tbuckley/cabot-search huggingface dataset:
Phase Ib study of recombinant human (rh)Apo2L/TRAIL in combination with paclitaxel, carboplatin, and bevacizumab (PCB) in patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: J. Soria, E. F. Smit, D. Khayat, B. Besse, J. Burton, X. Yang, M. Hsu, A. Braun, D. Reese, F. Blackhall
Journal: Journal of Clinical Oncology (2008)

3539 Background: rhApo2L/TRAIL is a pro-apoptotic receptor agonist acting through death receptors DR4 and DR5. In vitro, rhApo2L/TRAIL induced apoptosis in NSCLC cell lines while sparing normal cells; in vivo, it displayed cooperativity with biologically targeted and cytotoxic agents. In the first-in-human (FIH) study, rhApo2L/TRAIL was well tolerated and showed antitumor efficacy (Herbst et al. JCO 2006; 24: abstract 3013). Methods: The primary objective was to determine the maximum tolerated dose (MTD) of rhApo2L/TRAIL with PCB; the secondary objective was to determine pharmacokinetics (PK) of rhApo2L/TRAIL. The planned sample size was ∼24 pts. Eligibility criteria included pts ≥ 18 years, stage IIIb/IV non-squamous NSCLC, ECOG performance status (PS) 0–1, normal organ function, no brain metastases, and no prior therapy for NSCLC. rhApo2L/TRAIL was administered IV at 4 or 8 mg/kg/day on days 1–5, or at 15 or 20 mg/kg/day on days 1–2 of each 21-day cycle. P (200 mg/m2), C (AUC = 6), and B (15 mg/kg) were given on day 1 of each cycle. Results: As of 5 November 2007, 24 pts (6 per cohort) were treated with rhApo2L/TRAIL + PCB. Twelve pts were men, 21 had stage IV disease, 13 had ECOG PS of 1, and age ranged from 42–73 years. There were no dose-limiting toxicities. Adverse events possibly related to rhApo2L/TRAIL were reported in 19 pts, including arthralgia, rhinitis, epistaxis, myalgia and nausea. Twenty pts had transient transaminase elevations (ALT, AST; all CTCAE grade ≤ 2). Among 18 pts who have completed the study, 14 completed 6 cycles of therapy, and 3 received ≥ 3 cycles of therapy. Six pts remain on treatment. rhApo2L/TRAIL PK values (Cmax, AUC, t1/2) were similar to the FIH study (Ling et al. JCO 2006; 24: abstract 3047). Preliminary data indicate no effect of rhApo2L/TRAIL on PK of P, C or B. Of 18 pts in the first 3 cohorts, 10 had confirmed responses (9 partial, 1 complete) with an overall response rate of 56%. Conclusion: rhApo2L/TRAIL in combination with PCB appeared to be well tolerated with promising efficacy in pts with advanced NSCLC. Pharmacokinetics of all components of this regimen appeared unaltered. The MTD has not been reached. A randomized phase 2 trial in pts with advanced NSCLC is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Inc Amgen Inc
The Importance of the Biological Impact of Exposure to the Concept of the Exposome
Authors: Kristine K. Dennis, Scott S. Auerbach, David M. Balshaw, Yuxia Cui, Margaret Daniele Fallin, Martyn T. Smith, Avrum Spira, Susan Sumner, Gary W. Miller
Journal: Environmental Health Perspectives (2016)

Background:The term "exposome" was originally coined in 2005 and defined as the totality of exposures throughout the lifetime. The exposome provides an excellent scientific framework for studying human health and disease. Recently, it has been suggested that how exposures affect our biology and how our bodies respond to such exposures should be part of the exposome.Objectives:The authors describe the biological impact of the exposome and outline many of the targets and processes that can be assessed as part of a comprehensive analysis of the exposome.Discussion:The processes that occur downstream from the initial interactions with exogenous and endogenous compounds determine the biological impact of exposures. If the effects are not considered in the same context as the exposures, it will be difficult to determine cause and effect. The exposome and biology are interactive—changes in biology due to the environment change one's vulnerability to subsequent exposures. Additionally, highly resilient individuals are able to withstand environmental exposures with minimal effects to their health. We expect that the vast majority of exposures are transient, and chemicals underlying exposures that occurred weeks, months, or years ago are long gone from the body. However, these past chemical exposures often leave molecular fingerprints that may be able to provide information on these past exposures.Conclusions:Through linking exposures to specific biological responses, exposome research could serve to improve understanding of the mechanistic connections between exposures and health to help mitigate adverse health outcomes across the lifespan.Citation:Dennis KK, Auerbach SS, Balshaw DM, Cui Y, Fallin MD, Smith MT, Spira A, Sumner S, Miller GW. 2016. The importance of the biological impact of exposure to the concept of the exposome. Environ Health Perspect 124:1504–1510; http://dx.doi.org/10.1289/EHP140
Heterologous and Homologous Growth of Transplants During the Course of Development of Spontaneous Mammary Tumors in C3H Mice
Authors: Henry C. Browning
Journal: JNCI Journal of the National Cancer Institute (1948)

Heterologous and Homologous Growth of Transplants During the Course of Development of Spontaneous Mammary Tumors in C3H Mice Get access Henry C. Browning Henry C. Browning research fellow National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 8, Issue 4, February 1948, Pages 173–189, https://doi.org/10.1093/jnci/8.4.173 Published: 01 February 1948 Article history Received: 16 December 1947 Published: 01 February 1948
Carbohydrate Counting at Meal Time Followed by a Small Secondary Postprandial Bolus Injection at 3 Hours Prevents Late Hyperglycemia, Without Hypoglycemia, After a High-Carbohydrate, High-Fat Meal in Type 1 Diabetes
Authors: Matthew D. Campbell, Mark Walker, David King, Javier T. Gonzalez, Dean Allerton, Emma J. Stevenson, James A. Shaw, Daniel J. West
Journal: Diabetes Care (2016)

Patients with type 1 diabetes are provided guidance and structured education on adjusting their mealtime bolus insulin dose based on meal carbohydrate content. However, recent research in patients using continuous subcutaneous insulin infusion has highlighted the role of dietary fat in increasing prandial insulin requirements, particularly late into the postprandial period (1,2).

Many patients are treated with basal-bolus insulin injections, which is a less flexible method of insulin therapy than continuous subcutaneous insulin infusion, e.g., patients are unable to administer dual-wave/extended bolus at mealtime. It is important to consider that patients are encouraged to count carbohydrates and administer rapid-acting insulin units at mealtime and that the time-action profiles of lispro/aspart vary in a dose-dependent manner. The peak insulin concentration after a premeal bolus usually occurs within the first 60 min (3), but the peak action is usually observed between 90 and 120 min, and this duration can vary between 4 and 6 h. However, peak …
Cardiovascular Glycobiology11Acute hyperglycemia abolishes cardioprotection by remote ischemic perconditioning12Deregulation of thioredoxin system contributes to monocyte dysfunction in diabetes mellitus: Implications for impaired arteriogenesis in type2 diabetic patients13High glucose increases gamma-glutamyltransferase-induced tissue factor expression in human peripheral blood mononuclear cells
Authors: T Baranyai, R Godfrey, V Scalise, CT Nagy, G Koncsos, Z Onodi, M Karolyi-Szabo, A Makkos, ZV Varga, P Ferdinandy, Z Giricz, HM Schulten, SK Shanmuganathan, I Loeffler, N Mueller, G Wolf, UA Mueller, FD Boehmer, J Waltenberger, C Balia, S Cianchetti, V Carnicelli, F Faita, T Neri, R Zucchi, A Corti, A Celi, R Pedrinelli
Journal: Cardiovascular Research (2016)

Background: Remote ischemic perconditioning (RIPerC) has a promising therapeutic value to improve prognosis of acute myocardial infarction.Chronic comorbidities such as diabetes are known to interfere with conditioning interventions by modulating cardioprotective signaling pathways, such as e.g.autophagy.However, the effect of acute hyperglycemia on RIPerC has not been studied so far.Therefore, here we investigated the effect of acute hyperglycemia on the cardioprotective effect of RIPerC.Methods: Wistar rats were divided into normoglycemic (NG) and acute hyperglycemic (AHG) groups.Acute hyperglycemia was induced by glucose infusion to maintain a serum glucose concentration of 15 to 20 mM throughout the experimental protocol.NG rats received mannitol infusion of an equal osmolarity.Both groups were subdivided into an ischemic (Isch) and a RIPerC group.Each group underwent reversible occlusion of the left anterior descending coronary artery (LAD) for 40 min in the presence or absence of acute hyperglycemia.After 10 min LAD occlusion, RIPerC was induced by 3 cycles of 5 min unilateral femoral artery and vein occlusion and 5 min reperfusion.After 120 min reperfusion, infarct size was measured by triphenyltetrazolium chloride staining.To study underlying signaling mechanisms, hearts were harvested for immunoblotting after 35 min in both the NG and AHG groups.Results: Infarct size was significantly reduced by RIPerC in NG, but not in the AHG group (NG+Isch: 46.27+5.31% vs. NG+RIPerC: 24.65+7.45%,p,0.05;AHG+Isch: 54.19+4.07%vs. 52.76+3.80%).Acute hyperglycemia per se did not influence infarct size, but significantly increased the incidence and duration of arrhythmias.Acute hypreglycemia inhibited autophagy, as LC3II/LC3I ratio decreased and phosphorylated S6 increased possibly via the phosphorylation of Akt.Furthermore, acute hyperglycemia significantly elevated the nitrative stress in the heart (0.87+0.01 vs. 0.50+0.04mg 3-nitrotyrosine/mg protein, p,0.05).Conclusions: This is the first demonstration that acute hypreglycemia deteriorates cardioprotection by RIPerC.The mechanism of this phenomenon may involve an increased nitrative stress and decreased myocardial autophagy induced by acute hyperglycamia.
The early activation of memory B cells from Wiskott-Aldrich syndrome patients is suppressed by CD19 downregulation
Authors: Xiaoming Bai, Yongjie Zhang, Lu Huang, Jinzhi Wang, Wenyan Li, Linlin Niu, Hongyan Jiang, Rongxin Dai, Lina Zhou, Zhiyong Zhang, Heather Miller, Wenxia Song, Xiaodong Zhao, Chaohong Liu
Journal: Blood (2016)
Crizotinib-Resistant <i>ROS1</i> Mutations Reveal a Predictive Kinase Inhibitor Sensitivity Model for <i>ROS1</i>- and <i>ALK</i>-Rearranged Lung Cancers
Authors: Francesco Facchinetti, Yohann Loriot, Mei-Shiue Kuo, Linda Mahjoubi, Ludovic Lacroix, David Planchard, Benjamin Besse, Françoise Farace, Nathalie Auger, Jordi Remon, Jean-Yves Scoazec, Fabrice André, Jean-Charles Soria, Luc Friboulet
Journal: Clinical Cancer Research (2016)

The identification of molecular mechanisms conferring resistance to tyrosine kinase inhibitor (TKI) is a key step to improve therapeutic results for patients with oncogene addiction. Several alterations leading to EGFR and anaplastic lymphoma kinase (ALK) resistance to TKI therapy have been described in non-small cell lung cancer (NSCLC). Only two mutations in the ROS1 kinase domain responsible for crizotinib resistance have been described in patients thus far.A patient suffering from a metastatic NSCLC harboring an ezrin (EZR)-ROS1 fusion gene developed acquired resistance to the ALK/ROS1 inhibitor crizotinib. Molecular analysis (whole-exome sequencing, CGH) and functional studies were undertaken to elucidate the mechanism of resistance. Based on this case, we took advantage of the structural homology of ROS1 and ALK to build a predictive model for drug sensitivity regarding future ROS1 mutations.Sequencing revealed a dual mutation, S1986Y and S1986F, in the ROS1 kinase domain. Functional in vitro studies demonstrated that ROS1 harboring either the S1986Y or the S1986F mutation, while conferring resistance to crizotinib and ceritinib, was inhibited by lorlatinib (PF-06463922). The patient's clinical response confirmed the potency of lorlatinib against S1986Y/F mutations. The ROS1 S1986Y/F and ALK C1156Y mutations are homologous and displayed similar sensitivity patterns to ALK/ROS1 TKIs. We extended this analogy to build a model predicting TKI efficacy against potential ROS1 mutations.Clinical evidence, in vitro validation, and homology-based prediction provide guidance for treatment decision making for patients with ROS1-rearranged NSCLC who progressed on crizotinib. Clin Cancer Res; 22(24); 5983-91. ©2016 AACR.
Coelimination and Survival in Gene Network Evolution: Dismantling the RA-Signaling in a Chordate
Authors: Josep Martí-Solans, Olga V. Belyaeva, Nuria P. Torres-Aguila, Natalia Y. Kedishvili, Ricard Albalat, Cristian Cañestro
Journal: Molecular Biology and Evolution (2016)

The bloom of genomics is revealing gene loss as a pervasive evolutionary force generating genetic diversity that shapes the evolution of species. Outside bacteria and yeast, however, the understanding of the process of gene loss remains elusive, especially in the evolution of animal species. Here, using the dismantling of the retinoic acid metabolic gene network (RA-MGN) in the chordate Oikopleura dioica as a case study, we combine approaches of comparative genomics, phylogenetics, biochemistry, and developmental biology to investigate the mutational robustness associated to biased patterns of gene loss. We demonstrate the absence of alternative pathways for RA-synthesis in O. dioica, which suggests that gene losses of RA-MGN were not compensated by mutational robustness, but occurred in a scenario of regressive evolution. In addition, the lack of drastic phenotypic changes associated to the loss of RA-signaling provides an example of the inverse paradox of Evo–Devo. This work illustrates how the identification of patterns of gene coelimination—in our case five losses (Rdh10, Rdh16, Bco1, Aldh1a, and Cyp26)—is a useful strategy to recognize gene network modules associated to distinct functions. Our work also illustrates how the identification of survival genes helps to recognize neofunctionalization events and ancestral functions. Thus, the survival and extensive duplication of Cco and RdhE2 in O. dioica correlated with the acquisition of complex compartmentalization of expression domains in the digestive system and a process of enzymatic neofunctionalization of the Cco, while the surviving Aldh8 could be related to its ancestral housekeeping role against toxic aldehydes.
Surgical lung biopsy for the diagnosis of interstitial lung disease in England: 1997–2008
Authors: John P. Hutchinson, Tricia M. McKeever, Andrew W. Fogarty, Vidya Navaratnam, Richard B. Hubbard
Journal: European Respiratory Journal (2016)

International guidelines and new targeted therapies for idiopathic pulmonary fibrosis have increased the need for accurate diagnosis of interstitial lung disease (ILD), which may lead to more surgical lung biopsies. This study aimed to assess the risk of this procedure in patients from the UK. We used Hospital Episodes Statistics data from 1997 to 2008 to assess the frequency of surgical lung biopsy for ILD in England, UK. We identified cardiothoracic surgical patients using International Classification of Diseases revision 10 codes for ILD and Office of Population Censuses and Surveys Classification of Interventions and Procedures version 4 codes for surgical lung biopsy. We excluded those with lung resections or lung cancer. We estimated in-hospital, 30-day and 90-day mortality following the procedure, and linked to cause of death using data from the UK Office of National Statistics. We identified 2820 patients with ILD undergoing surgical lung biopsy during the 12-year period. The number of biopsies increased over the time period studied. In-hospital, 30-day and 90-day mortality were 1.7%, 2.4% and 3.9%, respectively. Male sex, increasing age, increasing comorbidity and open surgery were risk factors for mortality. Surgical lung biopsy for ILD has a similar mortality to lobectomy for lung cancer, and clinicians and patients should understand the likely risks involved.
Glimepiride and Serum Adiponectin Level in Type 2 Diabetic Subjects
Authors: Shoichiro Nagasaka, Ataru Taniguchi, Yoshitaka Aiso, Toshimitsu Yatagai, Tomoatsu Nakamura, Yoshikatsu Nakai, Mitsuo Fukushima, Akira Kuroe, Shun Ishibashi
Journal: Diabetes Care (2003)

We thank Yoshioka, Yoshida, and Yoshikawa for their comments on our article (1) in this issue of Diabetes Care (2). We reported that serum adiponectin concentration increased after 3 months’ glimepiride treatment in type 2 diabetic patients (1). They indicated that baseline values of serum adiponectin (22.1 ± 2.7 μg/ml, mean ± SE) seem to be higher than those expected from subjects with greater BMI (26.5 ± 0.9 kg/m2) and homeostasis model assessment of insulin resistance (5.0 ± 0.8) levels. First, we must apologize …
On the Mechanism of Cancer Induction by Ultraviolet Radiation
Authors: Harold F. Blum
Journal: JNCI Journal of the National Cancer Institute (1950)

Journal Article On the Mechanism of Cancer Induction by Ultraviolet Radiation Get access Harold F. Blum Harold F. Blum National Cancer Institute, National Institutes of Health, U. S. Public Health Service, Bethesda, Md., and Department of Biology, Princeton University, New Jersey Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 11, Issue 3, December 1950, Pages 463–495, https://doi.org/10.1093/jnci/11.3.463 Published: 01 December 1950 Article history Received: 20 June 1950 Published: 01 December 1950
Raised inflammatory markers may indicate poorer quality of life in advanced cancer
Authors: Ingrid Torjesen
Journal: BMJ (2016)

Controlling the immune system in people with terminal cancer may help improve their quality of life, a study published in the Journal of Clinical Oncology shows.1

A team at the University of Edinburgh assessed inflammation levels in 2520 cancer patients across Europe and found that the level of inflammation had a direct effect on how they felt in terms of pain, fatigue, loss of …
Fludarabine, Mitoxantrone and Cyclophosphamide Combination Therapy in Relapsed Chronic Lymphocytic Leukemia with or without G-CSF Results of the First Interim Ananlysis of a Phase III Study of the German CLL Study Group
Authors: Barbara F. Schmitt, Astrid Franke, O. Burkhard, R. Schlag, Georg Hopfinger, M. Stauch, Manuela Bergmann, Clemens M. Wendtner, Raymonde Busch, Bertold Emmerich, Michael Hallek, Gcllsg
Journal: Blood (2002)
Targeted therapy for advanced solid tumors based on molecular profiles: Early results from MyPathway, an open-label, phase IIa umbrella basket study.
Authors: John D. Hainsworth, Funda Meric-Bernstam, Charles Swanton, Herbert Hurwitz, David R. Spigel, Christopher Sweeney, Howard A. Burris, Ron Bose, Shuangli Guo, Coen Bernaards, Mary Stanley Beattie, Alisha Stein, Melissa Brammer, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2016)

LBA11511 Background: The MyPathway study (NCT02091141) evaluates agents targeting the HER2, BRAF, Hedgehog (Hh), or EGFR pathways in non-indicated tumors with relevant genetic abnormalities. Early results from MyPathway merit pre-planned tumor-cohort expansion. Methods: Eligible pts had advanced solid tumors with no curative therapy and molecular alterations in HER2, BRAF, Hh, or EGFR. Pts received standard doses of trastuzumab + pertuzumab (for the HER2 pathway), vemurafenib (BRAF), vismodegib (Hh), or erlotinib (EGFR) based on alteration. The primary endpoint is investigator-evaluated response rate within a tumor-pathway cohort (RECIST 1.1). Cohort size and expansion is determined by Simon’s two-stage design criteria. Results: By December 14, 2015, MyPathway included 129 pts with available baseline assessments and alterations in HER2 (n = 82; 53 amplifications, 23 mutations, 5 both, 1 RBMS-NRG1 fusion), BRAF (n = 33; 18 V600E, 15 other), Hh (n = 8; 7 PTCH1, 1 SMO), or EGFR (n = 6). Pts had a median of 3 (range, 0–10) prior lines of therapy. Best responses (n = 118) are shown below; 11 pts had insufficient follow-up for reevaluation and were not analyzed. 22 pts had PR/CR (1 CR); current response durations were up to 11 months. Conclusions: Targeted therapy produced responses in pts with 9 different tumor types outside of current drug indications. As enrollment increases for all tumor-pathway cohorts, analyses of tumor responses based on specific alterations (eg, HER2 amplifications vs. mutations) are planned. The HER2 amplified colorectal, bladder, and biliary, and the BRAF lung cohorts will be expanded based on observed activity. Clinical trial information: NCT02091141. [Table: see text]
Multiple Sclerosis
Authors: Dale E. McFarlin, Henry F. McFarland
Journal: New England Journal of Medicine (1982)

(Second of Two Parts)EpidemiologyApproximately 200 studies of the geographic distribution of multiple sclerosis have been conducted.60 They have shown regions of high prevalence (30 to 80 cases per 100,000 population) in northern Europe between 65 and 45° north latitude and in the northern United States and southern Canada, as well as in southern Australia and New Zealand. In contrast, regions of low risk, including most of Asia and Africa, have a prevalence of 5 or fewer cases per 100,000. In both Europe and North America, where the disease has been thoroughly evaluated, a clear north—south geographic gradient has . . .