tbuckley/cabot-search huggingface dataset:
<scp>TAK</scp>‐228 (formerly <scp>MLN</scp>0128), an investigational oral dual <scp>TORC</scp>1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non‐Hodgkin lymphoma, or Waldenström's macroglobulinemia
Authors: Irene M. Ghobrial, David S. Siegel, Ravi Vij, Jesus G. Berdeja, Paul G. Richardson, Rachel Neuwirth, Chirag G. Patel, Fabian Zohren, Jeffrey L. Wolf
Journal: American Journal of Hematology (2016)

The PI3K/AKT/mTOR signaling pathways are frequently dysregulated in multiple human cancers, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Waldenström's macroglobulinemia (WM). This was the first clinical study to evaluate the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and preliminary clinical activity of TAK-228, an oral TORC1/2 inhibitor, in patients with MM, NHL, or WM. Thirty-nine patients received TAK-228 once daily (QD) at 2, 4, 6, or 7 mg, or QD for 3 days on and 4 days off each week (QDx3d QW) at 9 or 12 mg, in 28-day cycles. The overall median age was 61.0 years (range 46-85); 31 patients had MM, four NHL, and four WM. Cycle 1 DLTs occurred in five QD patients (stomatitis, urticaria, blood creatinine elevation, fatigue, and nausea and vomiting) and four QDx3d QW patients (erythematous rash, fatigue, asthenia, mucosal inflammation, and thrombocytopenia). The MTDs were determined to be 4 mg QD and 9 mg QDx3d QW. Thirty-six patients (92%) reported at least one drug-related toxicity; the most common grade ≥3 drug-related toxicities were thrombocytopenia (15%), fatigue (10%), and neutropenia (5%). TAK-228 exhibited a dose-dependent increase in plasma exposure and no appreciable accumulation with repeat dosing; mean plasma elimination half-life was 6-8 hr. Of the 33 response-evaluable patients, one MM patient had a minimal response, one WM patient achieved partial response, one WM patient had a minor response, and 18 patients (14 MM, two NHL, and two WM) had stable disease. These findings encourage further studies including combination strategies.
Abstract 39: Organic Nitrates Improve Calcium Handling and Myofilament Sensitivity Impaired by Nitroso-Redox Disequilibrium
Authors: Raul A Dulce, Wayne E Balkan, Joshua M Hare
Journal: Circulation Research (2012)

Oxidative stress is a key factor in the dysfunctional calcium (Ca 2+ ) handling and contractile performance in heart disease. Organic nitrates are used for the treatment of cardiovascular afflictions, however endogenous nitric oxide (NO) has a broad spectrum of actions and the mechanisms by which it regulates Ca 2+ cycling and contractility is poorly understood. Neuronal NO synthase (nNOS) deficiency induces a nitroso-redox disequilibrium characterized by oxidative stress and altered contractility and calcium handling. We hypothesize that treatment of nNOS −/− mice with organic nitrates such as nitroglycerin (TNG) or isosorbide dinitrate (ISDN) reduces cytosolic calcium levels and restores myofilament responsiveness to calcium with no changes in contractility. Cardiomyocytes (CMs) were isolated from nNOS −/− (N=7) and wild type (WT) mice (N=3). Cells were loaded with fura-2 and then electrically evoked intracellular Ca 2+ and sarcomere length were simultaneously measured in an IonOptix system. It has been shown that L-type Ca 2+ current is exacerbated in nNOS −/− cardiomyocytes. In consequence, at 1 Hz pacing rate, Ca 2+ peak and transient amplitude were increased in nNOS −/− (Peak Ca 2+ : 571 ± 38 nM) compared to WT (401 ± 32 nM; p = 0.012) cardiomyocytes, which was reduced toward normal by 10 nmol/L TNG (453 ± 55 nM; p = 0.11) as well as 10 nmol/L ISDN (394 ± 65; p = 0.035). Phospholamban phosphorylation has been shown to be reduced in nNOS −/− CMs, possibly due to the enhanced activity of protein phosphatases induced by oxidative stress. Thus, Ca 2+ decay and sarcomere relaxation were slower in nNOS −/− compared to WT CMs ( p &lt; 0.0001). Treatment with TNG ( p &lt; 0.0001 vs. NOS1 −/− ) or ISDN ( p &lt; 0.0001 vs. NOS1 −/− ) accelerated Ca 2+ decay and relaxation. Ca 2+ sensitivity was impaired in nNOS −/− ( p &lt; 0.021 vs. WT). Although organic nitrates either reduce or do not affect myofilament sensitivity in normal myocytes, TNG and ISDN increased their responsiveness to Ca 2+ in nNOS −/− . In conclusion, restoration of NO availability and subsequent attenuation of the nitroso-redox imbalance, improved excitation-contraction coupling in nNOS −/− CMs, decreased intracellular Ca 2+ which is counteracted by the improved myofilament sensitivity resulting in no net change in contractility.
Study Finds Black Women Have Denser Breast Tissue Than White Women:
Authors: Sue Rochman
Journal: JNCI Journal of the National Cancer Institute (2015)

A study using a new tool to measure mammographic density found that black women have denser breast tissue than white women. The findings add to the research on breast density, cancer disparities, and risk-based screening. Breast density refers to the amount of fibroglandular tissue in the breast when observed on a mammogram. Dense breast tissue shows up white on a mammogram, as do cancer cells, making it difficult for the radiologist to spot a tumor. About half of all women who have screening mammography are found to have dense breast tissue. About 40% of these women have heterogeneously dense breast tissue and about 10% have extremely dense breast tissue. Breast density also serves as an independent predictor of breast cancer risk. Women with heterogeneously dense breast tissue have about a 1.2 times greater risk of developing breast cancer than that of women with average breast density. Women with extremely dense breast tissue have about twice the risk. Studies comparing breast density between black women and white women have had mixed results. For the new study, researchers quantified breast density on mammography images from 1,589 black women and 1,256 white women by using a validated, publicly available, automated software algorithm called LIBRA (Laboratory for Individualized Breast Radiodensity Measurement) developed at the University of Pennsylvania. (http:// www.cbica.upenn.edu/sbia/software/ LIBRA/) The analysis controlled for other known breast cancer risk factors, including body mass index, prior biopsy, age at menarche, menopause status, family history, age at first birth, and use of menopausal hormone therapy. Black women had statistically significantly higher absolute breast area density (40.1 cm2) than white women
Abstract 18222: Pacemaker Quantified Physical Activity Predicts All-Cause Mortality
Authors: Sudhi Tyagi, Marcie Berger, Judith Fox, Michael Curley, Scott Strath, Jason Rubenstein, James Roth, Michael Widlansky
Journal: Circulation (2014)

Background:  Cardiac implantable electronic devices provide a unique opportunity to collect precise quantitative longitudinal data with respect to sedentary time and physical activity. We hypothesized that individuals who have greater habitual physical activity based on pacemaker accelerometer measurements would have improved survival compared to those who were sedentary.   Methods:  Electronic medical records of 62 individuals who underwent de novo pacemaker implantation with a Medtronic EnRhythm™ device at a single center between January 1, 2005 and December 31, 2012 were reviewed. This pacemaker includes an internal accelerometer that measures per minute activity level as above or below a 70 steps/minute threshold and reports the average hours/day activity exceeding this threshold. Accelerometer data obtained from interrogations were abstracted and averaged over a 1 year time period following a 6-month blanking period following implantation. Individuals were categorized as having failed to reach (n=26) or met/exceeded the activity threshold for ≥2 hours/day (n=36). Survival was compared between groups by Kaplan-Meier estimate and Cox proportional hazards models.   Results:  Cohort average age was 70±12 years. 43.5% had prevalent CAD. Average follow-up time was 5.2±2.1 years. Death occurred in 17 patients (27.4%), 11/26 (42.3%) of the group that failed to achieve the activity threshold for ≥2 hours/day vs. 6 (16.7%) of the group achieving the threshold (p=0.02 by log rank test). Death was over 3 times more likely in the inactive group than the active group [OR 3.11, 95% CI (1.15-8.47), P=0.02]. Following adjustment for sex and CAD, low activity remained a significant risk factor for death [OR 2.99, 95% CI (1.08-8.26), P=0.036].   Conclusions:  Pacemaker accelerometer data effectively predicts mortality in pacemaker patients and demonstrates that physical inactivity is associated with reduced survival in this patient population.
Nanoparticulate mineralized collagen scaffolds induce in vivo bone regeneration independent of progenitor cell loading or exogenous growth factor stimulation
Authors: Xiaoyan Ren, Victor Tu, David Bischoff, Daniel W. Weisgerber, Michael S. Lewis, Dean T. Yamaguchi, Timothy A. Miller, Brendan A.C. Harley, Justine C. Lee
Journal: Biomaterials (2016)
Acquired EGFR Mutation as the Potential Resistance Driver to Crizotinib in a MET-Mutated Tumor
Authors: Marc-Antoine Benderra, Sandrine Aspeslagh, Sophie Postel-Vinay, Ludovic Bigot, Thierry De Baere, Yohann Loriot, Ludovic Lacroix, Christophe Massard, Gilles Vassal, Fabrice André, Jean-Charles Soria
Journal: Journal of Thoracic Oncology (2015)
Aset Study: Final Results of Patients with Locally Recurrent or Metastatic Renal Cell Carcinoma (Rcc) Treated with Mgn1601
Authors: V. Grünwald, S. Weikert, I. Schmidt-Wolf, S. Hauser, A. Magheli, K. Kapp, M. Schroff, M. Schmidt, B. Wittig
Journal: Annals of Oncology (2014)
Mucosal Melanoma: A Clinically and Biologically Unique Disease Entity
Authors: Richard D. Carvajal, Sharon A. Spencer, William Lydiatt
Journal: Journal of the National Comprehensive Cancer Network (2012)

Mucosal melanoma (MM) is an aggressive and clinically complex malignancy made more challenging by its relative rarity. Because of the rarity of MM as a whole, and because of the unique biology and clinical challenges of MM arising from each anatomic location, understanding of this disease and its optimal management remains limited. The impact of various treatment strategies on disease control and survival has been difficult to assess because of the small size of most reported series of MM arising from any one particular site, the retrospective nature of most series, and the lack of a uniform comprehensive staging system for this disease. This article summarizes the clinical, pathologic, and molecular features, and the diagnostic and therapeutic considerations for the management of MM, underscoring the similarities and differences from cutaneous melanoma. Furthermore, the distinct clinical features and management implications unique to melanoma arising from the mucosal surfaces of the head and neck, the anorectal region, and the female genital tract are highlighted.
Caesarean delivery and risk of childhood leukaemia: a pooled analysis from the Childhood Leukemia International Consortium (CLIC)
Authors: Erin L Marcotte, Thomas P Thomopoulos, Claire Infante-Rivard, Jacqueline Clavel, Eleni Th Petridou, Joachim Schüz, Sameera Ezzat, John D Dockerty, Catherine Metayer, Corrado Magnani, Michael E Scheurer, Beth A Mueller, Ana M Mora, Catharina Wesseling, Alkistis Skalkidou, Wafaa M Rashed, Stephen S Francis, Roula Ajrouche, Friederike Erdmann, Laurent Orsi, Logan G Spector
Journal: The Lancet Haematology (2016)
Molecular and Functional Characterization Of The Novel Protein-Coding Gene Tihl (Translocated in Hodgkin’s Lymphoma) in Hematopoiesis
Authors: Ujunwa Cynthia Okoye-Okafor, Laura Barreyro, Heng Rui Wang, Boris Bartholdy, Britta Will, Tihomira I Todorova, Swathi-Rao Narayanagari, Mario Pujato, Masahiro Kawahara, Bruce W. Woolcock, Randy D. Gascoyne, Christian Steidl, Ulrich Steidl
Journal: Blood (2013)
Tamoxifen: is it useful in the treatment of patients with metastatic melanoma?
Authors: E F McClay, M E McClay
Journal: Journal of Clinical Oncology (1994)

PURPOSE We have attempted to review the data regarding the activity of tamoxifen (TAM) to clarify the role of this agent in the treatment of metastatic melanoma. METHODS Using the Melvyl Medline system, we identified recent reports describing the results of clinical trials that used TAM either as a single agent or in combination with other cytotoxic agents. Additionally, we reviewed the abstracts from the 29th Annual Meeting of the American Society of Clinical Oncology held in May 1993. RESULTS Numerous articles have reported an overall response rate of 47% (95% confidence limit, 39.25 to 54.75) when patients with metastatic melanoma are treated with the combination of dacarbazine (DTIC), carmustine (BCNU), cisplatin (DDP), and TAM (DBDT). Additionally, recent laboratory studies have reported that synergism between TAM and DDP is at least partially responsible for the success of this regimen. CONCLUSION While TAM as a single agent is minimally active in treating patients with metastatic melanoma, when it is combined with DTIC, BCNU, and DDP, a marked improvement in the overall response rate is observed. Although a prospective randomized trial has yet to be completed, it appears that this four-drug combination has a higher overall and complete response (CR) rate when compared with single-agent DTIC. In light of the relatively modest toxicity observed with this regimen, the combination of DBDT represents a reasonable alternative to single-agent DTIC as first-line therapy for patients with metastatic melanoma.
Analysis of FDA Warning Letters issued to investigotors in oncology clinical trials from 1997 to 2002
Authors: S. M. Sharp
Journal: Journal of Clinical Oncology (2004)

6093 Background: The FDA conducts inspections of clinical trials of investigational drugs and devices. When very serious problems in the conduct of the trial are discovered the FDA notifies the responsible investigator through the issuance of a Warning Letter (“WL”). This study examines the frequency of such actions and the specific nature of the problems identified by the FDA. Methods: All WLs issued by the FDA from Jan. 1997 through Dec. 2003 publicly available under the Freedom of Information Act were reviewed and the violations of Federal Regulations alleged were categorized using a content analysis procedure. The violations of Federal Regulations that formed the basis for the complaint alleged in the WL were reviewed and categorized using a content-analysis approach. Results: 5,896 WLs were issued during this period; 97 (1.65%) to clinical investigators, of which 15 (15.5%) were for oncology trials; 66.7% of those for oncology trials went to academic investigators. The most frequent violations alleged were: failure to meet the general obligation of an investigator (86.7%), failure to maintain required records (66.7%), failure to properly report serious adverse events (46.7%) and failure to obtain proper informed consent ((40%). Conclusions: Although the absolute number of WLs for oncology trials is small, they represent a disproportionate percentage of those issued to clinical investigators and provide evidence of serious problems in the conduct of some studies. By examining the problems discovered during FDA inspections opportunities for improvement in investigator training, trial design and monitoring can be identified. No significant financial relationships to disclose.
Tumor-Virus Relationships in Gross Virus-Induced Mouse Lymphomas2
Authors: Donna L. Vredevoe, Esther F. Hays
Journal: JNCI Journal of the National Cancer Institute (1973)

Journal Article Tumor-Virus Relationships in Gross Virus-Induced Mouse Lymphomas Get access Donna L. Vredevoe, Donna L. Vredevoe Laboratory of Nuclear Medicine and Radiation Biology and School of Nursing, Center for the Health Sciences, University of California, Los Angeles, Calif. 90024 Search for other works by this author on: Oxford Academic PubMed Google Scholar Esther F. Hays Esther F. Hays Laboratory of Nuclear Medicine and Radiation Biology and Department of Medicine, School of Medicine, Center for the Health Sciences, University of California, Los Angeles, Calif. 90024 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 51, Issue 5, November 1973, Pages 1619–1625, https://doi.org/10.1093/jnci/51.5.1619 Published: 01 November 1973 Article history Received: 18 May 1973 Accepted: 23 July 1973 Published: 01 November 1973
Drugs as Reinforcers in Monkey and Man
Authors: Charles R. Schuster
Journal: Pharmacological Reviews (1975)

I have presented data to illustrate and evaluate the use of animal experiments on behavior maintained by drug injection as an animal model of human drug abuse. I believe, the data justify the cautious application of such an animal model for predicting the abuse potential of a new drug, for evaluating new forms of treatment, and finally, for investigating biological and environmental variables controlling drug taking behavior. However, there are a variety of assumptions whenever we extrapolate conclusions from laboratory studies to man in his natural environment.
Analysis of breast cancer tissues by Fourier Transform Infrared Rapid Scan Imaging
Authors: S. Rehman, P. Revell, I. U. Rehman
Journal: Journal of Clinical Oncology (2005)

3097 Background: Fourier Transform Infrared (FTIR) spectroscopy is a technique which provides information regarding biochemical composition of tissues. FTIR is based upon the absorption of infrared light by covalent bonds as they vibrate. Recently an FTIR chemical imaging technique has been developed which can rapidly scan a sample to extract a chemical image exhibiting the chemical distribution of various tissue components. It is a novel technique and not many studies have been reported in the literature with this technique yet. Methods: In this retrospective study, formalin - fixed, paraffin - wax embedded histopathological sections of 7 normal breast tissues and 60 breast cancer tissues were analysed by this technique to obtain chemical images and spectra. The cancerous tissues included 10 specimens each of lower - nuclear grade (LNG), intermediate - nuclear grade (ING) and high - nuclear grade ductal carcinoma in situ (DCIS); and well - differentiated, intermediate - differentiated and poorly - differentiated invasive ductal carcinoma (IDC). Infrared spectra were obtained using a Digilab rapid - scan FTIR spectrometer Excalibur FTS 3000 with the UMA-600 Infrared microscope equipped with a liquid nitrogen cooled MCTA detector and an MCT focal plane array detector. Spectra were taken from at least 3 nuclei from each specimen at 8cm−1 resolution averaging 256 scans. Results: Normal breast tissues showed significant spectral differences as compared to DCIS and IDC. Furthermore, DCIS grades and IDC grades also exhibited significant spectral differences. To our knowledge, this study reports for the first time spectral differences between DCIS grades. Previous studies reported in the literature have reported spectral differences between normal and malignant breast and one study has looked at IDC grades. Conclusions: FTIR chemical imaging allows analysis of same specimens used for histopathological evaluation. Its feasibility and reproducibility to demonstrate chemical structural differences between normal and cancerous breast and between DCIS grades and IDC grades is demonstrated which can help to establish a database of spectra for future studies to explore the potential of the technique as a diagnostic tool. No significant financial relationships to disclose.
Stilbestrol and Vaginal Cancer In Young Women
Authors: A L Herbst
Journal: CA A Cancer Journal for Clinicians (1972)

Regarding maternal ingestion of stilbestrol to high-risk pregnant patients during the late 1940's and early 1950's and the appearance of vaginal adenocarcinoma in their female offspring years later, physicians are advised to examine patients whose mothers received stilbestrol during pregnancy. Once these females reach the menarche, periodic vaginal examinations are required. A diagnosis of cancer should be considered when abnormal vaginal bleeding occurs. It is hypothesized that these cancers originate from adenomatous vaginal lesions that become malignant. The high incidence of benign vaginal adenosis suggests that an anomaly of vaginal epithelial development may be a predisposing condition. Since reporting on 8 patients in 1970, there is more evidence of an association between maternal stilbestrol administration and vaginal cancer in the offspring. More than 80 cases of vaginal and cervical adenocarcinoma in young women have been diagnosed. In most cases the maternal medical history revealed intrauterine exposure to stilbestrol, dienestrol or hexestrol. The Food and Drug Administration has warned all physicians that stilbestrol is contraindicated in pregnant women. Physicians who are contacted by worried mothers or anxious young women can be assured that, as yet, the risk appears to be low, but the public should be made aware that adolescent females and young women who had fetal exposure to stilbestrol need regular vaginal examination.
Life expectancy falls in Europe
Authors: Adrea Mach
Journal: BMJ (1998)

Laying the blame squarely on “poverty, unemployment, homelessness, excessive drinking, and smoking” and on health reforms that are too reliant on “market forces,” the World Health Organisation's latest report reveals that Europe's overall health is deteriorating for the first time in 50 years.

The report, which contains data on key indicators of health, was released at this week's meeting of the 50 active member states of the WHO's regional committee for Europe in Copenhagen. It shows that average life expectancy across Europe (although still higher than in the other WHO regions) has fallen for the first time since the second world war--from 73.1 years in 1991 to 72.3 in 1995.

The reason for the fall is the social …