tbuckley/cabot-search huggingface dataset:
The Best Guess Approach to Phase I Trial Design
Authors: Daniela D. Rosa, John Harris, Gordon C. Jayson
Journal: Journal of Clinical Oncology (2005)

Rosa, Daniela D Harris, John Jayson, Gordon C Case Reports United States Journal of clinical oncology : official journal of the American Society of Clinical Oncology J Clin Oncol. 2006 Jan 1;24(1):206-8.
Measuring Recent Thymic Emigrants in Blood of Normal and HIV-1–Infected Individuals before and after Effective Therapy
Authors: Linqi Zhang, Sharon R. Lewin, Martin Markowitz, Hsi-Hsun Lin, Eva Skulsky, Rose Karanicolas, Yuxian He, Xia Jin, Sarah Tuttleton, Mika Vesanen, Hans Spiegel, Rhonda Kost, Jan van Lunzen, Hans-Juergen Stellbrink, Steven Wolinsky, William Borkowsky, Paul Palumbo, Leondios G. Kostrikis, David D. Ho
Journal: The Journal of Experimental Medicine (1999)

The role of the thymus in HIV-1 pathogenesis remains unclear. We developed an assay to quantify the number of recent thymic emigrants in blood based on the detection of a major excisional DNA byproduct (termed alpha1 circle) of T cell receptor rearrangement. By studying 532 normal individuals, we found that alpha1 circle numbers in blood remain high for the first 10-15 yr of life, a sharp drop is seen in the late teen years, and a gradual decline occurs thereafter. Compared with age-matched uninfected control individuals, alpha1 circle numbers in HIV-1-infected adults were significantly reduced; however, there were many individuals with normal alpha1 circle numbers. In 74 individuals receiving highly active antiretroviral therapy, we found no appreciable effect on alpha1 circle numbers in those whose baseline values were already within the normal range, but significant increases were observed in those with a preexisting impairment. The increases in alpha1 circle numbers were, however, numerically insufficient to account for the rise in levels of naive T lymphocytes. Overall, it is difficult to invoke thymic regenerative failure as a generalized mechanism for CD4 lymphocyte depletion in HIV-1 infection, as alpha1 circle numbers are normal in a substantial subset of HIV-1-infected individuals.
<i>BRAF</i> V600E and <i>TERT</i> Promoter Mutations Cooperatively Identify the Most Aggressive Papillary Thyroid Cancer With Highest Recurrence
Authors: Mingzhao Xing, Rengyun Liu, Xiaoli Liu, Avaniyapuram Kannan Murugan, Guangwu Zhu, Martha A. Zeiger, Sara Pai, Justin Bishop
Journal: Journal of Clinical Oncology (2014)

To investigate the prognostic value of the BRAF V600E mutation and the recently identified TERT promoter mutation chr5:1,295,228C>T (C228T), individually and in their coexistence, in papillary thyroid cancer (PTC).We performed a retrospective study of the relationship of BRAF and TERT C228T mutations with clinicopathologic outcomes of PTC in 507 patients (365 women and 142 men) age 45.9 ± 14.0 years (mean ± SD) with a median follow-up of 24 months (interquartile range, 8 to 78 months).Coexisting BRAF V600E and TERT C228T mutations were more commonly associated with high-risk clinicopathologic characteristics of PTC than they were individually. Tumor recurrence rates were 25.8% (50 of 194;77.60 recurrences per 1,000 person-years; 95% CI, 58.81 to 102.38) versus 9.6% (30 of 313; 22.88 recurrences per 1,000 person-years; 95% CI, 16.00 to 32.72) in BRAF mutation-positive versus -negative patients (hazard ratio [HR], 3.22; 95% CI, 2.05 to 5.07) and 47.5% (29 of 61; 108.55 recurrences per 1,000 person-years; 95% CI, 75.43 to 156.20) versus 11.4% (51 of 446; 30.21 recurrences per 1,000 person-years; 95% CI, 22.96 to 39.74) in TERT mutation-positive versus -negative patients (HR, 3.46; 95% CI, 2.19 to 5.45). Recurrence rates were 68.6% (24 of 35; 211.76 recurrences per 1,000 person-years; 95% CI, 141.94 to 315.94) versus 8.7% (25 of 287; 21.60 recurrences per 1,000 person-years; 95% CI, 14.59 to 31.97) in patients harboring both mutations versus patients harboring neither mutation (HR, 8.51; 95% CI, 4.84 to 14.97), which remained significant after clinicopathologic cofactor adjustments. Disease-free patient survival curves displayed a moderate decline with BRAF V600E or TERT C228T alone but a sharp decline with two coexisting mutations.Coexisting BRAF V600E and TERT C228T mutations form a novel genetic background that defines PTC with the worst clinicopathologic outcomes, providing unique prognostic and therapeutic implications.
Factors contributing to the high prevalence of multidrug-resistant tuberculosis: a study from China
Authors: Libo Liang, Qunhong Wu, Lijun Gao, Yanhua Hao, Chaojie Liu, Yanguang Xie, Hong Sun, Xinglu Yan, Fabin Li, Honghai Li, Hongxia Fang, Ning Ning, Yu Cui, Liyuan Han
Journal: Thorax (2012)

<h3>Background</h3> The rapid spread of multidrug-resistant tuberculosis (MDR-TB) has attracted global concerns. This study aimed to identify factors contributing to the high prevalence of MDR-TB in China9s Heilongjiang province. <h3>Methods</h3> A cross-sectional survey following the WHO/International Union Against Tuberculosis and Lung Disease guidelines was conducted with consecutive recruitment of patients with TB in 30 counties selected at random in Heilongjiang in 2004. A total of 1995 patients were tested for MDR-TB. Factors associated with MDR-TB were identified through multilevel models and traditional logistic regression analysis, along with in-depth interviews with nine patients, five healthcare managers and four doctors. <h3>Results</h3> 241 patients (12%) were identified with MDR-TB. The retreatment patients were 5.48 times (95% CI 4.04 to 7.44) more likely to have MDR-TB than newly diagnosed patients. The patients who were treated with isoniazid and rifampin for &gt;180 days were 4.82 times (95% CI 2.97 to 7.81) more likely to develop MDR-TB than those treated &lt;180 days. Age and delay in initiating TB treatment were associated with MDR-TB. Financial burden, poor knowledge and side effects of TB treatment were perceived by the interviewees as influencing factors. Lack of coordination of services, unsatisfactory supervision of treatment and infection control jeopardised the control of MDR-TB. <h3>Conclusions</h3> Inappropriate treatment is the most important influencing factor of MDR-TB. Increasing people9s awareness of TB, early detection and appropriate treatment of patients with TB should become a priority, which requires strong commitment and collaboration among health organisations and greater compliance with TB treatment guidelines by service providers and patients.
Activation of Akt and eIF4E Survival Pathways by Rapamycin-Mediated Mammalian Target of Rapamycin Inhibition
Authors: Shi-Yong Sun, Laura M. Rosenberg, Xuerong Wang, Zhongmei Zhou, Ping Yue, Haian Fu, Fadlo R. Khuri
Journal: Cancer Research (2005)

Abstract The mammalian target of rapamycin (mTOR) has emerged as an important cancer therapeutic target. Rapamycin and its derivatives that specifically inhibit mTOR are now being actively evaluated in clinical trials. Recently, the inhibition of mTOR has been shown to reverse Akt-dependent prostate intraepithelial neoplasia. However, many cancer cells are resistant to rapamycin and its derivatives. The mechanism of this resistance remains a subject of major therapeutic significance. Here we report that the inhibition of mTOR by rapamycin triggers the activation of two survival signaling pathways that may contribute to drug resistance. Treatment of human lung cancer cells with rapamycin suppressed the phosphorylation of p70S6 kinase and 4E-BP1, indicating an inhibition of mTOR signaling. Paradoxically, rapamycin also concurrently increased the phosphorylation of both Akt and eIF4E. The rapamycin-induced phosphorylation of Akt and eIF4E was suppressed by the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002, suggesting the requirement of PI3K in this process. The activated Akt and eIF4E seem to attenuate rapamycin's growth-inhibitory effects, serving as a negative feedback mechanism. In support of this model, rapamycin combined with LY294002 exhibited enhanced inhibitory effects on the growth and colony formation of cancer cells. Thus, our study provides a mechanistic basis for enhancing mTOR-targeted cancer therapy by combining an mTOR inhibitor with a PI3K or Akt inhibitor.
Endogenous adenosine inhibits platelet aggregation during myocardial ischemia in dogs.
Authors: M Kitakaze, M Hori, H Sato, S Takashima, M Inoue, A Kitabatake, T Kamada
Journal: Circulation Research (1991)

The goal of this study was to clarify that blockade of adenosine receptors during myocardial ischemia causes further reductions in coronary blood flow due to platelet aggregation. Coronary perfusion pressure in 47 open-chest dogs was reduced such that coronary blood flow decreased to one fifth of the control value; thereafter, coronary perfusion pressure was maintained at the low levels. During hypoperfusion, coronary flow was kept low but constant with a massive release of adenosine. When 8-phenyltheophylline, an adenosine receptor antagonist, was infused during coronary hypoperfusion, coronary blood flow (18 +/- 2 ml/100 g/min) gradually decreased at 5-10 minutes of ischemia and reached almost zero at 20 minutes. Three minutes after the onset of ischemia, before further reduction of coronary flow, the microscopic examination revealed the existence of thromboembolization in the small coronary arteries, and the number of platelets in the regional coronary venous blood were significantly decreased, indicating that a further reduction of coronary flow due to treatment with 8-phenyltheophylline is attributed to thromboembolism caused by platelet aggregations. This reduction of coronary flow and formation of thromboembolism were inhibited by the treatments with dibutyryl cAMP, forskolin, and yohimbine, indicating that this thromboembolization during a lack of adenosine activity is due to platelet aggregation and that platelet aggregation caused by 8-phenyltheophylline is triggered by stimulation of alpha 2-adrenoceptors by released norepinephrine during ischemia. We demonstrate that adenosine, generated endogenously in response to ischemia, inhibits platelet aggregation. The finding that adenosine is not merely a vasodilator but that it also regulates thrombosis has major implications for designing new strategies of myocardial salvage.
P11.05 * LENALIDOMIDE IN THE TREATMENT OF RELAPSED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA (PCNSL)
Authors: C. Houillier, S. Choquet, V. Touitou, N. Martin-Duverneuil, K. Hoang-Xuan
Journal: Neuro-Oncology (2014)

BACKGROUND: Lenalidomide is an immunomodulator agent that exhibits efficacy in multiple myeloma and haematological malignancies including refractory/relapsed diffuse large B-cell (DLBC) systemic lymphoma. METHODS: Retrospective review of PCNSL patients treated with lenalidomide at the Pitié-Salpêtrière hospital. Inclusion criteria were: 1) immunocompetent status 2) pathologically proven diagnosis of DLBC-PCNSL, 3) recurrent or refractory disease after at least two prior chemotherapy treatments, including intravenous high-dose methotrexate and cytarabine based regimens, 4) lenalidomide administered orally, at a dose of 25 mg/day on days 1-21 of a 28-days cycle. MRI scans were performed monthly. Response was evaluated according to the IPCG criteria. RESULTS: Between June 2011 and March 2013, 6 patients (4 women and 2 men) met the inclusion criteria. Lenalidomide was given as 3rd line in four patients, as 4th line in one and 5th line in one. Median age was 73.5 years (range 64-78) and median Karnofsky Performance Status was 60 (range 40-70). Two patients achieved complete response (CR). Patient 1 received a total of 9 monthly cycles of lenalidomide without any steroids and is still in remission after a follow-up of 18 months from the start of the treatment. Patient 2 achieved a CR and was off-steroids at the time of CR, but relapsed during the 3rd cycle and died after 14 weeks. Patient 3 achieved a partial response after one cycle but died suddenly during the 2nd cycle. Patients 4, 5 and 6 progressed and died 2, 5 and 6 months respectively after the start of lenalidomide. One of them who suffered from an oculo-cerebral relapse demonstrated a partial ocular response while progressing in the brain. Apart from the sudden death of unknown cause, the treatment was well tolerated. None of the patients experienced any grade III or IV toxicity. CONCLUSIONS: These results suggest that lenalidomide exhibits activity in heavily pre-treated PCNSL and is well tolerated in elderly patients. Lenalidomide efficacy on PCNSL needs to be evaluated prospectively, alone or in association with other cytotoxic agents. A phase II trial combining rituximab and lenalidomide for recurrent PCNSL is on-going in France (NCT01956695).
Premorbid Social Functioning in Schizophrenia and Bipolar Disorder: Similarities and Differences
Authors: Mary Cannon, Peter Jones, Catherine Gilvarry, Larry Rifkin, Kwame McKenzie, Alice Foerster, Robin M. Murray
Journal: American Journal of Psychiatry (1997)

This research examined social functioning in childhood and adolescence among patients with schizophrenia and patients with bipolar disorder compared with healthy subjects and investigated the relation between premorbid adjustment and risk factors for psychosis.Maternal recall was used to assess the premorbid adjustment of patients with schizophrenia (N = 70) and patients with bipolar disorder (N = 28) recruited from a survey of consecutive hospital admissions for psychosis and of healthy comparison subjects (N = 100) drawn from the same catchment area.The patients with schizophrenia had significantly poorer premorbid adjustment in childhood and adolescence than the comparison subjects and were impaired in both sociability and school adjustment. The patients with bipolar disorder exhibited poorer social impairment in adolescence than the comparison subjects, though to a lesser degree than the schizophrenic subjects, but functioned well at school. There were significant linear trends in the risk of psychosis with worsening premorbid functioning, which was most marked in the schizophrenic group, and a specific linear relation between low birth weight and poor premorbid adjustment among the schizophrenic patients.Impaired premorbid social functioning is not specific to schizophrenia and is seen also in bipolar disorder. The data support the view that poor premorbid social adjustment is one manifestation of vulnerability to adult psychotic disorders. These results are consistent with other findings pointing to early developmental deficits in patients who subsequently develop psychosis.
Comparing cDNA and oligonucleotide array data: concordance of gene expression across platforms for the NCI-60 cancer cells
Authors: Jae K Lee, Kimberly J Bussey, Fuad G Gwadry, William Reinhold, Gregory Riddick, Sandra L Pelletier, Satoshi Nishizuka, Gergely Szakacs, Jean-Phillipe Annereau, Uma Shankavaram, Samir Lababidi, Lawrence H Smith, Michael M Gottesman, John N Weinstein
Journal: Genome biology (2003)

Microarray gene-expression profiles are generally validated one gene at a time by real-time RT-PCR. We describe here a different approach based on simultaneous mutual validation of large numbers of genes using two different expression-profiling platforms. The result described here for the NCI-60 cancer cell lines is a consensus set of genes that give similar profiles on spotted cDNA arrays and Affymetrix oligonucleotide chips. Global concordance is parameterized by a 'correlation of correlations' coefficient.
Arginine, citrulline, and nitric oxide metabolism in end-stage renal disease patients
Authors: Titus Lau, William Owen, Yong Ming Yu, Natan Noviski, Jeremy Lyons, David Zurakowski, Rita Tsay, Alfred Ajami, Vernon R. Young, Leticia Castillo
Journal: Journal of Clinical Investigation (2000)

The kidneys are thought to be a major site of net de novo arginine synthesis, but the quantitative status of arginine metabolism and its substrate precursor relationship to nitric oxide (NO) synthesis in end stage renal disease (ESRD) patients have not been characterized. We have investigated kinetic aspects of whole body arginine metabolism in six patients with ESRD. They received two pre- and two post-hemodialysis intravenous tracer infusion studies with L-[guanidino-15N2]arginine and L-[13C]leucine during the first study, and L-[5-13C]arginine and L-[5-13C-ureido,5,5,2H2]citrulline during the second study. Arginine homeostasis in ESRD patients was found to be associated with a lower rate of arginine oxidation, and despite the decrease in renal function, the rate of de novo arginine synthesis appeared to be preserved. Plasma citrulline concentrations and flux were also elevated in these subjects compared with healthy adults. The rate of whole body NO synthesis was increased in the ESRD patients, but apparently not different pre- and post-hemodialysis therapy. The anatomic site(s) responsible for the maintenance of net de novo arginine synthesis and for the elevated NO synthesis and its pathophysiological importance in ESRD remain to be established.
Distinct T cell receptor signaling requirements for perforin- or FasL-mediated cytotoxicity.
Authors: M T Esser, B Krishnamurthy, V L Braciale
Journal: The Journal of Experimental Medicine (1996)

A diverse array of signals are generated in a cytotoxic T lymphocyte (CTL) after the T cell receptor (TCR) engages the class I major histocompatibility complex (MHC) peptide complex. These signals result in a multitude of CTL effector functions, including cellular cytotoxicity, cell surface receptor expression, and cytokine secretion. We have examined signaling through the TCR in a wild type CD8+, MHC-restricted, antigen-specific CTL clone, 14-7, and its interleukin 2-dependent variant clone 14-7FD. We report here that 14-7FD is unable to kill via the perforin mechanism of killing, yet is able to kill via the Fas ligand/Fas mechanism and secrete interferon-gamma in an antigen-specific manner. 14-7FD has cytolytic granules that contain perforin and serine esterases, which are secreted after phorbol ester and Ca2+ ionophore treatment. Lastly, to investigate which TCR signaling requirements were operational in 14-7FD, we examined TCR-triggered intracellular Ca2+ mobilization in the two clones. After TCR engagement, 14-7FD failed to mobilize intracellular Ca2+, which may be the cause for its inability to trigger the perforin/granule exocytosis mechanism of killing. These results indicate that the signal transduction events that trigger perforin killing and the signaling requirements to induce FasL expression are distinct. We hypothesize that these two distinct TCR signal transduction requirements allow for separate activation of these two mechanisms of killing relating to their role in eradication of infected cells or regulation of immune responses.
Alveolar haemorrhage with pleural effusion as a manifestation of epithelioid haemangioendothelioma
Authors: D Struhar, P Sorkin, J Greif, S Marmor, E Geller
Journal: European Respiratory Journal (1992)

A 22 year old male was admitted with haemoptysis. A chest X-ray showed bilateral confluent alveolar infiltrates. Bronchoscopy revealed blood oozing from all bronchopulmonary segments. Open lung biopsy disclosed bilateral effusions and large necrotizing nodules with pleural adhesions. Histological examination showed tumour cells, which were negative to epithelial and embryogenic markers but positive to factor VIII. This confirmed the diagnosis of an epithelioid haemangioendothelioma. This rare tumour, usually has an indolent course, whereas in our case it was complicated by alveolar and intrapleural bleeding.
Renin Predicts Diastolic Blood Pressure Response to Nonpharmacologic and Pharmacologic Therapy
Authors: M. Donald Blaufox
Journal: JAMA (1992)

Plasma renin activity was measured at baseline and 6 months in a trial of nonpharmacologic therapy of mild hypertension to determine whether plasma renin activity predicts the diastolic blood pressure (DBP) response to nonpharmacologic therapy.Randomized controlled trial of volunteers from the general community with mild hypertension (DBP between 90 and 100 mm Hg), off all antihypertensive therapy at baseline, treated in special research clinics (n = 593).Subjects were randomly assigned to usual, weight loss, or low sodium/high potassium diet and then randomly assigned to receive placebo, chlorthalidone, or atenolol.Renin was analyzed as plasma renin activity and as a renin index (logarithm of 24-hour urinary sodium excretion times logarithm of plasma renin activity) (593 patients at baseline and 6 months) to correct for varied sodium intakes. The DBP was measured using the random zero device.Change in DBP at 6 months could be predicted from baseline plasma renin activity or renin index. The DBP was decreased after 6 months of therapy by 2 mm Hg for each unit increase in baseline plasma renin activity and by 0.16 mm Hg for each unit increase in baseline renin index. Patients in the highest renin index quartile had a greater DBP response to atenolol therapy, and patients in the lowest renin index quartile had a greater DBP response to chlorthalidone therapy. Weight loss diet achieved a greater reduction in DBP in patients with higher baseline renin index and had an additive effect on DBP response in both of the drug groups. Patients on a weight loss diet receiving placebo in the highest baseline renin index quartile had a reduction in DBP of 12.4 mm Hg, compared with 4.4 mm Hg in the lowest baseline renin index quartile (P = .009). A low sodium/high potassium diet had a lesser effect than a weight loss diet on pharmacologic therapy. As with the weight loss diet, patients on a low sodium/high potassium diet in the highest baseline renin index quartile had a greater reduction in DBP than patients in the lowest baseline renin index quartile.These data suggest a significant relationship between baseline levels of plasma renin index and the likelihood of success of nonpharmacologic treatment of hypertension.
IMMUNE RESPONSES AGAINST NATIVE AND CHEMICALLY MODIFIED ALBUMINS IN MICE
Authors: Volker Schirrmacher, Hans Wigzell
Journal: The Journal of Experimental Medicine (1972)

Immune cells induced by bovine serum albumin (BSA) and its methylated derivative (MBSA) have been compared in a cooperative cell transfer system for their content of BSA-specific antibody-forming cell precursors (AFCP, B) and BSA-specific helper (T) cells. When MBSA immune cells were transferred together with hapten-primed cells into recipient mice which were stimulated by a hapten-BSA conjugate, their cooperative secondary anti-hapten response was as good as in case of transferred BSA immune cells. Their secondary anti-BSA response, however, was markedly reduced (reduction factor > 30). Hapten-MBSA conjugates had the same capacity to react with BSA-specific helper cells in the cooperative secondary anti-hapten response as hapten-BSA conjugates but had a reduced ability to react with BSA-specific AFCP cells. In spite of the pronounced reduction of the B cell response, MBSA had the same threshold dose as BSA for activating BSA-specific T cells. These data suggest that B and T cells recognize different epitopes on the BSA molecule, only those recognized by B cells being affected by the methylation procedure.
Detection of Tuberculosis in HIV-Infected and -Uninfected African Adults Using Whole Blood RNA Expression Signatures: A Case-Control Study
Authors: Myrsini Kaforou, Victoria J. Wright, Tolu Oni, Neil French, Suzanne T. Anderson, Nonzwakazi Bangani, Claire M. Banwell, Andrew J. Brent, Amelia C. Crampin, Hazel M. Dockrell, Brian Eley, Robert S. Heyderman, Martin L. Hibberd, Florian Kern, Paul R. Langford, Ling Ling, Marc Mendelson, Tom H. Ottenhoff, Femia Zgambo, Robert J. Wilkinson, Lachlan J. Coin, Michael Levin
Journal: PLoS Medicine (2013)

Using a microarray-based approach, Michael Levin and colleagues develop a disease risk score to distinguish active from latent tuberculosis, as well as tuberculosis from other diseases, using whole blood samples. Please see later in the article for the Editors' Summary