tbuckley/cabot-search huggingface dataset:
Natual history of non-small cell lung cancer in non-smokers
Authors: R. Dibble, W. Langeburg, S. Bair, J. Ward, W. Akerley
Journal: Journal of Clinical Oncology (2005)

7252 Background: The natural history of NSCLC differs between never-smokers (NS) and ever-smokers (ES) in terms of incidence, phenotype and genotype. Also, NS with advanced NSCLC demonstrate greater benefit following therapy with EGFR inhibitors than ES. Hence, a greater understanding of the natural history of NS smokers with NSCLC is necessary to interpret the impact of EGFR inhibitor therapy. Methods: A database search for NSCLC from the Utah Cancer registry was performed for 1993–1998. Results: 1796 cases were identified and a smoking history was assessable in 1220 (68%). There were 180 NS, 1040 ES and 576 with unknown smoking history. For NS and ES, the median age was 74 and 68 yrs and the stage breakdown for local, regional and distant was 8.1, 20.9, 70.9% and 9.8, 34.0, 56.1%, respectively. For NS and ES, adenocarcinoma was found in 47.5% and 31% and squamous in 11.5% and 30.1%. For NS and ES, 5-YS for Local was 40.5 and 69.8% and 3-YS for Regional was 34.2 and 22.6%. For NS and ES, the 1, 2 and 3-YS were 23.4, 11.9, 9.3% and 18.6, 6.6, 3.2%. Conclusions: NS with NSCLC present with more advanced stage, greater frequency of adenocarcinoma, but demonstrate greater survival in distant stage than ES suggesting a different natural history for NS with NSCLC. These differences should be considered when interpreting trials of NS or EGFR inhibitors. No significant financial relationships to disclose.
Subjectivity may hinder the application of Kline's teaching framework in comparative contexts
Authors: Lewis G. Dean, Rachel L. Kendal
Journal: Behavioral and Brain Sciences (2015)

Abstract We welcome Kline's attempt to develop an overarching framework to allow much needed collaboration between fields in the study of teaching. While we see much utility in this enterprise, we are concerned that there is too much focus on the behavior of the teacher, without examining results or costs, and the categories within the framework are not sufficiently distinct.
Abstract 12856: Interleukin-33 and Soluble ST2 Are Expressed in Human Nonrheumatic Aortic Valve Stenosis
Authors: Hisashi Sawada, Yoshiro Naito, Shinichi Hirotani, Hirokuni Akahori, Toshihiro Iwasaku, Yoshitaka Okuhara, Kojiro Miki, Akiyo Eguchi, Masataka Mitsuno, Yuji Miyamoto, Masaaki L Kawabata, Takeshi Tsujino, Tohru Masuyama
Journal: Circulation (2012)

BACKGROUND The number of patients with nonrheumatic aortic valve stenosis (NR-AS) is increasing in recent years. Many studies demonstrated that the etiology of NR-AS is associated with a pathophysi...
Number of lymph nodes harvested from a mediastinal lymphadenectomy: Results of the randomized, prospective ACOSOG Z0030 trial
Authors: M. S. Allen, G. E. Darling, P. A. Decker, J. B. Putnam, R. A. Malthaner, R. I. Inculet, D. R. Jones, R. J. McKenna, R. J. Landreneau
Journal: Journal of Clinical Oncology (2007)

7555 Background: Lymph node status is a major determinant of stage and survival in patients with lung cancer; however, little information is available about the yield of a mediastinal lymphadenectomy done at the time of pulmonary resection. Methods: The ACOSOG Z0030 trial is a prospective, randomized trial of mediastinal lymph node sampling versus complete mediastinal lymphadenectomy during an operation for early stage lung cancer. Total enrollment from July 1999 to February 2004 was 1,111 patients, of which 1,023 were eligible and/or evaluable. There were 524 patients who underwent complete mediastinal lymph node resection after randomization to this arm that were declared eligible and/or evaluable with lymph node data available. The number of lymph nodes examined from each station was collected beginning in January 2002. Prospectively collected data from these patients was analyzed to determine the number of lymph nodes obtained. Results: Median age was 67 (range 37–87) and 267 (52%) were men. Histology was squamous cell in 141 (27%), adenocarcinoma in 227 (44%), large cell in 22 (4%), bronchoavelolar in 32 (6%) and other non-small cell in 99 (19%). There were 317 right sided cancers and 207 left sided cancers. For lymphadenectomy for cancers in the right lung the yield from station 2R was a median of 2 lymph nodes (range 1 to 15), station 4R was 2 (1 –17), station 7 was 2 (1–24), station 8 was 1 (1–5), station 9 was 1 (1–6) and station 10R was 1 (1–10). For lymphadenectomy for cancers on the left side the yield from station 2L was 2 (1–4), station 4L was 1 (1–12), station 5 was 2 (1–18), station 6 was 2 (1–11), station 7 was 2 (1–16), station 8 was 1 (1–3), station 9 was 1 (1–8) and 10L was 2 (1–12). The total number of lymph nodes or fragments obtained for right sided cancers was a median of 13.5 (range 1 to 56) and for left sided tumors 15 (range 4 to 81). Conclusions: Although high variability exists in the actual number of lymph nodes obtained from various nodal stations, a complete mediastinal lymphadenectomy should obtain one or more lymph nodes from each mediastinal station. Adequate mediastinal lymphadenectomy should include exploration and remove of lymph nodes from stations 2R, 4R, 7, 8, and 9 for right sided cancers and stations 4L, 5, 6, 7, 8 and 9 for left sided cancers. No significant financial relationships to disclose.
Selective phosphorylation of PKA targets after β-adrenergic receptor stimulation impairs myofilament function in<i>Mybpc3</i>-targeted HCM mouse model
Authors: Aref Najafi, Vasco Sequeira, Michiel Helmes, Ilse A.E. Bollen, Max Goebel, Jessica A. Regan, Lucie Carrier, Diederik W.D. Kuster, Jolanda Van Der Velden
Journal: Cardiovascular Research (2016)

Hypertrophic cardiomyopathy (HCM) has been associated with reduced β-adrenergic receptor (β-AR) signalling, leading downstream to a low protein kinase A (PKA)-mediated phosphorylation. It remained undefined whether all PKA targets will be affected similarly by diminished β-AR signalling in HCM. We aimed to investigate the role of β-AR signalling on regulating myofilament and calcium handling in an HCM mouse model harbouring a gene mutation (G > A transition on the last nucleotide of exon 6) in Mybpc3 encoding cardiac myosin-binding protein C.Cardiomyocyte contractile properties and phosphorylation state were measured in left ventricular permeabilized and intact cardiomyocytes isolated from heterozygous (HET) or homozygous (KI) Mybpc3-targeted knock-in mice. Significantly higher myofilament Ca²⁺sensitivity and passive tension were detected in KI mice, which were normalized after PKA treatment. Loaded intact cardiomyocyte force-sarcomere length relation was impaired in both HET and KI mice, suggesting a reduced length-dependent activation. Unloaded cardiomyocyte function revealed an impaired myofilament contractile response to isoprenaline (ISO) in KI, whereas the calcium-handling response to ISO was maintained. This disparity was explained by an attenuated increase in cardiac troponin I (cTnI) phosphorylation in KI, whereas the increase in phospholamban (PLN) phosphorylation was maintained to wild-type values.These data provide evidence that in the KI HCM mouse model, β-AR stimulation leads to preferential PKA phosphorylation of PLN over cTnI, resulting in an impaired inotropic and lusitropic response.
A phase I study examining weekly dosing and pharmacokinetics (PK) of a novel spectrum selective kinase inhibitor, XL999, in patients (pts) with advanced solid malignancies (ASM)
Authors: J. Cooper, M. M. Mita, J. Curtright, A. Ricart, A. Mita, C. Takimoto, A. Tolcher, A. Dowlati, S. Flick, K. P. Papadopoulos
Journal: Journal of Clinical Oncology (2006)

13024 Background: XL999 is a small molecule inhibitor of multiple kinases involved in tumor cell growth, angiogenesis, and metastasis, including VEGFR2 (KDR), PDGFRα/β, FGFR1/3, FLT-3, and SRC. A phase I study of XL999 administered as a 4 hr infusion every 2 weeks in pts with ASM showed that the maximum tolerated dose (MTD) was 3.2 mg/kg and the plasma t 1/2 was approximately 24 hrs. Three pts dosed at 0.2–1.6 mg/kg (anaplastic thyroid cancer [1], renal cell carcinoma [1], hepatic squamous cell carcinoma [1]) had partial responses and 9 pts had stable disease for 3 to 11 months. Based on these data, a weekly (wkly) dosing schedule with PK monitoring was explored. Methods: XL999 at 3.2 mg/kg was administered to pts as a 4 hr infusion on day (d) 1 and 8 with toxicity assessment. Pts received further doses of XL999 wkly in the absence of unacceptable toxicity, disease progression, or accumulation based on PK results. Results: Overall 15 pts were enrolled and 7 were initially dosed at 3.2 mg/kg. Two of these pts experienced severe drug related toxicities, including 1 pt with G3 fatigue who was able to continue wkly XL999 at 2.4 mg/kg and another pt who was discontinued after developing reversible cardiac dysfunction on d1. The next 8 pts were treated at 2.4 mg/kg and none of these has experienced any G2 or worse drug related adverse events. One asymptomatic pt with non-specific ECG changes after d1 was discontinued from study. Four of 11 evaluable pts had SD. In 7 evaluable pts treated at the 2.4 dose level, the mean Cmax was 519 ng/mL with moderate interpatient variability (coefficient of variation, CV) of 38%. Intrapatient variability in the Cmax values on d1 and d15 was moderate (≤3-fold); however, there was no evidence of drug accumulation on repeat dosing. Conclusions: XL999 administered wkly as a 4 hr infusion at a dose of 2.4 mg/kg appears to be well tolerated with no evidence of drug accumulation. The safety and PK data suggest that 2.4 mg/kg on a wkly schedule is appropriate for phase 2 studies. [Table: see text]
The relationship between tumor cell density in the pretreatment biopsy and survival after chemotherapy in OE02 trial esophageal cancer patients.
Authors: Matthew D. Hale, Matthew Guy Nankivell, Wolfram Mueller, Nicholas P. West, Sally Patricia Stenning, Alexander I. Wright, Darren Treanor, Ruth E. Langley, Lindsay C. Ward, William H. Allum, David Cunningham, Jeremy D. Hayden, Heike I. Grabsch
Journal: Journal of Clinical Oncology (2014)

49 Background: Neoadjuvant chemotherapy (chemo) followed by surgery is the standard treatment for UK patients with resectable oesophageal cancer [OeC] since the OE02 trial (Allum et al. J. Clin. Oncol, 2009), yet some patients receive no benefit from chemo. We investigated whether tumour cell density (TCD) in the pre-chemo biopsy can predict patient benefit from chemo among OE02 patients. Methods: Hematoxylin and eosin stained diagnostic biopsy slides from 281 OE02 trial OeC patients reflective of the whole trial population based on patient characteristics and survival (70% adenocarcinoma, surgery alone: n=141; chemo followed by surgery: n=140) were digitized. TCD (percentage of epithelial tumor cells/viable tumor mass) was quantified by point counting and cut offs for overall survival analyses were identified. The relationship between TCD and clinicopathological data and its predictive value (heterogeneity of treatment effect) were assessed. Results: TCD ranged between 16-99% with 85% of cases in the 25-75% range. TCD was initially divided into tertiles. The treatment hazard ratio (HR) was examined within each tertile showing evidence of heterogeneity with clear benefit from chemo seen only in the middle tertile. Cut offs were refined through examination of treatment HR within TCD quintiles. Treatment HRs were 1.25 (95%confidence interval 0.66, 2.35), 1.94 (1.39, 2.71) and 0.65 (0.36, 1.18), respectively, for TCD &lt;40% (n=46), 40-70% (n=183) and &gt;70% (n=52), suggesting that only patients with 40-70% TCD benefit from neoadjuvant chemo (HR&gt;1 favours chemo, heterogeneity p=0.006). Low Mandard tumor regression grade (1-3 versus 4-5) was related to a lower biopsy TCD (median: 47% versus 56%, p=0.0402). Conclusions: TCD appears to be able to predict survival benefit from neoadjuvant chemo in OeC patients and is associated with tumour regression. Our result requires validation in an independent dataset to confirm its potential clinical utility. If validated, TCD measurement in the diagnostic biopsy could be used to determine which OeC patients would benefit from neoadjuvant chemo versus those who would benefit most from management with surgery alone.
Unreported Male Sex Partners Among Men with Newly Diagnosed HIV Infection — North Carolina, 2011–2013
Authors: Hsiu Wu, Lisa B. Hightow-Weidman, Cynthia L. Gay, Xinjian Zhang, Steve Beagle, Laura Hall, Tonyka Jackson, Jenni Marmorino, Ann N. Do, Philip J. Peters
Journal: MMWR Morbidity and Mortality Weekly Report (2015)

Human immunodeficiency virus (HIV) prevention interventions, such as preexposure prophylaxis (PrEP), are often targeted to men who have sex with men (MSM) who self-report high-risk behaviors. Data from a prospective study evaluating methods to detect acute HIV infection among a primarily young (aged <25 years) and black or African American (African American) population from North Carolina were analyzed. In the study, participants were asked about risk behaviors during pretest counseling (at the time of testing) and then during a partner services interview (at HIV diagnosis). Participants whose disclosure of sexual risk behaviors during pretest counseling was different from their disclosure of sexual risk behaviors during their partner services interview were identified, and factors associated with these discordant responses were examined. Among 113 HIV-infected men, 26 (23.0%) did not disclose male sex partners at pretest counseling, but subsequently did disclose this information during their partner services interview. When compared with men who disclosed having male partners at pretest counseling, these 26 MSM who did not disclose male partners during pretest counseling were found to have a similar number of male partners during contact tracing, but were more likely to have a female partner (30.8% versus 6.9%). In addition, the proportions of MSM found to have at least one HIV-infected partner were similar for both groups (MSM who disclosed having male partners during pretest counseling and those who did not). To better customize HIV prevention interventions for MSM, HIV prevention programs might consider using novel strategies to accurately assess risk in this population.
VON WILLEBRAND'S DISEASE
Authors: Bruce M. Ewenstein, MD, PhD
Journal: Annual Review of Medicine (1997)

▪ Abstract von Willebrand's disease (vWD) arises from abnormalities in von Willebrand factor (vWF), an adhesive glycoprotein uniquely involved in key aspects of both primary and secondary hemostasis. The current classification distinguishes disorders arising from partial (type 1) or complete (type 3) deficiencies and from qualitative defects (type 2). Type 2 vWD is further divided into four subtypes (A, B, N, and M), reflecting distinct classes of functional abnormalities. Missense mutations account for most of type 2 vWD, whereas major disruptions in the vWF gene produce type 3 variants. The molecular basis of type 1 vWD is largely undefined. The laboratory diagnosis of vWD and its several variants is made on the basis of immunologic and functional studies of vWF, factor VIII levels, and specialized electrophoretic analyses (multimer gels). The mainstay of therapy for most patients with vWD is desmopressin, a pharmacologic agent that stimulates the release of endogenous pools of vWF. Cryoprecipitate and selected factor VIII concentrates are useful sources of exogenous vWF for the treatment of patients unresponsive to this desmopressin.
Abstract 9453: Dual Probe Hybrid Molecular PET/MR Imaging of Post-infarct Myocardial Inflammation and Healing
Authors: Maulik D Majmudar, Timo Heidt, Edmund Keliher, Jessica Truelove, Brena Sena, Rostic Gorbatov, Yoshiko Iwamoto, Marcelo F Di Carli, Ralph Weissleder, Matthias Nahrendorf
Journal: Circulation (2012)

Background: Myocardial infarction elicits a strong inflammatory response, with profound recruitment of innate immune cells. The magnitude of inflammation influences infarct size and severity of post-MI ventricular dysfunction. Inflammatory monocytes and macrophages produce substantial amounts of myeloperoxidase (MPO), which leads to oxidative stress. In addition, plasma transglutaminase factor XIII (FXIII) plays a key role in wound healing, via its contribution to extracellular matrix organization. Thus, we hypothesize that targeted molecular imaging of FXIII and MPO activity using a hybrid PET/ MRI approach will enable simultaneous in vivo assessment of infarct healing and post-infarct inflammation. Methods and Results: To assess in vivo FXIII activity, we developed a fluorine-18 labeled affinity peptide (18F-FXIII), with a blood half-life of 13.3 min, using a facile ‘click-chemistry’ approach. FXIII recognizes the PET probe as a substrate and cross-links it to extracellular matrix proteins, leading to local entrapment within the healing infarct. 18F-FXIII and gadolinium-based activatable sensor of MPO activity (MPO-Gd) were injected in C57BL/6 mice on day 4 after permanent coronary ligation. PET/MR imaging was performed and fusion was facilitated using external fiducial markers. 18F-FXIII uptake in the heart was significantly higher in animals with MI as compared to controls, as measured by scintillation counting (percent injected dose per gram tissue 0.29±0.01 vs 0.17± 0.03, p&lt;0.03). On autoradiography, 18F-FXIII uptake correlated well with infarct area on TTC staining. PET/MR imaging allowed for simultaneous in vivo assessment of MPO and FXIII activity (Figure). Conclusion: Dual probe hybrid PET/MR imaging with 18F-FXIII and MPO-Gd allows non-invasive assessment of post-infarct myocardial inflammation and infarct healing.
Sunitinib pharmacokinetic (PK) and safety data in subjects with renal impairment and on hemodialysis
Authors: R. Khosravan, M. Toh, J. LaFargue, G. Ni, C. Bello
Journal: Journal of Clinical Oncology (2008)

2578 Background: Sunitinib malate (SU) is an oral multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R and RET, approved multinationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. This study assessed the effect of severe renal impairment and hemodialysis on the PK and safety of SU and its primary active metabolite (SU12662) following a single dose of SU. Methods: In an open-label, single-dose, parallel-group study, subjects with normal renal function (n=8; CLcr >80 mL/min), severe renal impairment (n=8; CLcr <30 mL/min), and end-stage renal disease (ESRD) requiring hemodialysis (n=8) received SU 50 mg po. Serial blood samples were collected over 480 h for quantification of plasma concentrations of SU and SU12662 using a validated LC/MS/MS assay. For ESRD subjects, hemodialysis was started after collection of the 48-h sample. Safety was monitored throughout the study. Results: All 24 subjects completed the study. The preliminary mean±SD PK parameters for SU and SU12662 are presented below. A single dose of SU was found to be well tolerated when administered to subjects with severe renal impairment or ESRD; no serious adverse events were reported. Conclusions: Based on preliminary plasma concentration data, the PK of SU and SU12662 in subjects with severe renal impairment appeared similar to that in subjects with normal renal function. Plasma exposure to SU and SU12662 appeared lower in subjects with ESRD compared with subjects with normal renal function or severe renal impairment. PK parameter Normal (n=8) Severe (n=8) ESRD (n=8) SU Cmax, ng/mL 26.1±6.5 24.6±9.7 16.1±3.1 AUC0–48, ng·h/mL 809±58 764±322 489±97 AUC0-∞, ng·h/mL 1,921±531 1,814±1091 1,013±290 t1/2, h 83±12 84±20 72±17 SU12662 Cmax, ng/mL 5.7±1.3 4.7±1.7 4.1±1.2 AUC0- 48, ng·h/mL 196±31 153±66 135±27 AUC0-∞, ng·h/mL 778±109 627±262 538±116 t1/2, h 130±21 126±24 114±19 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Inc Pfizer Inc
Identification of adaptive changes in an evolving population of Escherichia coli: the role of changes with regulatory and highly pleiotropic effects.
Authors: A Kurlandzka, R F Rosenzweig, J Adams
Journal: Molecular Biology and Evolution (1991)

A population of Escherichia coli initiated with a single clone developed extensive morphological and physiological polymorphism after being maintained for 773 generations in glucose-limited continuous culture. To understand the mechanisms of adaptation to this environment, total protein patterns of four adaptive clones and of the parent strains were examined by two-dimensional gel electrophoresis. Approximately 20% of the proteins (approximately 160 in absolute numbers) showed significantly different levels of expression in pairwise comparisons of parent and adapted clones. The extent of these changes points to the importance of mutations with regulatory and/or highly pleiotropic effects in the adaptive process. The four evolved clones all expressed fewer proteins than did the parent strain, supporting the hypothesis of energy conservation during evolutionary change. Forty-two proteins that could be assigned to known cellular functions were identified. The changes in some of them indicated that the evolved clones developed different adaptive mechanisms to glucose-limited environment. Changes were observed in the expression levels of proteins associated with translation, membrane composition, shock response, and active transport. A fraction of the changes could not be either explained or predicted from a consideration of the nature of the environment in which the clones evolved.
Cellular Immune Reaction to Human Malignant Melanoma and Breast Carcinoma Cells2
Authors: Silvana Canevari, Giuseppe Fossati, Giuseppe Della Porta
Journal: JNCI Journal of the National Cancer Institute (1976)

An in vitro microassay was used to study cytotoxic reactivity of lymphocytes of 19 patients with malignant melanoma, 8 patients with breast carcinoma, and 18 normal subjects on cell cultures of malignant melanoma and breast carcinoma. In each of the twelve experiments, peripheral blood lymphocytes from individuals with and without cancer were tested simultaneously on two or three different target cells. Cytotoxic reactivity, evaluated by a comparison of the number of target cells remaining after incubation with lymphocytes with those incubated with medium only, was found in 20 cancer patients (74%) and 13 individuals without cancer (72%). The strength of lymphocyte reactivity of the cancer and of the non-cancer group did not differ significantly. Of the 27 cancer patients, 8 were positive only on the homologous target cells, 7 only on the opposite cells, and 5 on both types; 7 were negative. Short-term melanoma cell cultures were more lysable than were established cell lines; however, no direct correlation between the growth rate during the test period and susceptibility to lysis was seen. The blood group of the lymphocyte donors had no influence on cytotoxic reactivity.