tbuckley/cabot-search huggingface dataset:
Who should pay for clinical research?
Authors: G P Canellos
Journal: Journal of Clinical Oncology (1990)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1990.8.11.1775 Journal of Clinical Oncology - published online before print September 22, 2016 PMID: 2230866 Who should pay for clinical research? G P CanellosxG P CanellosSearch for articles by this author https://doi.org/10.1200/JCO.1990.8.11.1775 PDF "Who should pay for clinical research?." Journal of Clinical Oncology, 8(11), pp. 1775–1776© 1990 by American Society of Clinical OncologyKeywords: Biomedical and Behavioral Research... Show All
Neuropilin-1 expression in adenocarcinoma and squamous cell carcinoma of the lung is differentially regulated by hypoxia
Authors: G. P. Pidgeon, M. P. Barr, M. C. Cathcart, S. Gray, K. J. O’Byrne
Journal: Journal of Clinical Oncology (2006)

17152 Background: Neuropilin-1 (NRP-1) is an isoform-specific receptor for VEGF 165 and semaphorin3A, initially discovered on migrating neurons. NRP-1 expression has been reported on a number of tumour cell lines in the absence of the other VEGF receptors, where it mediates survival signals. In this study we examined the regulation of NRP-1 by hypoxia, its effect on survival in a panel of lung cancer cell lines and its potential as a biomarker in retrospective human lung tumours. Methods: A549, SK-MES1, H460 and H647 cells were grown in serum depleted media (0.5%) in normoxic or hypoxic (0.1% O 2 ) conditions and screened for NRP-1 expression by western and immunocytochemistry analysis. Cell survival and apoptosis was determined using BrdU and Annexin-V/PI staining respectively following treatment with an antibody to the extracellular NRP-1 domain. A panel of 100 retrospective resected lung tumours and matched normal samples were stained for NRP-1 expression by immunhistochemistry. Results: A549, SKMES-1 and H647 cell lines all expressed NRP-1 and displayed reduced survival following treatment with NRP-1 antibody (1ug/ml) compared to controls (A549 46%, SKMES-1 61%, H647 53%). H460 did not express NRP-1 and no survival inhibition was seen in the cell line (104%). Reduced survival was accompanied by increased apoptosis in all NRP-1 positive cell lines. Hypoxia strongly increased NRP-1 expression in the A549 adenocarcinoma (AC) cell line, while NRP-1 was decreased in SKMES-1 squamous cell carcinoma (SCC) following hypoxia. Neutralisation of NRP-1 had a greater effect in A549 cells under hypoxia (37%), with a lesser effect in SKMES-1 cells (82%). Western analysis of matched frozen normal and lung cancer biopsies showed NRP-1 overexpression in AC and decreased expression in SCC relative to normal. High NRP-1 expression was confirmed in AC and large cell carcinoma by immunohistochemistry, relative to normal. However, SCCs had a lower level of NRP-1 staining, supporting the results by western analysis and following hypoxia in vitro. Conclusions: These results implicate NRP-1 as an important survival pathway in lung cancer. Hypoxia differentially regulated NRP-1 mediated survival implicating this pathway as a potential therapeutic strategy in AC. No significant financial relationships to disclose.
Late-breaking abstract: Lung regional differences in tissue adaptation to chronic hypoxia (CH)
Authors: Alice Panariti, Alessandra Ferri, David Bishop, Giuseppe Miserocchi, Ilaria Rivolta
Journal: European Respiratory Journal (2011)

Hypoxia (H) impacts to all body tissues which have to adapt to a decrease in O 2  delivery. In CH (10% O 2  for 3 weeks) two lung regions from rats, the upper and the lower lobe, showed differences in interstitial tissue structure (Rivolta, I  et al . ERJ 2011; 37:943-9). On these samples, where the metabolic needs are related to a matrix remodeling, we evaluate how H effects mitochondrial activity. We estimated: mRNA level of KGF, that controls tissue remodeling and matrix components deposition; activity of mitochondrial citrate synthase (CS), index of oxidative activity; expression of the PGC-1a, strong O 2  sensor, and of HIF1a, key transcription factor of the O 2 -response system. 50% decrease in KGF mRNA level in lower lobe in normoxia, revealed a topographical difference in the two lobes matrix reorganization; H exposure had a little effect on its expression (0.8±0.3 and 0.7±0.4 hypoxic upper and lower lobe, respectively, relative to normoxic upper lobe). CS activity slightly but significantly decreased in upper lobe while it increased in hypoxic lower lobe. In H, HIF1a doubled but did not show regional differences, while PGC-1a increase was almost 66% greater in the lower compared to the upper lobe. We conclude that variances in tissue structure organization of the two lobes can be accounted for a topographic difference in the level of KGF present in normoxia. On this background, differences in the adaptive response to H might be mediated by differential expression of PGC-1a since HIF1a response was equally affected in both lobes. These results represent a breakthrough in the molecular mechanisms of H adaptation understanding, furthermore, this is the first study considering PGC-1a in the hypoxic lung.
Cancer Control in Susceptible Groups: Opportunities and Challenges
Authors: F P Li
Journal: Journal of Clinical Oncology (1999)

Cancer mortality rates in the United States have risen throughout most of this century, and a downward trend has just emerged in recent years. Nevertheless, it is predicted that cancer will soon be the leading cause of death among Americans. To gain new knowledge of etiology, we have studied persons at highest risk as human models of cancer susceptibility. Clinical observations at the bedside are used to generate etiologic hypotheses that are tested in epidemiologic studies. Companion laboratory studies can identify biologic mechanisms of predisposition. Data show that inborn mutations in cancer-predisposing genes, such as BRCA1 and BRCA2, markedly increase the risk of cancers at unusually early ages. Increasing numbers of these highly penetrant genes are being identified. These discoveries have created new opportunities for genetic testing to identify cancer-prone individuals. Individuals found to be carriers can be offered counseling to avoid environmental exposures that further elevate risk, intensive medical surveillance for early detection, participation in chemoprevention trials, and prophylactic surgery to remove at-risk tissues. However, genetic knowledge can have adverse effects, including psychologic distress, social stigmatization, and loss of health insurance. Research is needed to maximize benefits and minimize risks to the susceptible populations. Professional and public education can promote appropriate use of genetic data, and legislation may be required to prevent discrimination. Knowledge of these highly penetrant genes can be extended to common polymorphisms that modify cancer risk associated with exposures to environmental carcinogens. J Clin Oncol 17:719–725. © 1999 by American Society of Clinical Oncology.
Examining Variation in Hospice Visits by Professional Staff in the Last 2 Days of Life
Authors: Joan M. Teno, Mike Plotzke, Thomas Christian, Pedro Gozalo
Journal: JAMA Internal Medicine (2016)

IMPORTANCEIn the final days of life, symptoms are exacerbated and often families need both education and emotional support from hospice professional staff.The Medicare Hospice Benefit provides a per-diem payment with no requirements on the frequency of patient visits.OBJECTIVE To examine individual characteristics, hospice program, and geographic variation in hospice visits by professional staff during the last 2 days of life. DESIGN, SETTING, AND PARTICIPANTSThis retrospective cohort study of 661 557 Medicare hospice beneficiaries included all patients who died in federal fiscal year 2014 (October 1, 2013-September 30, 2014) in hospice services while receiving routine home care in the last 2 days of life.Data analysis was conducted from March 9 to August 25, 2015. MAIN OUTCOMES AND MEASURESMedicare regulations require that hospice care centers report daily the frequency and duration of patient visits by professional staff, as well as the type of hospice staff who conduct these visits.We examined visit variation by hospice professional staff (physician, nursing staff, and social worker) during the last 2 days of life using a multivariable logistic model adjusting for decedent and hospice program characteristics. RESULTSOf the 661 557 patients in the study, 81 478 (12.3%) received no professional staff visits in the last 2 days of life.State variation ranged from 590 of 15 399 patients (3.8%) in Wisconsin to 97 of 492 patients (19.7%) in Alaska, and hospice program interquartile variation ranged from 3.2% (25th percentile) to 19.5% (75th percentile).Black patients were less likely to have any visits than were white patients (7352 of 48 221 [15.2%] vs 70 365 of 585 377 [12.0%]; adjusted odds ratio, 1.30; 95% CI, 1.24-1.37).Those dying in a nursing home were 1.74 times less likely to have any visits than those dying at home (30 880 of 186 649 [16.5%] vs 40 973 of 386 654 [10.6%]; 95% CI, 1.62-1.88).Those dying on a Sunday were 3.35 times less likely to have a visit compared with persons dying on a Tuesday (19 519 of 95 979 [20.3%] vs 6784 of 92 127 [7.4%]; 95% CI, 3.17-3.55). CONCLUSIONS AND RELEVANCEHospice visits in the last 2 days of life by professional staff vary by race, hospice program, and geographic region of the country.Visits were less likely when the Medicare beneficiary was black, dying on a Sunday, and receiving care in a nursing home.
An Immunofluorescent Method for Yaba Virus Assay&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Dee O. N. Taylor, Melville R. Klauber, Edwin H. Lennette, Anna Wiener
Journal: JNCI Journal of the National Cancer Institute (1968)

A technique developed in this laboratory was adapted to the staining of large numbers of coverslip cultures of monkey kidney cells with fluorescein isothiocyanate conjugated to anti-Yaba γ-globulin, which allowed enumeration of specifically marked infectious foci. Maximum virus adsorption in this system required 8 hours and appeared to be related to the quantity of inoculum used. Sensitivity of the assay was slightly less than assay in rhesus monkeys inoculated intracutaneously. This difference may have been related to virus adsorption kinetics involved in the methods used. Tests indicated that spread of virus through the medium was negligible at the doses used for assay, which thus eliminated the need for agar overlays. Optimal incubation for the assay was 10 days, considerably less than the time needed for other methods. No medium changes were made during this period to avoid attrition of the cell monolayers. The assay system was tested for reliability by statistical analyses. Assuming the Poisson distribution, the hypothesis of homogeneity of individual coverslip focus counts within petri dishes was rejected. However, neither the hypothesis of normality nor of lognormality could be rejected, but the fit to the lognormal distribution was better. The lognormal model was used to compute confidence limits for the medians. The narrowness of these limits indicated the precision obtainable by the assay. A nonparametric method was used to test for the linearity of infectious focus counts plotted against increasing dilutions. Linearity could not be rejected.
PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer
Authors: T. Fujita, K. Kawasaki, D. Takabatake, H. Takahashi, Y. Ogasawara, H. Doihara
Journal: Journal of Clinical Oncology (2006)

10026 Background: Trastuzumab is the only HER2/neu-directed therapy for the treatment of patients with metastatic breast cancer. The efficacy of trastuzumab depends on the HER2/neu status of the tumor and the patient’s prior treatment, but even when patients are selected on the basis of HER2/neu gene amplification, the single-agent response rate ranges from 12 to 30% and few patients respond to trastuzumab monotherapy. Here we propose PTEN as a predictive biomarker for trastuzumab efficacy. Methods: Human breast cancer SKBR3 and drug-resistant SKBR3/R cells were analyzed, in vitro. Also we examined, retrospectively, clinical samples from patients who had been treated with trastuzumab for the metastatic disease and analyzed the relationship between trastuzumab efficacy and PTEN expression profile with immunihistochemistry. The PTEN expression level was scored semiquantitatively based on staining intensity and distribution using the immunoreactive score. Statistical analysis was performed using the two-tailed student’s t test, Fisher’s test and ANOVA. Results: The PI3K/Akt signaling pathway was observed to be highly active in the drug-resistant cells, and their level of PTEN was significanctly low compared with parental SKBR3 cells. Delivery of antisense PTEN duplex siRNA significantly decreased the trastuzumab chemosensitivity of parental SKBR3 cells, and marked activation of Akt signaling pathway was also recognized in oligonucleotid delivered parental cells. Moreover, in clinical analysis, immunohistochemical investigation revealed that trastuzumab treatment was remarkably successful in patients with elevated PTEN expression and statistically significant (p&lt;0.05). Conclusions: PTEN activity might play an important and major role in its HER2/PI3K/Akt-mediated anti-tumor effect, and could be a useful biomarker for predicting the efficacy of trastuzumab in the treatment of breast cancer. No significant financial relationships to disclose.
A new regimen of amsacrine with high-dose cytarabine is safe and effective therapy for acute leukemia.
Authors: Z A Arlin, T Ahmed, A Mittelman, E Feldman, R Mehta, P Weinstein, E Rieber, P Sullivan, P Baskind
Journal: Journal of Clinical Oncology (1987)

Amsacrine and high-dose cytarabine (HiDAc), when administered as single agents, are effective treatment of acute leukemia. When used in combination, a high remission rate is also possible. We treated 47 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and blastic phase of chronic myelogenous leukemia (CML) with a combination of amsacrine and HiDAc. The patients received amsacrine 200 mg/m2 daily for three days and, concurrently, HiDAc 3 g/m2 over three hours once daily for five days. Of 20 evaluable patients with AML in relapse, there were 12 remissions; of seven additional patients with primary refractory AML, there were two remissions, and of 12 patients with ALL in relapse, there were eight remissions. The three patients with blastic phase CML and the three patients with biphenotypic leukemia did not respond. Nausea, vomiting, stomatitis, hepatic dysfunction, and diarrhea were common, but cutaneous, conjunctival, and significant cerebellar and cerebral side effects were absent. We conclude that this regimen is highly effective therapy for AML and ALL and is also safe, eliminating the major toxicities encountered with HiDAc.
Psychotherapists' duties to third parties: Ramona and beyond
Authors: P S Appelbaum, R Zoltek-Jick
Journal: American Journal of Psychiatry (1996)

This paper explores the implications for psychotherapy of a series of court cases involving suspected childhood sexual abuse that have raised the question of when psychiatrists and other psychotherapists can be sued by third parties for their behavior in therapy.The authors begin by considering traditional legal approaches that until now, with few exceptions, granted only patients the right to sue caregivers for negligence. Then they turn to Ramona v. Ramona, the most publicized of a new line of cases, in which the California courts allowed a father accused of abusing his daughter to sue his daughter's therapists.The rationale for the abandonment of the previous restrictions on liability in Ramona was that since the father was a "direct victim" of the therapists' negligence, traditional limitations on the therapists' duties toward him should not apply. Related cases have used similar logic. Inherently difficult for the courts to apply, the direct victim standard would leave therapists unclear as to how to avoid duties to third parties, other than by refusing to treat patients with family members who may be potential litigants. Moreover, aggrieved third parties essentially would have the power to bring effective treatment to a halt by filing suit or threatening to do so.Although concern about therapeutic practices related to memories of childhood abuse may be warranted, abandonment of traditional rules against suits by nonpatients would be ill-advised. In the meantime, therapists can take steps to lessen the probability of their becoming involved in such litigation.
Association of BRAF mutations and EGFR Intron-1 L/L genotype with resistance to cetuximab plus irinotecan treatment in KRAS wild-type metastatic colorectal cancer patients
Authors: A. Ruzzo, C. Cremolini, F. Loupakis, L. Fornaro, D. Santini, B. Vincenzi, E. Canestrari, M. Magnani, A. Falcone, F. Graziano
Journal: Journal of Clinical Oncology (2009)

4058 Background: KRAS and BRAF mutations are associated with resistance to anti-EGFR monoclonal antibodies. EGFR Intron-1 (CA)n genotype has been suggested to influence the activity of cetuximab. Methods: We retrospectively assessed KRAS and BRAF mutational status and EGFR Intron-1 (CA)n genotypes in 117 irinotecan-refractory EGFR-positive mCRC patients treated with cetuximab plus irinotecan. We defined short (S) and long (L) allelic variants those presenting &lt; and ≥17 CA repeats respectively. Among KRAS wild-type patients, we investigated the association between BRAF mutational status and EGFR Intron-1 genotype and treatment outcome in terms of RR and PFS. Results: Among 66 (56%) KRAS wild-type patients, BRAF V600E mutation was detected in 9 (14%) patients. BRAF wild-type patients reported improved RR (0/9, 0% vs 19/57, 33%, p = 0.04) and PFS (3.3 vs 5.1 months, p = 0.076; HR = 0.54 [95%CI: 0.18–1.09]) in comparison with BRAF-mutated. EGFR Intron-1 L/L genotype was detected in 13 (20%) KRAS wild-type patients. Objective responses were reported in 1/13 (8%) EGFR Intron-1 L/L patients and in 18/53 (34%) S/L or S/S patients (p = 0.061). Significantly longer PFS was observed among EGFR Intron-1 S/L or S/S patients (5.3 vs 3.3 months, p = 0.0062; HR = 0.45 [95%CI: 0.14–0.72]). Among 57 KRAS and BRAF wild-type patients, 1/11 (9%) EGFR Intron-1 L/L patients and 18/46 (39%) S/L - S/S patients responded to treatment (p = 0.058), achieving median PFS of 3.7 and 5.4 months, respectively (p = 0.022; HR = 0.48 [95%CI: 0.15–0.87]). Conclusions: In KRAS wild-type patients, BRAF mutations are confirmed to predict resistance to cetuximab treatment. EGFR Intron-1 allelic variants are promising markers of benefit in patients with both KRAS and BRAF wild-type and may help to better select mCRC patients candidate to receive cetuximab-containing treatment. No significant financial relationships to disclose.
Aspirin induced asthma: Clinical relevance of finding was not explained
Authors: 崔玉瑾
Journal: BMJ (2005)

贵刊去年第5期教育与争鸣栏目刊登了一篇题为“急性心肌梗死后将急诊冠状动脉成形术作为首选治疗”的文章，这篇文章写得很好，阅读后获益颇多。两位专家各执己见，对急性心肌梗死后应该溶栓治疗还是行急诊介入治疗(PCI)进行了争论。争鸣的目的不在于结论，而在于分析的过程，在这一过程中教会我们面对实际问题应该如何思考。
Study links SSRIs to violent crime in young adults
Authors: Ingrid Torjesen
Journal: BMJ (2015)

Use of selective serotonin reuptake inhibitors (SSRIs) increases the rate of violent crime among young adults, indicates a study published in PLOS Medicine on Tuesday 15 September.1

Researchers from the University of Oxford and the Karolinska Institute in Stockholm extracted information from Swedish registries on the 856 493 Swedish people (10.8% of the population) to whom SSRIs were prescribed during 2006-09 and criminal records.

They used stratified Cox regression analyses to compare the incidence of violent crime while patients were prescribed SSRIs with the incidence among the same people when they were not receiving the drugs.

Their results showed that the likelihood of a criminal conviction for violent crimes was higher when people were taking SSRIs (hazard ratio 1.19 (95% confidence interval …
Exonic enhancers: proceed with caution in exome and genome sequencing studies
Authors: Nadav Ahituv
Journal: Genome Medicine (2016)

Exonic enhancers (eExons) are coding exons that also function as enhancers of the gene in which they reside or (a) nearby gene(s).Mutations that affect the enhancer activity of these eExons have been associated with human disease.Therefore, eExon mutations should be taken into account in exome and genome sequencing projects, not only because of the ability of these mutations to modify the encoded proteins but also because of their effects on enhancer activity.
NCCTG phase II trial of bevacizumab in combination with sorafenib in recurrent GBM.
Authors: E. Galanis, K. A. Jaeckle, S. Anderson, T. J. Kaufmann, J. H. Uhm, C. Giannini, S. Kumar, D. W. Northfelt, P. J. Flynn, J. C. Buckner
Journal: Journal of Clinical Oncology (2010)

2018 Background: Angiogenesis inhibition is a promising strategy in GBM treatment. We hypothesized that combination of the anti-VEGF antibody, bevacizumab with sorafenib, a small molecule kinase inhibitor of VEGFR2, PDGFRb and RAF kinases, would result in improved antiangiogenic and antitumor activity. Methods: Recurrent GBM patients (pts) who have received ≤ 1 regimens for progressive disease are eligible for the trial. Exclusion criteria include poorly controlled hypertension, bleeding diathesis, anticoagulation, and prior antiangiogenic therapy. A one stage, three outcome phase II trial design was applied with PFS6 being the primary endpoint. Pts received bevacizumab 5 mg/kg q 2 wks with sorafenib 200 mg bid, weekly, days 1-5. Results: A total of 39 pts have been enrolled. Toxicity analysis after the first 19 pts, showed high incidence of grade ≥ 3 nonhematologic toxicity: 36.8% (7/19) in cycles 1 or 2, mainly fatigue, thrombosis, hypophosphatemia, and muscle weakness; 68.4% (13/19) of pts experienced ≥ grade 2 fatigue. Despite a high objective response rate of 37% (7/19), toxicity resulted in early treatment discontinuation in 32% (6/19) and refusal in 10.5% (2/19) of pts. An additional 20 pts were enrolled following modification of the starting sorafenib dose to 200 mg qd: 13 have at least one cycle of toxicity information. There is significantly improved tolerance with a 15.4% (2/13) incidence of ≥ grade 3 nonhematologic toxicity in the first two treatment cycles. Initial correlative laboratory analysis data, including assessment of molecular and cellular markers of angiogenesis, indicated a decrease in circulating endothelial cells starting in the first treatment cycle with subsequent increase at progression. DCE perfusion and permeability MR imaging was performed at baseline, day 2-3, day 30, and q 2 mo thereafter. Decreased contrast enhancement was observed as early as 24 hours after treatment initiation. Conclusions: Bevacizumab, 5 mg/kg q 2 wks, with sorafenib 200 mg bid days 1-5 has resulted in high objective response rate, but with significant toxicity. Sorafenib dose decrease improved tolerance. Updated toxicity, efficacy, correlative analysis and imaging data will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Antisense Pharma, Bayer, Bristol-Myers Squibb, EMD Serono, Exelixis, Genentech Bayer