recurred in 2.1% in FCA group and in 3.6% in non-FCA after one year (p=0.499 by Log-rank test). Multivariate analysis adjusted for age and eGFR revealed that FCA was associated with reduced all-cause mortality after one year (HR, 0.371; 95%CI, 0.197-0.703; p=0.003). However, FCA was not associated necessarily reduced with cardiac mortality after one year (HR, 0.280; 95%CI, 0.064-1.188; p=0.083).   Conclusions:  FCA at chronic phase is independently associated with better long-term prognosis and therefore seems to be beneficial in patients with AMI. Its cost effectiveness needs to be determined.
Risk of Severe Hypoglycemia in Type 1 Diabetes Over 30 Years of Follow-up in the DCCT/EDIC Study
Authors: Rose A. Gubitosi-Klug, Barbara H. Braffett, Neil H. White, Robert S. Sherwin, F. John Service, John M. Lachin, William V. Tamborlane
Journal: Diabetes Care (2017)

OBJECTIVE During the Diabetes Control and Complications Trial (DCCT), intensive diabetes therapy achieving a mean HbA1c of ∼7% was associated with a threefold increase in the rate of severe hypoglycemia (defined as requiring assistance) compared with conventional diabetes therapy with a mean HbA1c of 9% (61.2 vs. 18.7 per 100 patient-years). After ∼30 years of follow-up, we investigated the rates of severe hypoglycemia in the DCCT/Epidemiology of Diabetes Inverventions and Complications (EDIC) cohort. RESEARCH DESIGN AND METHODS Rates of severe hypoglycemia were reported quarterly during DCCT and annually during EDIC (i.e., patient recall of episodes in the preceding 3 months). Risk factors influencing the rate of severe hypoglycemia over time were investigated. RESULTS One-half of the DCCT/EDIC cohort reported episodes of severe hypoglycemia. During EDIC, rates of severe hypoglycemia fell in the former DCCT intensive treatment group but rose in the former conventional treatment group, resulting in similar rates (40.8 vs. 36.6 episodes per 100 patient-years, respectively) with a relative risk of 1.12 (95% CI 0.91–1.37). A preceding episode of severe hypoglycemia was the most powerful predictor of subsequent episodes. Entry into the DCCT study as an adolescent was associated with an increased risk of severe hypoglycemia, whereas insulin pump use was associated with a lower risk. Severe hypoglycemia rates increased with lower HbA1c similarly among participants in both treatment groups. CONCLUSIONS Rates of severe hypoglycemia have equilibrated over time between the two DCCT/EDIC treatment groups in association with advancing duration of diabetes and similar HbA1c levels. Severe hypoglycemia persists and remains a challenge for patients with type 1 diabetes across their life span.
How to Study the Gallbladder
Authors: Health and Policy Committee
Journal: Annals of Internal Medicine (1988)

Position Paper1 November 1988How to Study the GallbladderHealth and Policy CommitteeHealth and Policy CommitteeAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-109-9-752 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptBetween the introduction of the oral cholecystogram in 1924 and the early 1970s, soon after ultrasonography was introduced [1.2], evaluation of the gallbladder remained relatively static. Over the last 15 years, however, the revolution in diagnostic imaging has led to remarkable changes in approaches to suspected gallbladder disease. An entire generation of diagnostic procedures has been replaced, for the most part, by new technologies. This discussion focuses on the evaluation of suspected cholecystitis; evaluation of common bile duct abnormalities involves a somewhat different approach and is not a part of this review.At the present time, the two major tests... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: *This paper was authored by Keith I. Marton, MD; and Peter Doubilet, MD, PhD; and was developed for the Health and Public Policy Committee by the Clinical Efficacy Assessment Subcommittee: Paul F. Griner, MD, Chairman; Charles C. Smith, Jr., MD; Paul Calabresi, MD; Lockhart B. McGuire, MD; Earl P. Steinberg, MD; Harold J. Sox, Jr., MD. Members of the Health and Public Policy Committee were: Richard G. Farmer, MD, Chairman; Michael A. Nevins, MD; Charles E. Lewis, MD; Joseph E. Johnson III, MD; Paul F. Griner, MD; John M. Eisenberg, MD; F. Daniel Duffy, MD; Donald L. Feinstein, MD; C.S. Lewis, Jr., MD; Steven A. Schroeder, MD; Quentin D. Young, MD. This paper was approved by the Board of Regents on 15 January, 1988. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byGallbladder and biliary treeGallbladderRandomization to Surgery or Observation in Patients with Symptomatic Gallbladder Stone Disease: The Problem of Evidence-Based Medicine in Clinical PracticeNuclear medicine Competitors or collaborators?Increased volume and decreased emptying of the gallbladder in large (Morbidly obese, tall normal, and muscular normal) peopleIntegrating Practice Guidelines with Financial IncentivesDiagnosing Gallbladder DiseaseGerbail T. Krishnamurthy, MD 1 November 1988Volume 109, Issue 9Page: 752-754KeywordsBile ductsDiagnostic imagingForecastingGallbladderPrevention, policy, and public healthPublic policySafetySub-specialty careUltrasound imaging ePublished: 1 December 2008 Issue Published: 1 November 1988 Copyright & Permissions©1988 American College of PhysiciansPDF downloadLoading ...
Preparation and in vitro evaluation of an acidic environment-responsive liposome for paclitaxel tumor targeting
Authors: Lianqin Wang
Journal: Asian Journal of Pharmaceutical Sciences (2017)

Paclitaxel (PTX) is an important cancer chemotherapeutic drug. To ameliorate the disadvantages of paclitaxel, this study designed liposomes to load paclitaxel, adding the acid-sensitive material cholesteryl hemisuccinate (CHEMS) to increase the accumulation of the drug in the tumor site. To begin, we used a high-performance liquid chromatography (HPLC) method to determine the content of PTX and the encapsulation efficiency. Then, we prepared paclitaxel-loaded acid-sensitive liposomes (PTX ASLs) by a thin-film dispersion method. We investigated the physical and chemical properties of the liposomes. The particle size was 210.8 nm, the polydispersity index (PDI) was 0.182 and the ζ-potential was −31.2 mV. The liposome shape was observed by transmission electron microscopy (TEM), and the results showed that the liposomes were round with a homogenous size distribution. The release characteristics of the liposomes in vitro were studied via a dynamic dialysis method. The results showed that the prepared liposomes had acid sensitivity and sustained release properties. An in vitro cellular uptake assay of MCF-7 cells showed that the cell uptake of coumarin-6-loaded acid-sensitive liposomes was significantly higher than that of free coumarin-6. The cytotoxicity of the PTX ASLs was significantly higher than that of paclitaxel. In conclusion, these results showed that the prepared liposomes had clear acid-sensitive release characteristics and a higher cell uptake rate and cytotoxicity than free PTX. The system is very suitable for targeted cancer therapy with paclitaxel.
GERM-02. IMMUNOHISTOCHEMICAL EVALUATION FOR THE PATHOGENESIS OF INTRACRANIAL GERM CELL TUMORS: EXPRESSION OF PLURIPOTENCY AND CELL DIFFERENTIATION MARKERS
Authors: Tadashi Miyagawa, Hisayuki Murai, Yasuo Iwadate
Journal: Neuro-Oncology (2017)

INTRODUCTION: Primary intracranial germ cell tumors (iGCT) are rare neoplasms that occur in children and adolescents. This study examined both the pathogenesis and the origin of these tumors, as it has been hypothesized that they originate from a totipotent primordial germ cell. MATERIALS AND METHODS: We applied recent knowledge from gonadal germ cell tumors and analyzed expression of a wide panel of stem cell-related proteins(C-KIT, OCT-3/4 (POU5F1), NANOG, SOX2, CD30 and PLAP). Expression shown by immunohistochemistry was analyzed in 12 children and young adults with iGCT, contributing to a careful description of these unusual tumors and adding to the understanding of pathogenesis. RESULTS: Immunohistochemistry showed 5/5 positive in Oct3/4, 5/5 in NANOG, 9/9 in C-KIT and 1/5 in SOX2. All cases that showed positive staining in Oct3/4 or NANOG indicated that the tumors contained germinoma or embryonal carcinoma component. Immunohistochemistry revealed that stem cell related proteins were highly expressed in iGCT, and many similarities were detected with their gonadal equivalents, including a close similarity with primordial germ cells. CONCLUSION: The expression of genes associated with embryonic stem cell pluripotency in CNS germ cell tumors strongly suggests that these tumors are derived from cells that retain, at least partially, an embryonic stem cell-like phenotype, which is a hallmark of primordial germ cells. In addition, these data can be applied to stratify iGCT for treatment strategy in order to provide good survival rate and good functional outcome.
Erratum: Increased small dense LDL and intermediate-density lipoprotein with albuminuria in type 1 diabetes (Diabetes Case (1999) 22 (1165-1170))
Authors: S. D. Sibley, J. E. Hokanson, M. W. Steffes, Jonathan Purnell, S. M. Marcovina, P. A. Cleary, J. D. Brunzell
Journal: Diabetes Care (1999)
Dealing With the Nocebo Effect: Taking Physician–Patient Interaction Seriously
Authors: Guy Widdershoven, Gerben Meynen, Suzanne Metselaar
Journal: The American Journal of Bioethics (2017)

In “When Respecting Autonomy Is Harmful: A Clinically Useful Approach to the Nocebo Effect,” Fortunato, Wasserman, and Menkes (2017) argue that, seeking to respect patient autonomy, physicians ofte...
Analysis of correlation between weight at diagnosis, weight gain after breast cancer treatment, and recurrence in women with early-stage breast cancer (EBC).
Authors: Palma Fedele, Assunta Maria Lapolla, Laura Orlando, Paola Schiavone, Angelo Nacci, Antonella Marino, Margherita Cinefra, Nicola Calvani, Antonino Ardizzone, Maria De Pasquale, Saverio Cinieri
Journal: Journal of Clinical Oncology (2012)

e11001 Background: Overweight at the time of EBC diagnosis has been linked frequently to poorer survival in most studies and some evidence suggests that women who gain weight after breast cancer diagnosis are at increased risk of cancer recurrence and death. Most previous studies on this topic have relied on retrospective chart reviews. The aim of this prospective, observational, single-center study is to determine whether weight at diagnosis and weight gain after EBC treatment can be predictive of BC recurrence. Methods: From December 1990 to January 2012, the study included atotal of 311 EBC patients (stage I-IIIa).We assessed weight and body mass index (BMI=kg/m 2 ) at baseline (≤ 1 month after surgery) and 24 months after completion of treatment (chemotherapy ± radiotherapy). The chi square test (X 2 ) was conducted to determine if a significant correlation exists between BC recurrence and 3 categories of BMI at diagnosis (lean weight: BMI &lt;25; overweight: BMI 25-30; obese: BMI &gt;25) and BC recurrence and weight changes after EBC treatment (loss of &lt;1 kg/m 2 ; loss of ≥ 1 kg/m 2 ; gain of &lt;2kg/m 2 ; gain of &gt;2 kg/m 2 ). Results: Median age was 56 years (range28-81); 68% of patients were postmenopausal, stage I-II in 88%; ER+/PGR+ in 66%; ER+/PGR- in 12%; HER2+ in 14%; 72% underwent conservative surgery+radiotherapy; 57% received chemotherapy (CT) and 78% received endocrine therapy alone or after CT. Median BMI at diagnosis was 27.03, after treatment 28.04. After a median follow-up of 13 years 104 patients recurred. Statistical analysis is reported in the table. Conclusions: Our findings show that EBC patients gain weight after treatment. No significant correlation was found between weight at diagnosis, weight changes after EBC treatment and recurrence. At ASCO meeting we will report results of the prognostic associations of baseline biological features, menopausal status and comorbid disease. [Table: see text]