tbuckley/cabot-search huggingface dataset:
Prognostic factors for 90-day mortality in patients with solid malignancies treated on Phase 1 trials sponsored by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute.
Authors: Kit Man Wong, Larry Rubinstein, Matthew Rinker, Gary Lee Smith, Elad Sharon, S. Gail Eckhardt, Wells A. Messersmith, Stephen Leong, Pamela Jo Harris, Dexiang Gao
Journal: Journal of Clinical Oncology (2016)

2533 Background: The appropriate selection of cancer patients with reasonable life expectancy is critical in Phase 1 trials. The ability to predict patient outcomes prior to enrollment, particularly their 90-day mortality (90DM), would improve selection, avoid harm in those unlikely to benefit, and maximize the meaningful data obtained. There is currently no standard prognostication strategy. We analyzed the prognostic factors of patients on Phase 1 trials sponsored by CTEP. Methods: 5,477 patients with solid tumors enrolled in CTEP Phase 1 trials from 2000 to 2015 were included. Patient, disease and lab characteristics within 30 days prior to first dose, study treatments and outcomes were extracted from a prospective database. Adjusted hazard ratios (aHR) for 90DM were analyzed by multivariate Cox regression. Results: The study population had a median age of 58 (18-90) years and 49% males. Most common tumor types were: 35% gastrointestinal, 11% breast, 10% genitourinary (GU); 94% of patients had ECOG 0-1. Most subjects received combination therapy (63%). The majority of trials tested a targeted agent (76%). 90DM was 16%; median duration on therapy (DoT) was 56 (0-1,358) days; response rate was 9%. 90DM was independently associated with worse ECOG (2 vs 0: aHR 3.8, 95% CI 2.5-5.7), high ALP ( > 2.5xULN vs < ULN: aHR 2.2, 95% CI 1.5-3.1), high LDH ( > 2.5xULN vs < ULN: aHR 2.3, 95% CI 1.7-3.1), low albumin ( < 3.0 vs > 3.5 g/dL: aHR 2.7, 95% CI 1.9-3.7), high bilirubin ( ≥ 1.3 vs < 1.3 mg/dL: aHR 1.6, 95% CI 1.2-2.2), and high white blood cells ( > 11 vs ≤ 11 x109/L: aHR 1.7, 95% CI 1.3-2.2). Those on combination regimens were more likely to live in the first 90 days (vs monotherapy: aHR 0.75, 95% CI 0.59-0.95). Therapy type (cytotoxic, targeted, immunotherapy) and tumor site were not determinants of 90DM. Similar variables predicted DoT; additional factors associated with longer DoT were GU cancers and regimens containing non-cytotoxic agents. Conclusions: This is the largest prognostic analysis of 90DM in Phase 1 trial patients. ECOG status, specific labs, and number of agents appear to be important factors. A prognostic tree algorithm will be presented.
Long Noncoding RNAs and Angiogenesis
Authors: Anna Zampetaki, Manuel Mayr
Journal: Circulation (2017)

Accumulating evidence supports the notion that the mammalian genome is pervasively transcribed.A large proportion of the transcripts do not encode a protein and are thus regarded as noncoding RNAs.Based on their length, they can be divided into small RNAs (<200 nucleotides) and long noncoding RNAs (lncRNAs; >200 nucleotides). 1,2LncRNAs can be encoded in the same or opposite strand to protein-coding DNA and can be either within or separate to proteincoding genes.They can be exported to the cytoplasm or remain in the nucleus.Although their function is not fully understood, lncRNAs have been reported to mediate the expression of other genes, affect the organization of the nucleus, and modify other RNAs. 1,2n this issue of Circulation, Leisegang and colleagues 3 identify a novel lncRNA that regulates angiogenesis.Previous work by this group highlighted the role of a histone demethylase, the protein JARID1B, in maintaining the angiogenic capacity of human umbilical vein endothelial cells. 4In the present study, the authors performed a transcriptomic screen following knockdown of JARID1B in human umbilical vein endothelial cells.They discovered a novel lncRNA, named MANTIS, to be strongly upregulated.MANTIS is located in the antisense strand of an intronic region of the gene for Annexin A4, a calcium and phospholipid binding protein.MANTIS is a nuclear lncRNA that is enriched in endothelial cells but also expressed in other cell types.Reducing MANTIS levels led to impaired endothelial sprouting, tube formation, and attenuated endothelial migration.It is notable that human umbilical vein endothelial cells lost their ability to orientate themselves in the direction of flow.On silencing MANTIS, gene expression profiling revealed downregulation of angiogenesis-related genes.Brahma-like gene 1 (BRG1) was identified as a direct interaction partner of MANTIS, implying a role of MANTIS in the formation of the switch/sucrose nonfermentable (SWI/SNF) complex (Figure).The SWI/SNF complex is one of the best characterized chromatin remodeling complexes.It uses energy released from ATP hydrolysis to alter the shape of chromatin, making DNA accessible for transcription initiation and thus promoting gene expression. 5Different catalytic subunits that confer this ATPase activity can be recruited to the complex.In the cardiovascular system, Brahma or BRG1 are particularly important and mutually exclusive. 6Binding of lncRNAs to specific ATPase subunits of the SWI/SNF complex has emerged as a common regulatory mechanism. 7-10Recruitment of specific lncRNAs might confer uniqueness to the ubiquitous SWI/SNF complex and allows it to target a distinct group of genes in different cell types (Figure).In the case of MANTIS, binding to BRG1 was shown to stabilize the BRG1 interaction with the chromatin remodeling factor BAF155.BAF155 affects the ATPase activity of BRG1.It is intriguing that this finding was shown to occur in the transcription initia- Long Noncoding RNAs and Angiogenesis
Management of Pressure UlcersManagement of Pressure Ulcers
Authors: Lane Strathearn
Journal: JAMA (2003)

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Noninvasive Brain Stimulation for Depression — The Devil Is in the Dosing
Authors: Sarah H. Lisanby
Journal: New England Journal of Medicine (2017)

In this issue of the Journal, Brunoni and colleagues report on transcranial direct-current stimulation (tDCS) in the treatment of major depression.1 This technique, which delivers weak electrical direct current to the scalp to modulate brain function, is one of a growing number of noninvasive brain stimulation interventions that change brain function and offer an opportunity to study brain–behavior relationships in health and disease. These tools have the potential to translate knowledge of the neural circuitry of the brain and patterns of electrical activity within those circuits (known as neural oscillatory dynamics) into treatments for psychiatric and neurologic disorders. Other related . . .
Dynamic Edematous Response of the Human Heart to Myocardial Infarction
Authors: Rodrigo Fernández-Jiménez, Manuel Barreiro-Pérez, Ana Martin-García, Javier Sánchez-González, Jaume Agüero, Carlos Galán-Arriola, Jaime García-Prieto, Elena Díaz-Pelaez, Pedro Vara, Irene Martinez, Ivan Zamarro, Beatriz Garde, Javier Sanz, Valentin Fuster, Pedro L. Sánchez, Borja Ibanez
Journal: Circulation (2017)

Clinical protocols aimed to characterize the post-myocardial infarction (MI) heart by cardiac magnetic resonance (CMR) need to be standardized to take account of dynamic biological phenomena evolving early after the index ischemic event. Here, we evaluated the time course of edema reaction in patients with ST-segment-elevation MI by CMR and assessed its implications for myocardium-at-risk (MaR) quantification both in patients and in a large-animal model.A total of 16 patients with anterior ST-segment-elevation MI successfully treated by primary angioplasty and 16 matched controls were prospectively recruited. In total, 94 clinical CMR examinations were performed: patients with ST-segment-elevation MI were serially scanned (within the first 3 hours after reperfusion and at 1, 4, 7, and 40 days), and controls were scanned only once. T2 relaxation time in the myocardium (T2 mapping) and the extent of edema on T2-weighted short-tau triple inversion-recovery (ie, CMR-MaR) were evaluated at all time points. In the experimental study, 20 pigs underwent 40-minute ischemia/reperfusion followed by serial CMR examinations at 120 minutes and 1, 4, and 7 days after reperfusion. Reference MaR was assessed by contrast-multidetector computed tomography during the index coronary occlusion. Generalized linear mixed models were used to take account of repeated measurements.In humans, T2 relaxation time in the ischemic myocardium declines significantly from early after reperfusion to 24 hours, and then increases up to day 4, reaching a plateau from which it decreases from day 7. Consequently, edema extent measured by T2-weighted short-tau triple inversion-recovery (CMR-MaR) varied with the timing of the CMR examination. These findings were confirmed in the experimental model by showing that only CMR-MaR values for day 4 and day 7 postreperfusion, coinciding with the deferred edema wave, were similar to values measured by reference contrast-multidetector computed tomography.Post-MI edema in patients follows a bimodal pattern that affects CMR estimates of MaR. Dynamic changes in post-ST-segment-elevation MI edema highlight the need for standardization of CMR timing to retrospectively delineate MaR and quantify myocardial salvage. According to the present clinical and experimental data, a time window between days 4 and 7 post-MI seems a good compromise solution for standardization. Further studies are needed to study the effect of other factors on these variables.
Metastasis of murine Renca kidney cancer cells to the lungs of Balb/c mice is strongly suppressed by TLR9 or TLR7 agonists
Authors: Astrid Leja, Hans-Peter Hofmann, Thomas Maier, Daniela Drache, Carola Grebe, Susanne Fischer, Petra Gimmnich, Karl Sanders, Volker Gekeler
Journal: Cancer Research (2007)

3552  Tumor metastasis is a most severe aspect of tumor development in patients, largely because tumors are detected too late when metastasis already has occurred. Established tumor therapies mostly include cytotoxic drugs with rather narrow therapeutic windows. Hence, for the treatment in earlier tumor stages, where the suppression of metastasis spread might still be possible, the need is high for new therapies with good tolerability and safety. The activation of the immune system, and in particular, the activation of toll-like receptor (TLR) signaling offers new promising approaches. Several immune-stimulatory TLR9 agonistic oligonucleotides containing a phosphorothioate backbone and CpG subsequences (CpG-ODN) are in advanced clinical trials. A clear clinical proof of concept (POC), though, was achieved so far solely with the imidazoquinoline imiquimod, which activates TLR7. Imiquimod is approved for topical application, where it has remarkable efficacy on superficial basal cell carcinomas. The POC for systemic application of TLR agonists in oncology is still pending, though. CpG-ODN such as H1826 or H2006 (Hartmann et al, 2000) can strongly suppress growth of established human xenograft tumors in nude mice (devoid of T-cells), upon repeated i.v. administration (Gekeler et al, 2006). Here we show remarkable efficacy of CpG-ODN (qdx4 i.v.) with doses as low as 1 mg/kg in suppression of metastasis of murine Renca kidney cancer cells to the lungs of immune competent Balb/c mice without any sign of intolerance. Classical cytotoxics such as 5-fluor-uracil (20 mg/kg, qdx4 i.v.) showed only moderate efficacy in this setting. Furthermore, CpG-ODN-5mC having C-5 methylated cytosine throughout the molecule were totally inactive in this model, providing evidence that the tumor suppressing activity is dependent on TLR9. Since expression of TLR7 on immune cells is similar to TLR9 expression we asked whether similar metastasis suppressing activity might be seen with TLR7 agonists of different chemical structures. The guanosine derivative isatoribine (7-thia-8-oxoguanosine) and an imiquimod derivative were tested in the same setting (qdx4 i.v.) with doses of up to 30 mg/kg. Remarkably, a virtually full suppression of development of lung metastases was observed with both molecules with good tolerability. In vitro assays using hPBMC (human peripheral blood mononuclear cell) fractions approved a specific cytokine response (e.g. IL6, IP10) which was induced by these molecules. Our work provides a convincing rational for clinical development of TLR9 or TLR7 agonists for suppression of cancer metastasis and points to the possibility of systemic application of such drugs.
Abstract P391: Marine N-3 Fatty Acids Reduce Atherosclerosis Cardiovascular Disease: A Systemic Review and Meta-analysis of Clinical Trials
Authors: Akira Sekikawa, Nobutake Hirooka, Abhishek Vishnu, Vashudha Ahuja, Emmanuel Sampene, Mary Lou Klem, Krishna Desai, Tomonori Okamura, Rhobert W Evans, Katsuyuki Miura, Bradley Willocx, Kamal Masaki, Hirotsugu Ueshima, Matthew F Muldoon, Lewis H Kuller
Journal: Circulation (2013)

Introduction: Although marine n-3 fatty acids are believed to be cardioprotective through their anti-arrhythmic, anti-thrombotic, anti-atherogenic and other effects, results from recent meta-analyses of marine n-3 fatty acids on cardiovascular disease (CVD) are controversial. We performed a meta-analysis of marine n-3 fatty acids on CVD outcomes in randomized clinical trials (RCTs) to test the hypothesis that marine n-3 fatty acids are anti-atherogenic. We also tested the hypothesis that such benefit is dose-dependent. Methods: A systematic review of English language articles using PubMed, EMBASE and Cochrane Library through Aug 2012 was performed selecting RCTs evaluating the effect of marine n-3 fatty acids intake for 2 years or more on cardiovascular diseases, coronary disease, arteriosclerosis, cardiac imaging techniques, and carotid artery ultrasound. Descriptive and quantitative information was extracted. Odds ratios were calculated for cardiac event outcome. Correlation coefficients were obtained from studies of which outcome is intima-media thickness (IMT) and coronary lumen diameter (CD). We converted the estimates into a single effect size; the log odds ratio and its corresponding standard error. Results: Of 14,236 citations retrieved, 13 studies were selected, including studies reporting IMT (n=3) and CD (n=2) and major CVD events (n=8). Overall, marine n-3 fatty acids significantly reduced atherosclerotic CVD (RR 0.94: 95%CI 0.90 to 0.99, p&lt;0.05). There was no evidence of heterogeneity (p=0.65) or publication bias (p=0.37, Begg’s test). A sub-analysis among 8 studies of major CVD events showed the similar results (RR 0.94: 95% CI 0.89 to 0.99, p&lt;0.05). Another sub-analysis among 4 studies excluding sudden cardiac death as an outcome showed RR of 0.91 (95% CI 0.82 to 1.02, p=0.097). A meta-regression analysis shows that dose of marine n-3 fatty acids was inversely associated with CVD outcome, although the association was not statistically significant (p=0.06). Conclusions: The result of our meta-analysis supports a modest anti-atherogenic effect of marine n-3 fatty acids. This benefit may be proportional to the amount of marine n-3 fatty acids consumed.
Moving forward with steady strokes in paralympic sports medicine
Authors: Hilde Moseby Berge
Journal: British Journal of Sports Medicine (2017)

We have just returned from the 5th IOC World Conference on Prevention of Illness and Injuries in Sport in Monaco. As always, it was great to meet old and new colleagues in sport and exercise medicine, listen to interesting talks, and participate in the workshops. The new sessions on Paralympic sports medicine were highlights for many of us.

The extra challenges of taking care of paralympic athletes are highlighted by Melbourne’s Liam West et al ( see page 1050 ) in their editorial on how to manage concussion in disability sport. In another editorial, Tweedy et al ( see page 1048 ) discuss how enabling technology can improve the performance of paralympic athletes, to such an extent that take-off velocity of a unilateral below-knee amputee with a long jump-speciﬁc prosthesis is higher than that of able-bodied athletes. Strikingly, the athlete with a disability has a personal best that would have won Gold at the London Olympics. …
HGCSG 1201: Phase II study of trastuzumab with irinotecan in HER2-positive metastatic or advanced gastric cancer patients previously treated with trastuzumab
Authors: Takahide Sasaki, Yasuyuki Kawamoto, Satoshi Yuki, Takashi Meguro, Kazuteru Hatanaka, Minoru Uebayashi, Ichiro Iwanaga, Michio Nakamura, Kazunori Eto, Hiroyuki Okuda, Masakazu Abe, Ayane Oba, Nobuhiko Abe, Atsushi Sato, Hiroshi Nakatsumi, Kazuaki Harada, Tetsuhito Muranaka, Masataka Yagisawa, Koji Oba, Yuh Sakata, Yoshito Komatsu
Journal: Annals of Oncology (2017)
A retrospective cohort study of the relations between progress of chemotherapy and outcomes for metastatic pancreatic cancer
Authors: Yasuyuki Kawamoto, Satoshi Yuki, Masataka Yagisawa, Tetsuhito Muranaka, Kazuaki Harada, Hiroshi Nakatsumi, Kazumichi Kawakubo, Masaki Kuwatani, Naoya Sakamoto, Yoshito Komatsu
Journal: Annals of Oncology (2017)
Reply to Ferreira et al.
Authors: Elisabeth Waldmann, Georg Heinze, Monika Ferlitsch
Journal: Endoscopy (2017)

We appreciate the comments by Ferreira et al. on our paper “Trends in quality of screening colonoscopy in Austria” published in the December issue of Endoscopy [1]. As the authors recognized, an interesting finding of the paper was that all 20 perforations occurred when sedation was used. However, we did not conclude a causal relationship between the use of sedation and perforation because there was no significant association (P = 0.17). This was clearly described in the results section, but not mentioned in the letter.
Identification of serum biomarkers for lung cancer using mass spectrometry
Authors: Sung Baek, Elzbieta Izbicka, Robert Streeper, David Campos, Armando Diaz
Journal: Clinical Cancer Research (2007)

A77  Background: Symptoms of lung cancer (LC) often do not appear until the disease is advanced; only 15% of the LC cases are found in the early stages. Carcinogen exposure, asthma and smoking have been recognized as some of the risk factors for LC. Prevention and early detection of LC could have a major impact on the natural history of the disease. The objective of the study was to apply mass spectrometric (MS) methods to identify a panel of biomarkers for early detection of LC.  Methods: Normal (NO) serum controls (n=30) from healthy volunteers and lung cancer (n=30) were acquired from a commercial vendor. Baseline (pre-treatment) serum specimens from individuals with asthma (AST; n=30) and lung cancer risk (LCR; n=73) were available from clinical trials of two novel agents that are being developed by JBNI Inc. for the respective indications. Serum proteins were analyzed using MS platform to identify biomarkers that are expressed in a significantly different manner in individuals with LC, LCR, or AST in comparison with NO subjects. Specimens were digested with trypsin and analyzed by liquid chromatography electrospray ionization mass spectrometry (LC-ESIMS). Differential analysis of the resulting mass spectral data allowed for the identification of differentially expressed mass/time signals which were then subjected to both on line and off line mass spectrometry-mass spectrometry (MSMS) analysis for the determination of peptide sequences. Data were analyzed using Mascot search software. Putative matches were cross checked against the raw data and peak identity, charge multiplicity, isotope distribution and flanking charge states were confirmed.  Results and conclusions: We have identified a number of heretofore unrecognized differentially expressed proteins in LC, LCR and AST samples relative to NO samples. The identified proteins include putative expressed proteins identified in prior genetic sequencing efforts, several patented proteins having functions that have not been described in the literature, proteins involved in intracytoplasmic protein membrane anchorage, proteasome components, cellular immune response, as well as several MHC associated proteins. Our results support an extended MS analysis of serum biomarker profiles as supplementary tools in the identification of target molecules and systems for the subsequent application of quantitative validation techniques for the identification and molecular characterization of the condition and development of novel agents for prevention, early detection and treatment of LC.  Supported by JBNI Inc.