tbuckley/cabot-search huggingface dataset:
Challenging the current paradigm of melanoma progression: brain metastasis as isolated first visceral site
Authors: M. W. Ma, M. Qian, D. J. Lackaye, R. S. Berman, R. L. Shapiro, A. C. Pavlick, J. G. Golfinos, E. C. Parker, F. Darvishian, E. Hernando, Y. Shao, I. Osman
Journal: Neuro-Oncology (2012)

Melanoma brain metastasis that develops as the isolated first visceral site challenges the current paradigm of tumor progression in which brain metastasis is regarded as the final stage. Here we test the hypothesis that melanoma patients who develop brain metastasis as the isolated first visceral site have distinct clinicopathological features at the time of primary melanoma diagnosis. Cutaneous melanoma patients enrolled in 2 prospectively collected databases were studied (Cohort 1: 1972–1982, Cohort 2: 2002–2009). Patients who developed brain metastasis as isolated first visceral site were compared with (1) all other patients, (2) patients who developed visceral metastasis: extracranial only or extracranial and brain, and (3) patients who progressed to other isolated visceral sites first. Two hundred seven of 2280 (9.1%) patients developed brain metastasis (median follow–up, 5.2 y). Seventy–four of 207 (35.7%) brain metastasis patients progressed to brain metastasis as the isolated first visceral site. These patients presented with primaries that were thinner and had no mitosis compared with all other visceral metastasis patients (Fisher's combined P = .02, .05, respectively), and there was a significant difference in American Joint Committee on Cancer stage distribution at initial melanoma diagnosis (combined P = .02). Post–visceral metastasis survival, however, was shorter in patients with brain metastasis as isolated first visceral site than in patients with visceral metastasis: extracranial and brain (combined P = .03). Brain metastasis as isolated first visceral site is a distinct clinicopathological entity. Studies are needed to better understand the biological factors driving this phenotype at the time of primary melanoma diagnosis and to determine its clinical implications.
Combined-Modality Therapy With Gemcitabine and Radiotherapy As a Bladder Preservation Strategy: Results of a Phase I Trial
Authors: Elizabeth Kent, Howard Sandler, James Montie, Cheryl Lee, Joseph Herman, Peg Esper, Judith Fardig, David C. Smith
Journal: Journal of Clinical Oncology (2004)

We conducted a phase I trial of gemcitabine given twice weekly with concurrent radiotherapy in patients with muscle-invasive bladder cancer.Eligible patients underwent maximal transurethral resection of their bladder tumors followed by twice-weekly infusion of gemcitabine with 2 Gy/d concurrent radiotherapy to the bladder, for a total of 60 Gy over 6 weeks. The starting dose of gemcitabine was 10 mg/m(2) with subsequent dose levels of 20, 27, 30, and 33 mg/m(2). The primary end point was the determination of the maximum-tolerated dose (MTD) of twice weekly gemcitabine with concurrent radiotherapy. Secondary end points included assessment of toxicity associated with combined-modality therapy and initial assessment of the rate of bladder preservation.Twenty-four patients were enrolled and 23 were assessable for toxicity and response. No significant toxicity was demonstrated at the 10 or 20 mg/m(2) twice-weekly doses. Dose-limiting toxicity (DLT) occurred in two of three patients treated at 33 mg/m(2). Intermediate dose levels of 27 and 30 mg/m(2) were then evaluated. The MTD of gemcitabine was 27 mg/m(2). The DLT was systemic, manifested as an elevation in liver function tests, malaise, and edema. Fifteen of 23 patients (65%) are alive with bladders intact and no evidence of recurrent disease at a median follow-up of 43 months.Twice-weekly gemcitabine with concurrent radiotherapy at 2 Gy/d to a total dose of 60 Gy is well-tolerated. The MTD of gemcitabine is 27 mg/m(2). There is a high rate of bladder preservation in this selected group of patients.
Plasma Nitrosothiols Contribute to the Systemic Vasodilator Effects of Intravenously Applied NO
Authors: Tienush Rassaf, Petra Kleinbongard, Michael Preik, André Dejam, Putrika Gharini, Thomas Lauer, Julia Erckenbrecht, Alexej Duschin, Rainer Schulz, Gerd Heusch, Martin Feelisch, Malte Kelm
Journal: Circulation Research (2002)

Higher doses of inhaled NO exert effects beyond the pulmonary circulation. How such extrapulmonary effects can be reconciled with the presumed short half-life of NO in the blood is unclear. Whereas erythrocytes have been suggested to participate in NO transport, the exact role of plasma in NO delivery in humans is not clear. Therefore, we investigated potential routes of NO decomposition and transport in human plasma. NO consumption in plasma was accompanied by a concentration-dependent increase in nitrite and S -nitrosothiols (RSNOs), with no apparent saturation limit up to 200 μmol/L. The presence of red blood cells reduced the formation of plasma RSNOs. Intravenous infusion of 30 μmol/min NO in healthy volunteers increased plasma levels of RSNOs and induced systemic hemodynamic effects at the level of both conduit and resistance vessels, as reflected by dilator responses in the brachial artery and forearm microvasculature. Intravenous application of S -nitrosoglutathione, a potential carrier of bioactive NO, mimicked the vascular effects of NO, whereas nitrite and nitrate were inactive. Changes in plasma nitrosothiols were correlated with vasodilator effects after intravenous application of S -nitrosoglutathione and NO. These findings demonstrate that in humans the pharmacological delivery of NO solutions results in the transport and delivery of NO as RSNOs along the vascular tree.
The Home Treatment of Psychotic Patients: An Analysis of 154 Cases
Authors: ROGER E. MEYER, LAWRENCE F. SCHIFF, ALVIN BECKER
Journal: American Journal of Psychiatry (1967)

The Home Treatment Service of Boston State Hospital seeks to provide alternatives to hospitalization for the mentally ill by means of a referral network in the community conducive to early therapeutic intervention and by drawing the family as well as the patient into the treatment alliance. Of 154 patients reported here, all of whom were initially diagnosed as functionally psychotic, the HTS was able to avert hospitalization for 62 percent. HTS was more effective in maintaining patients in the community than in enhancing community adjustment.
Preferential localization of systemically administered radiolabeled interleukin 1alpha in experimental inflammation in mice by binding to the type II receptor.
Authors: C J van der Laken, O C Boerman, W J Oyen, M T van de Ven, R Chizzonite, F H Corstens, J W van der Meer
Journal: Journal of Clinical Investigation (1997)

Previously, we have shown that systemically administered radiolabeled interleukin 1alpha (IL-1alpha) accumulates preferentially in inflammatory foci in mice. Since inflammation is characterized by influx of leukocytes, which represent IL-1 receptor (IL-1R) positive cells, radiolabeled IL-1 may specifically localize in inflammation by binding to its receptors on infiltrated leukocytes. This hypothesis was tested in a series of studies in mice with acute focal inflammations. Evidence for specific IL-1-IL-1R interaction in induced inflammation was found: microscopic autoradiography revealed that 125I-IL-1alpha localized at the site of inflammatory cells with time; 125I-myoglobin, a similar-sized protein with no known interactions in vivo, was not retained in the inflammation. Furthermore, the uptake 125I-IL-1alpha in inflammatory tissue was significantly lower in neutropenic mice than in immunocompetent mice (0.05+/-0.004 vs. 0.65+/-0.06% ID/g at 48 h after injection, P < 0.0007). Moreover, the uptake of 125I-IL-1alpha at the inflammatory site could be blocked with the anti-IL-1R type II antibody 4E2. At 48 h after injection, the uptake with and without blocking the type II IL-1R was 0.13+/-0.01 and 0. 65+/-0.05% ID/g, respectively (P < 0.0001). These in vivo studies provide evidence that systemically administered radiolabeled IL-1alpha localizes in inflammatory tissue by specific receptor binding, predominantly by binding to the type II IL-1R.
Metabolic Control Improves Long-Term Renal Allograft and Patient Survival in Type 1 Diabetes
Authors: Christian Morath, Martin Zeier, Bernd Do[Combining Diaeresis]hler, Jan Schmidt, Peter P. Nawroth, Gerhard Opelz
Journal: Journal of the American Society of Nephrology (2008)

It is a matter of debate whether pancreas allografts independently contribute to renal allograft and patient survival in individuals who have type 1 diabetes and receive a simultaneous pancreas and kidney transplant (SPK). Using data from the Collaborative Transplant Study, we studied patients who had type 1 diabetes and were recipients of deceased-donor kidneys (DDK), living-donor kidneys (LDK), or SPK. We analyzed graft and patient survival rates with a maximum of 18 yr of follow-up. DDK recipients had inferior graft and patient survival compared with LDK and SPK recipients. LDK recipients had superior graft and patient survival rates initially, but SPK recipients demonstrated equal survival rates toward the end of follow-up. Multivariate analysis, adjusting for pretransplantation cardiovascular risk, showed that patient survival of SPK recipients was superior to that of LDK recipients beyond the 10th year after transplantation (hazard ratio 0.55; P = 0.005). In summary, the early survival advantage of LDK over SPK is lost during long-term follow-up, probably as a result of improved glycemic control in SPK recipients.
Cigarette Smoking, Suicidal Behavior, and Serotonin Function in Major Psychiatric Disorders
Authors: Kevin M. Malone, Christine Waternaux, Gretchen L. Haas, Thomas B. Cooper, Shuhua Li, J. John Mann
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: Cigarette smoking is associated with a higher risk for suicide and attempted suicide, but psychopathological or biological explanations for this association have not been explored. Lower serotonin function and impulsive/aggressive traits are associated with suicidal acts, including completed suicide. The authors hypothesized that the relationship that may exist between cigarette smoking and suicidal behavior may be associated with lower serotonin function and the presence of impulsive/aggressive traits. METHOD: Study subjects were 347 patients with a psychiatric disorder (175 with depression, 127 with schizophrenia, and 45 with other disorders). Fifty-three percent of the subjects (N=184) had a lifetime history of suicide attempt, and 47% (N=163) had never attempted suicide. Smoking behavior, lifetime suicidal behavior, and psychopathology were assessed. Serotonin function was assessed in a subgroup of patients with depression (N=162) by using a fenfluramine challenge test and/or measurement of CSF levels of 5-hydroxyindoleacetic acid. RESULTS: Among all patients, smokers were more likely to have made a suicide attempt (adjusted odds ratio=2.60, 95% confidence interval=1.60–4.23) and had higher suicidal ideation and lifetime aggression scores, compared with nonsmokers. An inverse relationship was observed between amount of cigarette smoking and both indices of serotonin function. CONCLUSIONS: The association between cigarette smoking and the presence and severity of suicidal behavior across major psychiatric disorders may be related to lower brain serotonin function in smokers with depression. Further investigation is required to replicate these findings, to measure serotonin function in patients with disorders other than depression, and to test potential therapeutic effects of serotonin-enhancing treatments on both smoking behavior and suicide risk.
Characterization of ICAM-2 and evidence for a third counter-receptor for LFA-1.
Authors: A R de Fougerolles, S A Stacker, R Schwarting, T A Springer
Journal: The Journal of Experimental Medicine (1991)

In an endeavor to further characterize human intercellular adhesion molecule-2 (ICAM-2), two murine monoclonal antibodies (mAb) were generated to ICAM-2 transfected COS cells, and designated CBR-IC2/1 and CBR-IC2/2. Immunoprecipitated, reduced ICAM-2 migrated as a broad band of Mr 60,000 in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Treatment with N-glycanase revealed a peptide backbone of Mr 31,000, consistent with the size predicted from the cDNA. ICAM-2 had a broad distribution on hematopoietic cell lines and little expression on other cell lines, the sole exception being cultured endothelial cells which possess high levels of ICAM-2. Resting lymphocytes and monocytes expressed ICAM-2, while neutrophils did not. Staining of tissue sections with anti-ICAM-2 mAb confirmed their strong reactivity to vascular endothelium, but demonstrated a lack of ICAM-2 expression on other tissues. Small clusters of ICAM-2 positive cells were, however, seen in germinal centers. In contrast to ICAM-1 there was little or no induction of ICAM-2 expression on lymphocytes or cultured endothelium upon stimulation with inflammatory mediators. One of the two mAb, CBR-IC2/2, was found to totally inhibit binding of ICAM-2+ COS cells to purified lymphocyte function-associated antigen-1 (LFA-1). Using this mAb, LFA-1-dependent binding to both stimulated and unstimulated endothelium was found to be totally accounted for by ICAM-1 and ICAM-2. Homotypic aggregation of an Epstein-Barr virus-transformed B cell line, JY, was found to be solely ICAM-1 and ICAM-2-dependent, while in the case of the T cell lymphoma cell line, SKW3, anti- ICAM-2 mAb in conjunction with anti-ICAM-1 mAb could not inhibit the LFA-1-dependent aggregation. This suggests an additional LFA-1 ligand exists. Using a cell binding assay to purified LFA-1 in conjunction with anti-ICAM-1 and anti-ICAM-2 mAb, we have demonstrated that this putative third ligand for LFA-1 exists on SKW3 and other cell lines.
E6 and E7 Gene Silencing and Transformed Phenotype of Human Papillomavirus 16-Positive Oropharyngeal Cancer Cells
Authors: T. Rampias, C. Sasaki, P. Weinberger, A. Psyrri
Journal: JNCI Journal of the National Cancer Institute (2009)

The E6 and E7 genes of human papillomavirus type 16 (HPV16) encode oncoproteins that bind and degrade p53 and retinoblastoma (pRb) tumor suppressors, respectively. We examined the effects of repressing E6 and E7 oncogene expression on the transformed phenotype of HPV16-positive oropharyngeal cancer cell lines. Human oropharyngeal squamous cell cancer 147T and 090 (harboring integrated HPV16 DNA) and 040T (HPV DNA–negative) cells were infected with retroviruses that expressed a short hairpin RNA (shRNA) targeting the HPV16 E6 and E7 genes or a scrambled-sequence control shRNA. Flow cytometry, terminal deoxynucleotidyltransferase–mediated UTP end-labeling assay, and immunoblotting for annexin V were used to assess apoptosis in shRNA-infected cell lines. Biochemical analysis involved quantitative real-time polymerase chain reaction analysis of p53- and pRb-target gene expression and immunoblotting for p53 and pRb protein expression. In 147T and 090 cells, shRNA-mediated inhibition of HPV16 E6 and E7 expression reduced the E6 and E7 mRNA levels by more than 85% compared with control cells that expressed a scrambled-sequence shRNA. E6 and E7 repression resulted in restoration of p53 and pRB protein expression, increased expression of p53-target genes ( p21 and FAS ), decreased expression of genes whose expression is increased in the absence of functional pRb ( DEK and B-MYB ), and induced substantial apoptosis in 147T and 090 cells compared with the control shRNA–infected cells (from 13.4% in uninfected to 84.3% in infected 147T cells and from 3.3% in uninfected to 71.2% in infected 090 cells). Repression of E6 and E7 oncogenes results in restoration of p53 and pRb suppressor pathways and induced apoptosis in HPV16-positive oropharyngeal squamous cell cancer cell lines.
Grinding up Wheat: A Massive Loss of Nucleotide Diversity Since Domestication
Authors: A Haudry, A Cenci, C Ravel, T Bataillon, D Brunel, C Poncet, I Hochu, S Poirier, S Santoni, S Glémin, J David
Journal: Molecular Biology and Evolution (2007)

Several demographic and selective events occurred during the domestication of wheat from the allotetraploid wild emmer (Triticum turgidum ssp. dicoccoides). Cultivated wheat has since been affected by other historical events. We analyzed nucleotide diversity at 21 loci in a sample of 101 individuals representing 4 taxa corresponding to representative steps in the recent evolution of wheat (wild, domesticated, cultivated durum, and bread wheats) to unravel the evolutionary history of cultivated wheats and to quantify its impact on genetic diversity. Sequence relationships are consistent with a single domestication event and identify 2 genetically different groups of bread wheat. The wild group is not highly polymorphic, with only 212 polymorphic sites among the 21,720 bp sequenced, and, during domestication, diversity was further reduced in cultivated forms--by 69% in bread wheat and 84% in durum wheat--with considerable differences between loci, some retaining no polymorphism at all. Coalescent simulations were performed and compared with our data to estimate the intensity of the bottlenecks associated with domestication and subsequent selection. Based on our 21-locus analysis, the average intensity of domestication bottleneck was estimated at about 3--giving a population size for the domesticated form about one third that of wild dicoccoides. The most severe bottleneck, with an intensity of about 6, occurred in the evolution of durum wheat. We investigated whether some of the genes departed from the empirical distribution of most loci, suggesting that they might have been selected during domestication or breeding. We detected a departure from the null model of demographic bottleneck for the hypothetical gene HgA. However, the atypical pattern of polymorphism at this locus might reveal selection on the linked locus Gsp1A, which may affect grain softness--an important trait for end-use quality in wheat.
Contribution of Recirculation and Fat Diffusion to Myocardial Washout Curves Obtained by External Counting in Man
Authors: ATTILIO MASERI, ANTONIO PESOLA, ANTONIO L'ABBATE, CARLO CONTINI, CLAUDIO MICHELASSI, TOMMASO D'ANGELO
Journal: Circulation Research (1974)

133 Xenon and 125 I-iodoantipyrine (IAP) solutions were simultaneously injected into the left coronary artery in four normal patients and four patients with coronary artery obstructions. Recirculation was computed by convolution of the fractional decrease of the curve following inlet injection over a second curve obtained following right atrial injection. Uncorrected xenon and IAP curves were not statistically different in spite of the lower myocardium-blood partition coefficient and the recirculation of xenon. Corrected IAP curves could be followed down to 1.7%, whereas xenon curves could be followed only to 7.5%, indicating significant xenon diffusion holdup in fat. Corrected IAP curves deviated from a monoexponential course below 5% of peak in normal patients and at about 10% in patients with coronary artery obstructions. Stochastic analysis gave flow values 22% lower and 45% higher, respectively, than those computed from monoexponential extrapolation of corrected IAP and uncorrected xenon curves. With the double-injection technique, IAP washout can be calculated down to about 1% of peak, accounting for the distribution of 99% of the flow through the tissue to which the indicator is delivered. Monoexponential analysis of corrected IAP curves overestimates flow, because it cannot fit the initial delay component and the final reduction of slope. Xenon washout does not allow quantification of myocardial flow in man.
Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: influences of age, gender and osteoarthritis affecting other joints
Authors: Daniel Prieto-Alhambra, Andrew Judge, M Kassim Javaid, Cyrus Cooper, Adolfo Diez-Perez, Nigel K Arden
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> Data on the incidence of symptomatic osteoarthritis (OA) are scarce. We estimated incidence of clinical hip, knee and hand OA, and studied the effect of prevalent OA on joint-specific incident OA. <h3>Methods</h3> SIDIAP contains primary care records for&gt;5 million people from Catalonia (Spain). Participants aged ≥40 years with an incident diagnosis of knee, hip or hand OA between 2006 and 2010 were identified using International Classification of Diseases (ICD)-10 codes. Incidence rates and female-to-male rate ratios (RRs) for each joint site were calculated. Age, gender and body mass index-adjusted HR for future joint-specific OA according to prevalent OA at other sites were estimated using Cox regression. <h3>Results</h3> 3 266 826 participants were studied for a median of 4.45 years. Knee and hip OA rates increased continuously with age, and female-to-male RRs were highest at age 70–75 years. In contrast, female hand OA risk peaked at age 60–64 years, and corresponding female-to-male RR was highest at age 50–55 years. Adjusted HR for prevalent knee OA on risk of hip OA was 1.35 (99% CI 1.28 to 1.43); prevalent hip OA on incident knee OA: HR 1.15 (1.08 to 1.23). Prevalent hand OA predicted incident knee and hip OA: HR 1.20 (1.14 to 1.26) and 1.23 (1.13 to 1.34), respectively. <h3>Conclusions</h3> The effect of age is greatest in the elderly for knee and hip OA, but around the menopause for hand OA. OA clusters within individuals, with higher risk of incident knee and hip disease from prevalent lower limb and hand OA.
Factors influencing response rates for advanced colorectal cancer chemotherapy
Authors: R. Labianca, G. Pancera, G. Luporini
Journal: Annals of Oncology (1996)

Background: The activity of various chemotherapy regimens used in the treatment of advanced colorectal cancer is assessed by different groups of investigators and in various trials by what appear to be common criteria.However, there may be substantial inter-trial variation in the interpretation and application of these criteria which contributes to differences in response rates reported for the same regimen.Materials and methods: This paper reviews the most prominent studies in this field and examines the factors which may influence the assessment of activity in clinical trials such as patient selection, the definition and application of response criteria, the methods of assessment of time to progression and duration of response, factors related to the therapeutic regimen and statistical methods.Each factor is critically discussed.Results: The analysis confirms that there is a large variability among the different studies and that an inter-trial comparison is often impossible, with subsequent difficulties for clinicians in determining the true impact of therapies.Discussion: After briefly commenting on the various issues, this review makes recommendations about how to achieve consistency among trials, for instance by using standard criteria, by extending the use of randomization even in phase II trials and by evaluating high quality, well conducted clinical trials in a meta-analysis, thereby making possible comparison across trials.The conclusions, although specific to colorectal cancer, are also applicable to other advanced malignancies.