tbuckley/cabot-search huggingface dataset:
Abstract IA06: Adaptive designs and adaptive learning for biomarker-based clinical trials for targeted therapies.
Authors: J. Jack Lee
Journal: Clinical Cancer Research (2014)

Abstract Rapid advancements in genomics have changed the landscape of target identification and drug development for targeted therapies. Targeted agents work well when drugs are given to patients with the actionable targets. For example, TKI works well for lung cancer patients with EGFR mutation and crizotinib is highly effective for patients with EML4-ALK translocation. Targeted agents, however, do not work for everyone and may not work at all. Hence, the goals for developing target agents include (1) testing the treatment efficacy, (2) identifying prognostic and predictive markers, and (3) providing better treatments to patients enrolled in the trial. Several novel designs have been introduced to achieve these objectives. For example, Bayesian adaptive designs can assign more patients to the more effective treatments based on the available data at the time via the outcome-adaptive randomization. More frequent interim monitoring can drop the ineffective treatments early for futility. New treatments can be added, and effective treatments can graduate for further evaluation. The concepts of the basket design and the N-of-1 design have also been proposed to study the targeted agents based on patients' genomic profiles across different disease sites. Information collected from such trials can be put together to form a continuously updated knowledge database for adaptive learning. Statistical methods such as the hierarchical model and Individual level meta-analysis can be applied to model data collected in the knowledge database to estimate the treatment effect, the marker effect, and their interactions. A platform of a clinical trial infrastructure can be established to facilitate the conduct of such trials. In the talk, pros and cons of various designs will be discussed. Examples and lessons learned from the recently completed BATTLE trial and the on-going BATTLE-2 trial in non-small cell lung cancer will be given. Citation Format: J. Jack Lee. Adaptive designs and adaptive learning for biomarker-based clinical trials for targeted therapies. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr IA06.
Roxithromycin Inhibits Constitutive Activation of Nuclear Factor κB by Diminishing Oxidative Stress in a Rat Model of Hepatocellular Carcinoma
Authors: Shinichi Ueno, Dai Aoki, Fumitake Kubo, Kiyokazu Hiwatashi, Kenji Matsushita, Tohru Oyama, Ikuro Maruyama, Takashi Aikou
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Recently, 14-member macrolide antibiotics such as clarithromycin and roxithromycin have been shown to have anticancer and antiangiogenic effects. We investigated the suppressive effect of roxithromycin on accelerated hepatocellular carcinoma growth in a rat hepatocarcinogenetic model and compared results with effects from TNP-470. Experimental Design: Tumor was induced by oral diethylnitrosamine administration for 17 weeks. Normal saline, TNP-470 (50 mg/kg), or roxithromycin (40 or 100 mg/kg) was administered i.p. thrice per week from week 10 to 17. Results: Carcinomatous tissue growing outside dysplastic nodules and a marked expression of placental glutathione S-transferase were detected in rats with induced carcinogenesis. Tumor growth was accompanied by augmented expression of inducible nitric oxide synthase, activation of nuclear factor κB, and increased lipid peroxidation level. All these effects were absent in animals that received roxithromycin or TNP-470. The inhibitory effect of roxithromycin was dose dependent and no clear differences were noted between groups given roxithromycin 100 mg/kg and TNP-470 50 mg/kg. Conclusions: Our results indicate that roxithromycin inhibits oxidative stress, nitric oxide production, and nuclear factor κB activation induced by experimental hepatocarcinogenesis. The data provide additional evidence for the potential use of roxithromycin in treatment of hepatocellular carcinoma prevention.
Ultrastructural morphometric analysis of myocardium from dogs, rats, hamsters, mice, and from human hearts.
Authors: J Schaper, E Meiser, G Stämmler
Journal: Circulation Research (1985)

Volume densities of mitochondria, myofibrils, and unspecified cytoplasm were measured by ultrastructural morphometry in myocardium from dogs, rats, hamsters, mice, and in biopsied tissue from human hearts. Human myocardium was composed of 23% mitochondria, 59% myofibrils, and 18% cytoplasm. Volume densities for mitochondria were 22% for dogs, 28% for rats and hamsters, and 32% for mice. Myofibrillar volume densities were highest in dogs with 63%, 57% for rats and hamsters, and 49% for mice. Differences were significant between all except man and dog, and rat and hamster. In an extensive analysis of canine myocardium, it could be shown that the quantitative composition of tissue from the left ventricular free wall (anterior, lateral, posterior) and the papillary muscles was identical. There were also no differences between subepi- and subendocardium as well as the midmyocardium. Volume densities from longitudinal sections were identical to those from transversal sections. Fixation with glutaraldehyde by perfusion or immersion provided identical results. There were no differences between volume densities in samples from the left ventricular free wall (anterior, lateral, and posterior) in rats, hamsters, and mice. It is concluded that each mammalian species is characterized by a very typical quantitative composition of the myocardium. The increase in mitochondrial volume correlated well with the increase in heart rate and oxygen consumption in smaller animals. These quantitative data are regarded as the morphological correlate of the differing functional capacity of hearts from different species.
INVERSION OF THE APPENDIX AND CAECUM
Authors: W. J. Greer
Journal: BMJ (1909)

rDEC. 18, I9.an increase of the urine passed next day after operation,' and it was passed naturally.There was no increased tendency to haemorrhage.The only disadvantage observed was that there was a tendency to reaction after the effect of the injection had passed off, but this was transitory, and the patient was then over the worst period.I have to thank Mr. Stamford for permission to publish the first two cases, and Dr. Foulds for the third.
Early Percutaneous Coronary Intervention, Platelet Inhibition With Eptifibatide, and Clinical Outcomes in Patients With Acute Coronary Syndromes
Authors: Neal S. Kleiman, A. Michael Lincoff, Greg C. Flaker, Karen S. Pieper, R. G. Wilcox, Lisa G. Berdan, Todd J. Lorenz, Dennis V. Cokkinos, Maarten L. Simoons, Eric Boersma, Eric J. Topol, Robert M. Califf, Robert A. Harrington
Journal: Circulation (2000)

Background —Platelet glycoprotein (GP) IIb/IIIa antagonists prevent the composite end point of death or myocardial infarction (MI) in patients with acute coronary syndromes. There is uncertainty about whether this effect is confined to patients who have percutaneous coronary interventions (PCIs) and whether PCIs further prevent death or MI in patients already treated with GP IIb/IIIa antagonists. Methods and Results —PURSUIT patients were treated with the GP IIb/IIIa antagonist eptifibatide or placebo; PCIs were performed according to physician practices. In 2253 of 9641 patients (23.4%), PCI was performed by 30 days. Early (&lt;72 hours) PCI was performed in 1228 (12.7%). In 34 placebo patients (5.5%) and 10 treated with eptifibatide (1.7%) ( P =0.001), MI preceded early PCI. In patients censored for PCI across the 30-day period, there was a significant reduction in the primary composite end point in eptifibatide patients ( P =0.035). Eptifibatide reduced 30-day events in patients who had early PCI (11.6% versus 16.7%, P =0.01) and in patients who did not (14.6% versus 15.6%, P =0.23). After adjustment for PCI propensity, there was no evidence that eptifibatide treatment effect differed between patients with or without early PCI ( P for interaction=0.634). PCI was not associated with a reduction of the primary composite end point but was associated with a reduced (nonspecified) composite of death or Q-wave MI. This association disappeared after adjustment for propensity for early PCI. Conclusions —Eptifibatide reduced the composite rates of death or MI in PCI patients and those managed conservatively.
Olanzapine Versus Placebo in the Treatment of Adolescents With Bipolar Mania
Authors: Mauricio Tohen, Ludmila Kryzhanovskaya, Gabrielle Carlson, Melissa DelBello, Janet Wozniak, Robert Kowatch, Karen Wagner, Robert Findling, Daniel Lin, Carol Robertson-Plouch, Wen Xu, Ralf W. Dittmann, Joseph Biederman
Journal: American Journal of Psychiatry (2007)

Objective: The purpose of this study was to evaluate the efficacy and safety of olanzapine for the treatment of acute manic or mixed episodes associated with bipolar disorder in adolescents. Method: A 3-week multicenter, parallel, double-blind, randomized placebo-controlled trial was conducted at 24 sites in the United States and two sites in Puerto Rico. The participants were outpatient and inpatient male and female adolescents 13–17 years of age with an acute manic or mixed episode. Subjects received either olanzapine (2.5–20 mg/day [N=107]) or placebo (N=54). The mean change from baseline to endpoint in the Young Mania Rating Scale total score was the primary outcome measure. Results: The mean baseline-to-endpoint change in the Young Mania Rating Scale total score was significantly greater for patients receiving olanzapine relative to patients receiving placebo, and a greater proportion of olanzapine-treated patients met response and remission criteria (44.8% versus 18.5% and 35.2% versus 11.1%, respectively). The mean baseline-to-endpoint weight change was significantly greater for patients receiving olanzapine relative to patients receiving placebo (3.7 kg versus 0.3 kg), and the incidence of treatment-emergent weight gain ≥7% of baseline was higher for olanzapine-treated patients (41.9% versus 1.9%). The mean baseline-to-endpoint changes in prolactin, fasting glucose, fasting total cholesterol, uric acid, and the hepatic enzymes aspartate transaminase and alanine transaminase were significantly greater in patients treated with olanzapine relative to patients receiving placebo. Conclusions: Olanzapine was effective in the treatment of bipolar mania in adolescent patients. Patients treated with olanzapine, however, had significantly greater weight gain and increases in the levels of hepatic enzymes, prolactin, fasting glucose, fasting total cholesterol, and uric acid.
Phase II Study of Oxaliplatin for Treatment of Patients With Mucosa-Associated Lymphoid Tissue Lymphoma
Authors: Markus Raderer, Stefan Wöhrer, Rupert Bartsch, Gerald Prager, Johannes Drach, Michael Hejna, Alexander Gaiger, Karl Turetschek, Ulrich Jaeger, Berthold Streubel, Christoph C. Zielinski
Journal: Journal of Clinical Oncology (2005)

Various chemotherapeutic regimens have been applied for treatment of mucosa-associated lymphoid tissue (MALT) lymphoma, but no standard regimen has been identified to date. In view of the activity of oxaliplatin (L-OHP) in various types of lymphoma, we performed a phase II study to evaluate the activity of L-OHP for treatment of MALT lymphoma. The primary objective of this study was to determine the objective response rate according to WHO standard criteria.A total of 16 patients with MALT lymphoma of various sites of origin (four of the ocular adnexa, five of the salivary glands, three of the stomach, two of the lung, and one of the colon and the breast) were administered L-OHP at a dose of 130 mg/m2 infused during 2 hours every 3 weeks. Restaging was performed every two cycles; treatment was continued until complete remission (CR) or for a maximum of six cycles in responders.Sixty-five cycles were administered (median, four; range, two to six); toxicity consisted of transient sensory neuropathy in eight patients and nausea/emesis WHO grade 2 in two patients, whereas hematologic adverse effects (thrombocytopenia and leukocytopenia grade 2) occurred in only one patient each. Fifteen patients responded to chemotherapy, with nine achieving CR (56%), six (37.5%) achieving partial response, and one achieving stable disease; the median time to response was 4 months (range; 2 to 4 months).These data suggest L-OHP is a highly active agent for treatment of MALT lymphoma. However, a longer follow-up is needed to judge whether these remissions are durable.
Systematic Interrogation of 3q26 Identifies <i>TLOC1</i> and <i>SKIL</i> as Cancer Drivers
Authors: Daniel Hagerstrand, Alexander Tong, Steven E. Schumacher, Nina Ilic, Rhine R. Shen, Hiu Wing Cheung, Francisca Vazquez, Yashaswi Shrestha, So Young Kim, Andrew O. Giacomelli, Joseph Rosenbluh, Anna C. Schinzel, Nicole A. Spardy, David A. Barbie, Craig H. Mermel, Barbara A. Weir, Levi A. Garraway, Pablo Tamayo, Jill P. Mesirov, Rameen Beroukhim, William C. Hahn
Journal: Cancer Discovery (2013)

3q26 is frequently amplified in several cancer types with a common amplified region containing 20 genes. To identify cancer driver genes in this region, we interrogated the function of each of these genes by loss- and gain-of-function genetic screens. Specifically, we found that TLOC1 (SEC62) was selectively required for the proliferation of cell lines with 3q26 amplification. Increased TLOC1 expression induced anchorage-independent growth, and a second 3q26 gene, SKIL (SNON), facilitated cell invasion in immortalized human mammary epithelial cells. Expression of both TLOC1 and SKIL induced subcutaneous tumor growth. Proteomic studies showed that TLOC1 binds to DDX3X, which is essential for TLOC1-induced transformation and affected protein translation. SKIL induced invasion through upregulation of SLUG (SNAI2) expression. Together, these studies identify TLOC1 and SKIL as driver genes at 3q26 and more broadly suggest that cooperating genes may be coamplified in other regions with somatic copy number gain.These studies identify TLOC1 and SKIL as driver genes in 3q26. These observations provide evidence that regions of somatic copy number gain may harbor cooperating genes of different but complementary functions.
Evidence-Based Medicine
Authors: Gordon Guyatt
Journal: JAMA (1992)

A NEW paradigm for medical practice is emerging. Evidence-based medicine de-emphasizes intuition, unsystematic clinical experience, and pathophysiologic rationale as sufficient grounds for clinical decision making and stresses the examination of evidence from clinical research. Evidence-based medicine requires new skills of the physician, including efficient literature searching and the application of formal rules of evidence evaluating the clinical literature. An important goal of our medical residency program is to educate physicians in the practice of evidence-based medicine. Strategies include a weekly, formal academic half-day for residents, devoted to learning the necessary skills; recruitment into teaching roles of physicians who practice evidence-based medicine; sharing among faculty of approaches to teaching evidence-based medicine; and providing faculty with feedback on their performance as role models and teachers of evidence-based medicine. The influence of evidencebased medicine on clinical practice and medical education is increasing. <h3>CLINICAL SCENARIO</h3> A junior medical resident working in a teaching hospital
Genomic Sequencing in Newborn Screening Programs
Authors: Wybo J. Dondorp, Guido M. W. R. de Wert, Martinus F. Niermeijer
Journal: JAMA (2012)

1. Koh HK, Piotrowski JJ, Kumanyika S, Fielding JE. Healthy people: a 2020 vision for the social determinants approach. Health Educ Behav. 2011;38(6):551557. 2. Freedman DS; Centers for Disease Control and Prevention (CDC). Obesity— United States, 1988-2008. MMWR Surveill Summ. 2011;60(suppl):73-77. 3. Ogden CL, Lamb MM, Carroll MD, Flegal KM. Obesity and socioeconomic status in children and adolescents: United States, 2005-2008. NCHS Data Brief. 2010; (51):1-8. 4. Flegal KM, Pamuk ER. Interpreting trends estimated from national survey data. Prev Med. 2007;45(2-3):115-116.
Gastric cancer and other endoscopic diagnoses in patients with benign dyspepsia
Authors: N P Breslin
Journal: Gut (2000)

<h3>BACKGROUND</h3> It has been suggested that endoscopy could be replaced with non-invasive assessment of helicobacter status in the initial work up of young dyspeptic patients without sinister symptoms. <h3>AIMS</h3> To determine the incidence of gastro-oesophageal malignancy in young dyspeptic patients. <h3>METHODS</h3> The Alberta Endoscopy Project captured clinical and demographic data on all endoscopies performed from April 1993 to February 1996 at four major adult hospitals in Alberta. The endoscopic and histological diagnosis in a subgroup of patients under 45 years of age without alarm symptoms that had undergone gastroscopy was reviewed. In addition, a random list of 200 patients was generated and their medical records reviewed in order to assess the proportion with symptoms suitable for a non-invasive management strategy. <h3>RESULTS</h3> Gastroscopy was performed in 7004 patients under 45 years. In 3634 patients (56% female) alarm type symptoms were absent; 78.9% of patients had symptoms amenable to a non-invasive initial approach, giving a corrected sample size of 2867 patients (correction factor 0.789). Three gastric cancers, one case of moderate dysplasia, 10 biopsy proved cases of Barrett9s oesophagus, and 19 oesophageal strictures/rings were detected within this sample. The corrected prevalence of gastric cancer in this select population was 1.05 per thousand patients. <h3>DISCUSSION</h3> Endoscopy yielded three gastric cancers in this sample of under 45 year old dyspeptic patients without sinister symptoms. While initial non-invasive screening with one-week triple therapy for helicobacter positive individuals is unlikely to have a detrimental outcome the physician is advised to consider endoscopy in patients with persisting, recurrent, or sinister symptoms.
CD8− DCs induce IL-12–independent Th1 differentiation through Delta 4 Notch-like ligand in response to bacterial LPS
Authors: Dimitris Skokos, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2007)

Toll-like receptor (TLR) ligation is believed to skew T cell responses toward T helper (Th)1 differentiation by inducing interleukin (IL)-12 secretion by CD8(+) dendritic cells (DCs). However, TLR-dependent Th1 responses occur in the absence of IL-12. To determine how DCs induce Th1 differentiation in the absence of IL-12, we examined the response of IL-12-deficient DCs to bacterial lipopolysaccharide (LPS). We find that LPS activates MyD88-dependent Delta 4 Notch-like ligand expression by CD8(-) DCs, and that these cells direct Th1 differentiation by an IL-12-independent and Notch-dependent mechanism in vitro and in vivo. Thus, activation of the two DC subsets by TLR4 leads to Th1 responses by two distinct MyD88-dependent pathways.
<i>Yersinia</i>-induced Apoptosis In Vivo Aids in the Establishment of a Systemic Infection of Mice
Authors: Denise M. Monack, Joan Mecsas, Donna Bouley, Stanley Falkow
Journal: The Journal of Experimental Medicine (1998)

Pathogenic Yersinia cause a systemic infection in mice that is dependent on the presence of a large plasmid encoding a number of secreted virulence proteins called Yops. We previously demonstrated that a plasmid-encoded Yop, YopJ, was essential for inducing apoptosis in cultured macrophages. Here we report that YopJ is a virulence factor in mice and is important for the establishment of a systemic infection. The oral LD50 for a yopJ mutant Yersinia pseudotuberculosis increases 64-fold compared with wild-type. Although the yopJ mutant strain is able to reach the spleen of infected mice, the mutant strain seldom reaches the same high bacterial load that is seen with wild-type Yersinia strain and begins to be cleared from infected spleens on day 4 after infection. Furthermore, when in competition with wild-type Yersinia in a mixed infection, the yopJ mutant strain is deficient for spread from the Peyer's patches to other lymphoid tissue. We also show that wild-type Yersinia induces apoptosis in vivo of Mac-1+ cells from infected mesenteric lymph nodes or spleens, as measured by quantitative flow cytometry of TUNEL (Tdt-mediated dUTP–biotin nick-end labeling)-positive cells. The levels of Mac-1+, TUNEL+ cells from tissue infected with the yopJ mutant strain were equivalent to the levels detected in cells from uninfected tissue. YopJ is necessary for the suppression of TNF-α production seen in macrophages infected with wild-type Yersinia, based on previous in vitro studies (Palmer, L.E., S. Hobbie, J.E. Galan, and J.B. Bliska. 1998. Mol. Microbiol. 27:953–965). We conclude here that YopJ plays a role in the establishment of a systemic infection by inducing apoptosis and that this is consistent with the ability to suppress the production of the proinflammatory cytokine tumor necrosis factor α.
B cells keep on editing
Authors: Mitch Leslie
Journal: The Journal of Experimental Medicine (2008)

B cells are famous for rearranging their antibody genes. Contrary to conventional wisdom, this tinkering continues even after the cells leave their birthplace in the bone marrow, Wang et al. reveal on page 3079.






Figure 1

B cells (brown) undergo peripheral receptor editing.




Antibody genes typically undergo several rounds of revision. The gene segments first reshuffle to produce uniquely shaped antibodies. Some B cell genes undergo a further tweak, known as receptor editing, to revamp antibody genes that might lead to attacks on self antigens. The timing of receptor editing is controversial. Most researchers assume it occurs while B cells are maturing in the bone marrow. However, some findings suggest that B cells continue the process even after they relocate to the lymph nodes and spleen.

Wang et al. chanced across fresh evidence while studying the origin of a lymphatic cancer. Whenever it happens, receptor editing involves breaking the DNA and then healing it through a process called non-homologous end-joining (NHEJ). Failure of NHEJ in other situations can lead to cancer-causing chromosome instability, so the researchers wanted to test whether disrupting this type of repair promotes lymphatic tumors.

They created a mouse line in which a key NHEJ gene malfunctions in B cells that have exited the bone marrow. Sure enough, B cell–derived tumors sprouted in the mice. To the researchers' surprise, the cells that gave rise to the tumors had performed not only the initial reshuffling, but also receptor editing, thus supporting the hypothesis that at least some receptor editing occurs outside the bone marrow. The caveat, the scientists say, is that the tumor cells might not duplicate what happens in normal B cells. The benefits of late revisions aren't clear, but they might allow the immune system to further expand its repertoire of antibodies.