tbuckley/cabot-search huggingface dataset:
Delayed Cutaneous Sensitivity Reactions to Extracts of Autologous Malignant Melanoma: A Second Look&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Avrum Z. Bluming, M.D., Charles L. Vogel, M.D., John L. Ziegler, M.D., Jovan W. M. Kiryabwire, F.R.C.S.
Journal: JNCI Journal of the National Cancer Institute (1972)

Sixteen consecutively admitted patients with malignant melanoma were skin tested with autologous tumor extract (ATE), a variety of cutaneous antigens, and when available, autologous normal skin extracts (ASE). A protein concentration of 1 mg/ml was used as the critical antigenic challenge for both ATE and ASE testing. Anergy was not encountered in any of this group. Positive delayed sensitivity reactions to ATE were elicited in 11 patients, 9 of whom were also tested with ASE. Six of the nine (67%) reacted to the ASE as well. The implications of concomitant ATE and ASE reactivity are discussed. No correlation was noted between ASE reactivity and the presence of vitiligo in these patients. No correlation was noted between ATE skin-test reactivity and sex, age, length of history prior to hospitalization, primary disease site, presence of regional node involvement, distant metastases, vitiligo, or duration of remission, even in the 3 patients reacting to ATE and not to ASE. Naturally occurring cutaneous reactivity to extracts of autologous melanoma cells does not currently appear to represent an effective immunological barrier to tumor progression, though future studies may suggest significant clinical application of this phenomenon.
Rapid, Robust and Accessible Molecular Profiling of Biologically and Clinically Relevant Copy Number Alterations in Multiple Myeloma from Small Amounts of Tumor DNA
Authors: Martin F Kaiser, Paula Proszek, Dil Begum, Nasrin Dahir, Brian A Walker, Suvi Savola, Eileen M Boyle, David C Johnson, David A Cairns, Walter Gregory, Graham Jackson, Roger G Owen, Gordon Cook, Mark T Drayson, Faith E Davies, Gareth J Morgan
Journal: Blood (2014)
NICE recommends PCSK9 inhibitors for patients not responding to statins
Authors: Susan Mayor
Journal: BMJ (2016)

The National Institute for Health and Care Excellence (NICE) has recommended the PCSK9 inhibitors alirocumab and evolocumab for patients with primary hypercholesterolaemia or mixed dyslipidaemia that is not controlled with statins, in final draft guidance based on manufacturers providing the drugs at discounted prices.

The drugs are monoclonal antibodies that target proprotein convertase subtilisin/kexin type 9 (PCSK9), which slows the degradation of low density lipoprotein receptors in the liver. This helps to reduce levels of low density lipoprotein (LDL) cholesterol.

NICE …
ECG-Triggered, Single Cardiac Cycle, High-Speed, 3D, Intracoronary OCT
Authors: Sun-Joo Jang, Hyun-Sang Park, Joon Woo Song, Tae Shik Kim, Han Saem Cho, Sunwon Kim, Brett E. Bouma, Jin Won Kim, Wang-Yuhl Oh
Journal: JACC. Cardiovascular imaging (2016)
Can the Stage and Grade of Disease Be Predicted with Preoperative Peripheral Blood Parameters in Patients with Primary Urothelial Cancer of Urinary Bladder?
Authors: A. Demirtas, H. Tosun, V. Sabur, N. Baydilli, E.C. Akinsal, O. Ekmekcioglu, A. Tatlisen
Journal: Annals of Oncology (2014)
LncRNA GClnc1 Promotes Gastric Carcinogenesis and May Act as a Modular Scaffold of WDR5 and KAT2A Complexes to Specify the Histone Modification Pattern
Authors: Tian-Tian Sun, Jie He, Qian Liang, Lin-Lin Ren, Ting-Ting Yan, Ta-Chung Yu, Jia-Yin Tang, Yu-Jie Bao, Ye Hu, Yanwei Lin, Danfeng Sun, Ying-Xuan Chen, Jie Hong, Haoyan Chen, Weiping Zou, Jing-Yuan Fang
Journal: Cancer Discovery (2016)

Long noncoding RNAs (lncRNA) play a role in carcinogenesis. However, the function of lncRNAs in human gastric cancer remains largely unknown. In this study, we identified a novel lncRNA, GClnc1, which was upregulated and associated with tumorigenesis, tumor size, metastasis, and poor prognosis in gastric cancer. GClnc1 affected gastric cancer cell proliferation, invasiveness, and metastasis in multiple gastric cancer models. Mechanistically, GClnc1 bound WDR5 (a key component of histone methyltransferase complex) and KAT2A histone acetyltransferase, acted as a modular scaffold of WDR5 and KAT2A complexes, coordinated their localization, specified the histone modification pattern on the target genes, including SOD2, and consequently altered gastric cancer cell biology. Thus, GClnc1 is mechanistically, functionally, and clinically oncogenic in gastric cancer. Targeting GClnc1 and its pathway may be meaningful for treating patients with gastric cancer.This report documents a novel lncRNA, GClnc1, which may act as a scaffold to recruit the WDR5 and KAT2A complex and modify the transcription of target genes. This study reveals that GClnc1 is an oncogenic lncRNA in human gastric cancer. Cancer Discov; 6(7); 784-801. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 681.
A phase I/II clinical trial of belinostat (PXD101) in combination with doxorubicin in patients with soft tissue sarcomas (STS).
Authors: Joanna Vitfell-Rasmussen, Maja Lind-Hansen, Akmal Safwat, Philip Rossen, Poul Knoblauch, Robin L Jones, Ian Robert Judson, Anders Krarup-Hansen
Journal: Journal of Clinical Oncology (2015)

10516 Background: Belinostat is a novel histone deacetylase (HDAC) inhibitor. This study assessed the MTD and DLTs of the combination of belinostat and doxorubicin in solid tumours (phase I) and efficacy as measured by response rate (RR) in advanced STS (phase II). Methods: Belinostat was administered as a 30-minute IV infusion on Day 1-4 and on Day 5 in combination with doxorubicin. It was dose escalated using a belinostat starting dose of 600 mg/m2 combined with 50 mg/m2 doxorubicin (cohort 1), in subsequent cohorts doxorubicin was administered at 75 mg/m2 with 600 mg/m2 belinostat (cohort 2), 800 mg/m2 (cohort 3) and 1000 mg/m2 (cohort 4). A phase II trial was then performed in STS patients (pts) using the doses in cohort 4. A stopping rule determined that the phase II trial was stopped if no more than 2 responses (CR/PR) were seen among the 20 pts within the first 2 treatment cycles. The following pharmacokinetic parameters were determined: elimination half-life (t1/2), maximum concentration (Cmax), time to maximum concentration (tmax), area under the curve (AUC0-tf and AUC∞), elimination rate constant (λz) and volume of distribution (Vc and Vss). Results: A total of 41 pts were included (25 in phase I, 20 in phase II (including 4 pts with STS from cohort 4). Common drug-related toxicities included: fatigue (95%), nausea (76%) and alopecia (63%). One DLT was observed, Rash - Hand and Foot Syndrome, CTC grade 3, in cohort 3 on Day 22. The MTD was declared the highest tested dose level: belinostat 1000 mg/m2 combined with 75 mg/m2 doxorubicin. Dose normalised AUC0-tlast and Cmax appeared relatively consistent across the different cohorts on both Days 4 and 5 indicating that belinostat exhibited linear pharmacokinetics across the dose range and that doxorubicin had no effect on belinostat exposure. Two responses were observed in phase I at cycle 4 (2 PR, RR of 8% (95% CI, 1 - 26%)) and in the phase II trial there were 2 responses (1 PR (cycle 4) /1 CR (cycle 2), RR of 13% (95% CI, 2 - 38%)) and 9 SD, hence the trial was stopped after 20 pts were enrolled. Conclusions: The combination of belinostat and doxorubicin was well tolerated and showed activity in 12/20 pts with advanced STS in the MTD population, which warrants further investigation. Clinical trial information: NCT00878800.
Blitz rape and confidence rape: a typology applied to 1,000 consecutive cases
Authors: D C Silverman, S M Kalick, S I Bowie, S D Edbril
Journal: American Journal of Psychiatry (1988)

The case records of 1,000 consecutive rape victims seen at a crisis center were analyzed to identify important categories of rape victimization. The most noteworthy finding was a replication and extension of the blitz rape and confidence rape typology. The distinction between these two types of rape corresponded to a series of significant differences in the victims' characteristics, the rape settings, the victims' activities before they were raped, the assailants' characteristics, and the victims' immediate responses to the assaults. The authors discuss the implications of these differences with respect to specific strategies of outreach and treatment for victims of different types of rape.
And We’re Off!
Authors: William G. Couser, Allison Eddy
Journal: Journal of the American Society of Nephrology (2002)

This issue of JASN represents the second assembled by the new editorial team that took over in July of 2001 from the team led by Craig Tisher. Most of the articles are still ones that were accepted by the previous team; several are not. The proportion of papers accepted by the new team will increase as we go forward and publish the accumulated papers from 2001 in the larger January and February issues. One familiar feature will now be missing; Milestones in Nephrology, edited by Mark Knepper, has run its course and will not be continued into 2002, as previously announced. Several new features will begin to appear. This issue contains the second installment of “Highlights,” short synopses of some of the more interesting articles in each issue of JASN. These synopses are designed to highlight articles that the editors consider to be particularly important advances in clinical or basic science. They are intended to make the essence of these papers more easily appreciated by a clinical audience. There will also be more editorials with a similar mission in the new JASN, and more new features are in preparation. In July, we will begin to link some of the Diseases of the Month, Reviews, and Science Watches to focus on a bench-to-bedside approach to a single topic, a feature we are calling “Frontiers in Nephrology,” which will begin with renal tubular acidosis. In September, NephSAP, edited by Dr. Richard Glassock, will begin publishing in-depth clinical reviews with CME questions for credit on alternate months accompanying JASN. NephSAP will be linked when possible to Disease of the Month to further broaden our coverage of clinical topics. As we go forward, I remind you that the primary purpose of JASN is to publish the best clinical and basic renal research available. These new features will not deter or delete that effort. However, we do feel an obligation as we proceed to ensure that all of JASN is accessible to all readers within our diverse constituency of scientists, clinicians, and trainees. Our success can only be judged by you. We welcome any feedback you wish to provide.
MESH: Phase II trial of methotrexate as a synthetic lethal therapy for metastatic MSH2-deficient colorectal and other tumors.
Authors: M. Hewish, C. Saffery, Y. Barbachano, A. Wotherspoon, G. Brown, S. A. Martin, C. J. Lord, I. Chau, A. Ashworth, D. Cunningham
Journal: Journal of Clinical Oncology (2010)

TPS338 Background: We have previously showed that MSH2-deficient tumor cells are exquisitely sensitive at submicromolar doses to treatment with the antifolate methotrexate. This synthetic lethal effect was associated with an increase in oxidative DNA damage and apoptosis (Martin SA et al., 2009. EMBO Molecular Medicine 1[6-7]:323-337). Based on these observations, we have initiated a clinical trial to assess the antitumor effects of low-dose methotrexate in MSH2-deficient cancer cells in the clinical setting. Methods: Eligible patients must have histological evidence of an MSH2-deficient metastatic cancer (defined by the absence of MSH2 on immunohistochemistry, or a loss-of-function germline mutation in MSH2). Patients must be refractory to standard palliative chemotherapy, or have other reasons why they cannot receive standard treatment. This trial originally opened to patients with colorectal cancer, but due to the low prevalence of MSH2 deficiency in the metastatic population, resulting in slow accrual, we are seeking to expand it to other primary sites, including gastric, endometrial, ovarian, and pancreatic tumors. Methotrexate will be administered at a dose of 35 mg/m2 on D1 and D8 of a 3 weekly cycle, with optional dose escalation after 2 cycles. Treatment may be continued indefinitely. The primary end point is objective response rate. The planned sample size is 29 patients. Using a Simon 2 stage optimal design with an expected response rate of 30% and an unacceptable response rate of 10%, > 1/10 patients would need to respond in the first stage for the study to continue to the second stage. Analysis of 8-OHdG, a marker of oxidative stress, has been incorporated as a candidate biomarker of treatment response. Optional biopsy substudies and functional imaging substudies have also been included. No significant financial relationships to disclose.
CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity
Authors: Patrick L. Crosswhite, Joanna J. Podsiadlowska, Carol D. Curtis, Siqi Gao, Lijun Xia, R. Sathish Srinivasan, Courtney T. Griffin
Journal: Journal of Clinical Investigation (2016)

The chromatin-remodeling enzyme CHD4 maintains vascular integrity at mid-gestation; however, it is unknown whether this enzyme contributes to later blood vessel or lymphatic vessel development. Here, we addressed this issue in mice harboring a deletion of Chd4 specifically in cells that express lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), which include lymphatic endothelial cells (LECs) and liver sinusoidal endothelial cells. Chd4 mutant embryos died before birth and exhibited severe edema, blood-filled lymphatics, and liver hemorrhage. CHD4-deficient embryos developed normal lymphovenous (LV) valves, which regulate the return of lymph to the blood circulation; however, these valves lacked the fibrin-rich thrombi that prevent blood from entering the lymphatic system. Transcripts of the urokinase plasminogen activator receptor (uPAR), which facilitates activation of the fibrin-degrading protease plasmin, were upregulated in Chd4 mutant LYVE1+ cells, and plasmin activity was elevated near the LV valves. Genetic reduction of the uPAR ligand urokinase prevented degradation of fibrin-rich thrombi at the LV valves and largely resolved the blood-filled lymphatics in Chd4 mutants. Urokinase reduction also ameliorated liver hemorrhage and prolonged embryonic survival by reducing plasmin-mediated extracellular matrix degradation around sinusoidal blood vessels. These results highlight the susceptibility of LV thrombi and liver sinusoidal vessels to plasmin-mediated damage and demonstrate the importance of CHD4 in regulating embryonic plasmin activation after mid-gestation.
Mesenchymal stromal cell-derived extracellular vesicles rescue radiation damage to murine marrow hematopoietic cells
Authors: S Wen, M Dooner, Y Cheng, E Papa, M Del Tatto, M Pereira, Y Deng, L Goldberg, J Aliotta, D Chatterjee, C Stewart, A Carpanetto, F Collino, S Bruno, G Camussi, P Quesenberry
Journal: Leukemia (2016)
Abstract P018: Association Between Markers of Inflammation and Total Stroke by Hypertensive Status Among Women
Authors: Monik C Jimenez, Kathryn M Rexrode, Gregory Kotler, Brendan M Everett, Robert J Glynn, I-Min Lee, Julie E Buring, Paul M Ridker, Howard D Sesso
Journal: Circulation (2016)

Background and Purpose: High sensitivity C-reactive protein (hsCRP), soluble intercellular adhesion molecule-1 (sICAM-1) and fibrinogen are markers of systemic inflammation that have been associated with a greater risk and severity of total and ischemic stroke, as well as with elevated blood pressure, a primary risk factor for stroke. However, few studies have examined whether the role of these inflammatory risk factors on stroke pathophysiology is influenced by hypertension status. Methods: Blood samples were collected and assayed for hsCRP, sICAM-1, and fibrinogen among 27,330 initially healthy women from the Women’s Health Study who were followed from 1992-2014. Self-reported hypertension status, cardiovascular risk factors, lifestyle and alcohol consumption were obtained from the baseline questionnaire prior to randomization. New cases of stroke were ascertained by self-report on annual follow-up questionnaires and counted only if confirmed by medical records according to the National Survey of Stroke criteria. The primary outcome was total stroke with ischemic and hemorrhagic evaluated as secondary outcomes. Multivariable Cox models were utilized to estimate the overall association between each marker of inflammation and stroke, and also separately stratified by hypertension status. Results: We observed 629 incident total strokes over 477, 278 person-years. In overall multivariable analyses, the highest quartile of hsCRP and sICAM-1 were associated with a significantly greater risk of total stroke compared to the lowest quartile (hsCRP: HR=1.76, 95% CI: 1.38, 2.24, p-trend&lt;0.001; sICAM-1: HR=1.29, 95% CI: 1.01, 1.65, p-trend =0.01). Fibrinogen was not significantly associated with risk of total stroke in multivariable models. All main effect estimates were attenuated when adjusted for baseline hypertension status. In analyses stratified by hypertension status at baseline, elevated hsCRP (extreme quartiles) was significantly associated with risk of total stroke only among prehypertensive (p-trend=0.03) and hypertensive women (p-trend=0.07), although the interaction was not statistically significant. In analyses by stroke type, the findings for ischemic stroke were similar to those of total stroke, while there was no significant association observed with hemorrhagic stroke for any of the measured markers of inflammation, among the limited number of events (n=111). Conclusions: In this cohort of women free of cardiovascular disease at baseline, elevated hsCRP and sICAM-1 were significantly associated with risk of stroke. Furthermore, the association between hsCRP and stroke may be restricted to prehypertensive and hypertensive women.
Differential roles of high gamma and local motor potentials for movement preparation and execution
Authors: Aysegul Gunduz, Peter Brunner, Mohit Sharma, Eric C. Leuthardt, Anthony L. Ritaccio, Bijan Pesaran, Gerwin Schalk
Journal: Brain-Computer Interfaces (2016)

Determining a person's intent, such as the planned direction of their movement, directly from their cortical activity could support important applications such as brain-computer interfaces (BCIs). Continuing development of improved BCI systems requires a better understanding of how the brain prepares for and executes movements. To contribute to this understanding, we recorded surface cortical potentials (electrocorticographic signals; ECoG) in 11 human subjects performing a delayed center-out task to establish the differential role of high gamma activity (HGA) and the local motor potential (LMP) as a function of time and anatomical area during movement preparation and execution. High gamma modulations mostly confirm previous findings of sensorimotor cortex involvement, whereas modulations in LMPs are observed in prefrontal cortices. These modulations include directional information during movement planning as well as execution. Our results suggest that sampling signals from these widely distributed cortical areas improves decoding accuracy.
Rebound Relapses After Ceasing Another Disease-Modifying Treatment in Patients With Multiple Sclerosis
Authors: Rhonda Voskuhl
Journal: JAMA Neurology (2016)

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When New Medicare Payment Systems Collide
Authors: Robert E. Mechanic
Journal: New England Journal of Medicine (2016)

Interview with Robert Mechanic on what happens when patients are treated by multiple providers participating in different Medicare payment models. (09:58)Download As Medicare expands its new payment programs, more patients will be treated by different providers participating in different payment models. Such overlaps make evaluation of outcomes difficult and create financial distortions that may undermine the models' goals.
Association of Environmental Toxins With Amyotrophic Lateral Sclerosis
Authors: Feng-Chiao Su, Stephen A. Goutman, Sergey Chernyak, Bhramar Mukherjee, Brian C. Callaghan, Stuart Batterman, Eva L. Feldman
Journal: JAMA Neurology (2016)

Persistent environmental pollutants may represent a modifiable risk factor involved in the gene-time-environment hypothesis in amyotrophic lateral sclerosis (ALS).
The Affordable Care Act and Cancer Stage at Diagnosis Among Young Adults
Authors: Xuesong Han, Ka Zang Xiong, Michael R Kramer, Ahmedin Jemal
Journal: JNCI Journal of the National Cancer Institute (2016)

The Affordable Care Act–dependent coverage expansion provision implemented in 2010 allows young adults to be covered under their parents’ health insurance until age 26 years, and millions of young adults have gained insurance as a result. The impact of this policy on cancer patients has yet to be determined. Using 2007 to 2012 data from 18 registries of the Surveillance, Epidemiology, and End Results Program, comparing cancer patients age 19 to 25 years to a control group of patients age 26 to 34 years who were not affected by the provision, we observed a 2.0 (95% confidence interval [CI] = 0.7 to 3.4) percentage point decrease in uninsured rate and a 2.7 (95% CI = 0.6 to 4.8) percentage point increase in diagnosis at stage I disease for patients age 19-25 years. Further analyses by specific cancer site revealed that the statistically significant shifts were confined to carcinoma of cervix (21.2, 95% CI = 9.6 to 32.7 percentage points) and osseous and chondromatous neoplasms (14.4, 95% CI = 0.3 to 28.5 percentage points), which are detectable by either screening or clinical manifestation. These early observations suggest the policy has had positive benefits in cancer outcomes.
Predictive value of the steady-state peripheral blood progenitor cell (PBPC) counts for the yield of PBPC collected by leukapheresis after mobilization by granulocyte colony-stimulating factor (G-CSF) alone or chemotherapy and G-CSF [letter; comment]
Authors: B Husson, C Ravoet, M Dehon, G Wallef, N Hougardy, A Delannoy
Journal: Blood (1996)