tbuckley/cabot-search huggingface dataset:
Circulating Tumor Cells and [<sup>18</sup>F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography for Outcome Prediction in Metastatic Breast Cancer
Authors: Ugo De Giorgi, Vicente Valero, Eric Rohren, Shaheenah Dawood, Naoto T. Ueno, M. Craig Miller, Gerald V. Doyle, Summer Jackson, Eleni Andreopoulou, Beverly C. Handy, James M. Reuben, Herbert A. Fritsche, Homer A. Macapinlac, Gabriel N. Hortobagyi, Massimo Cristofanilli
Journal: Journal of Clinical Oncology (2009)

Circulating tumor cells (CTCs) and [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) are two new promising tools for therapeutic monitoring. In this study, we compared the prognostic value of CTC and FDG-PET/CT monitoring during systemic therapy for metastatic breast cancer (MBC).A retrospective analyses of 115 MBC patients who started a new line of therapy and who had CTC counts and FDG-PET/CT scans performed at baseline and at 9 to 12 weeks during therapy (midtherapy) was performed. Patients were categorized according to midtherapy CTC counts as favorable (ie, < five CTCs/7.5 mL blood) or unfavorable (> or = five CTCs/7.5 mL blood) outcomes. CTC counts and FDG-PET/CT response at midtherapy were compared, and univariate and multivariate analyses were performed to identify factors associated with survival.In 102 evaluable patients, the median overall survival time was 14 months (range, 1 to > 41 months). Midtherapy CTC levels correlated with FDG-PET/CT response in 68 (67%) of 102 evaluable patients. In univariate analysis, midtherapy CTC counts and FDG-PET/CT response predicted overall survival (P < .001 and P = .001, respectively). FDG-PET/CT predicted overall survival (P = .0086) in 31 (91%) of 34 discordant patients who had fewer than five CTCs at midtherapy. Only midtherapy CTC levels remained significant in a multivariate analysis (P = .004).Detection of five or more CTCs during therapeutic monitoring can accurately predict prognosis in MBC beyond metabolic response. FDG-PET/CT deserves a role in patients who have fewer than five CTCs at midtherapy. Prospective trials should evaluate the most sensitive and cost-effective modality for therapeutic monitoring in MBC.
Paradoxical Reduction in HDL-C With Fenofibrate and Thiazolidinedione Therapy in Type 2 Diabetes: The ACCORD Lipid Trial
Authors: Peter E. Linz, Laura C. Lovato, Robert P. Byington, Patrick J. O’Connor, Lawrence A. Leiter, Daniel Weiss, Rex W. Force, John R. Crouse, Faramarz Ismail-Beigi, Debra L. Simmons, Vasilios Papademetriou, Henry N. Ginsberg, Marshall B. Elam
Journal: Diabetes Care (2013)

OBJECTIVE To determine the occurrence of extremely low HDL cholesterol (HDL-C) among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial and to examine the relationship of this finding with treatment with fenofibrate and thiazolidinedione (TZD). RESEARCH DESIGN AND METHODS The ACCORD Lipid Trial was a randomized, double-blind, placebo-controlled study conducted in patients with type 2 diabetes at 77 clinical centers across the U.S. and Canada in a 5,518-patient subset of the larger 10,251 ACCORD Glycemia Trial. Patients were enrolled from 11 January 2001 to 29 October 2005 and followed until the end of study visits between 1 March and 30 June 2009. Follow-up in the ACCORD Lipid Trial was 4–8 years (mean 4.7 years). Patients were treated with blinded fenofibrate or placebo on a background of simvastatin therapy. The main outcome measures for these descriptive, post hoc analyses was the occurrence of extremely low HDL-C (defined as &amp;lt;25 mg/dL [0.647 mmol/L]) during the trial. RESULTS Among ACCORD Lipid Trial participants, the occurrence of extremely low HDL-C ever during study follow-up was 106% higher among those randomized to fenofibrate (10.1% fenofibrate vs. 4.9% placebo, P &amp;lt; 0.001). The occurrence of low HDL-C was associated with concurrent treatment with fenofibrate and TZD (7.0% for both vs. 2.2% for neither at 48 months postrandomization). CONCLUSIONS Idiosyncratic and marked reduction in HDL-C can occur in some patients treated with both fenofibrate and TZD. Practitioners should recognize this important potential idiosyncratic reaction and take appropriate corrective action.
Preservation of pressure-induced cutaneous vasodilation by limiting oxidative stress in short-term diabetic mice
Authors: C DEMIOT, B FROMY, J SAUMET, D SIGAUDOROUSSEL
Journal: Cardiovascular Research (2005)

Objective: Pressure-induced vasodilation (PIV) allows skin blood flow to increase in response to locally applied pressure and may be protective against pressure ulcers. We previously showed that PIV was absent in 1-week diabetic mice exhibiting no neuropathy. Our aim was to determine whether the diabetes-induced PIV alteration could be prevented.
Clinical characteristics and survival of BRAF-mutant (BRAF+) metastatic melanoma patients (pts) treated with BRAF inhibitor (BRAFi) dabrafenib or vemurafenib beyond disease progression (PD).
Authors: Matthew Chan, Lauren Haydu, Alexander M. Menzies, Mary W. F. Azer, Oliver Klein, Alexander Guminski, Richard Kefford, Georgina Long
Journal: Journal of Clinical Oncology (2013)

9062 Background: Accelerated tumor growth has been demonstrated on BRAFi cessation in BRAFi-resistant melanoma cell lines. In BRAFi-treated pts initial response rates are high but most have PD at 6+ months. The benefit of ongoing BRAFi after PD is unknown. We sought to describe the characteristics of pts treated beyond progression (TBP) vs those not TBP, and whether TBP prolongs survival. Methods: Clinicopathologic data were collected on 112 pts enrolled in phase I-IV clinical trials at Westmead Hospital and Melanoma Institute Australia from July 2009 to Sept 2012 with unresectable stage IIIC or IV BRAF+ melanoma treated with single agent dabrafenib or vemurafenib. TBP was defined as ongoing BRAFi &gt;28 days beyond RECIST PD. Pt and disease characteristics at baseline and at PD were examined, as well as survival data. Results: 92/112 (82%) pts had RECIST PD. 36/92 (39%) pts were TBP (mean 144 days, median 93 days, range 29–572 days). Pts TBP were significantly more likely to have achieved a RECIST response (CR/PR) prior to PD, have a lower ECOG at PD, presence of brain metastases at PD, have PD treated locally and a smaller RECIST sum of diameters (SoD) at PD, compared with those not TBP (all p&lt;0.05). Median OS from commencement of BRAFi in those TBP was longer than those not TBP (15.0 vs 6.5 months, p&lt;0.001), as was OS from RECIST PD (7.4 vs 1.9 mo, p=0.001). In multivariate analysis of all pts, TBP improved OS from RECIST PD (HR 0.32, p=0.012) even after adjusting for other potential prognostic factors at PD (see table). Within the TBP cohort, RECIST SoD at PD was the only factor that influenced OS from PD (p=0.009), and presence of brain metastases did not. Conclusions: Treatment with BRAFi may be continued after RECIST PD in selected pts, and is associated with a prolonged OS compared with ceasing treatment at PD. [Table: see text]
Tumour necrosis factor- (-308) gene polymorphism in obstructive sleep apnoea-hypopnoea syndrome
Authors: R. L. Riha, P. Brander, M. Vennelle, N. McArdle, S. M. Kerr, N. H. Anderson, N. J. Douglas
Journal: European Respiratory Journal (2005)

Patients with obstructive sleep apnoea–hypopnoea syndrome (OSAHS) have elevated circulating levels of tumour necrosis factor (TNF)-α. The hypothesis in this study was that OSAHS might be associated with the TNF-α (−308A) gene polymorphism, which results in increased TNF-α production. This hypothesis was examined in OSAHS patients, their siblings and population controls. A total of 206 subjects were recruited. All underwent sleep studies and clinical review, and were subsequently classified as having OSAHS or not depending on apnoea–hypopnoea frequency, sex, age and symptoms. All subjects had blood collected and genotyping was performed on DNA extracted from peripheral leukocytes. Some 192 random UK blood donors were used as population controls. The results demonstrated a significant association for TNF-α (−308A) allele carriage with OSAHS (OR = 1.8; 95% Confidence interval: 1.18–2.75) when compared with population controls. Siblings with OSAHS were significantly more likely to carry the TNF-α (−308A) allele. In addition, 21 pairs of male siblings discordant for carriage of the −308A allele showed a significant level of discordance for the OSAHS phenotype. In conclusion, this study demonstrates an association of tumour necrosis factor-α (−308A) carriage with obstructive sleep apnoea–hypopnoea syndrome, suggesting that inflammation may be implicated in the pathogenesis of this condition.
The limited roles of unconscious computation and representation in self-organizational theories of mind
Authors: Ralph D. Ellis
Journal: Behavioral and Brain Sciences (2002)

In addressing the shortcomings of computationalism, we should not throw the baby out with the bathwater. That consciousness is not merely an epiphenomenon with optional access to unconscious computations does not imply that unconscious computations, in the limited domain where they do occur (e.g., occipital transformations of visual data), cannot be reformulated in a way consistent with a self-organizational view
Reflex and Tonic Autonomic Markers for Risk Stratification in Patients With Type 2 Diabetes Surviving Acute Myocardial Infarction
Authors: Petra Barthel, Axel Bauer, Alexander Müller, Nadine Junk, Katharina M. Huster, Kurt Ulm, Marek Malik, Georg Schmidt
Journal: Diabetes Care (2011)

Diabetic postinfarction patients are at increased mortality risk compared with nondiabetic postinfarction patients. In a substantial number of these patients, diabetic cardiac neuropathy already preexists at the time of the infarction. In the current study we investigated if markers of autonomic dysfunction can further discriminate diabetic postinfarction patients into low- and high-risk groups.We prospectively enrolled 481 patients with type 2 diabetes who survived acute myocardial infarction (MI), were aged ≤ 80 years, and presented in sinus rhythm. Primary end point was total mortality at 5 years of follow-up. Severe autonomic failure (SAF) was defined as coincidence of abnormal autonomic reflex function (assessed by means of heart rate turbulence) and of abnormal autonomic tonic activity (assessed by means of deceleration capacity of heart rate). Multivariable risk analyses considered SAF and standard risk predictors including history of previous MI, arrhythmia on Holter monitoring, insulin treatment, and impaired left ventricular ejection fraction (LVEF) ≤ 30%.During follow-up, 83 of the 481 patients (17.3%) died. Of these, 24 deaths were sudden cardiac deaths and 21 nonsudden cardiac deaths. SAF identified a high-risk group of 58 patients with a 5-year mortality rate of 64.0% at a sensitivity level of 38.0%. Multivariately, SAF was the strongest predictor of mortality (hazard ratio 4.9 [95% CI 2.4-9.9]), followed by age ≥65 years (3.4 [1.9-5.8]), and LVEF ≤ 30% (2.6 [1.5-4.4]).Combined abnormalities of autonomic reflex function and autonomic tonic activity identifies diabetic postinfarction patients with very poor prognoses.
ET-22 * CONVECTION-ENHANCED DELIVERY OF THE AUGER-ELECTRON-EMITTER 125I-UdR: A HIGHLY EFFICIENT THERAPY IN AN ORTHOTOPIC GLIOBLASTOMA XENOGRAFT MODEL
Authors: B. Halle, H. Thisgaard, C. Aaberg-Jessen, B. Olsen, J. Dam, N. Langkjaer, S. Munthe, K. Nagren, P. F. Hoilund-Carlsen, B. Kristensen
Journal: Neuro-Oncology (2014)

BACKGROUND: Glioblastomas (GBMs), the most common and malignant primary brain tumors, always recur after standard treatment. In order to develop more efficient therapies, we tested a novel therapeutic approach using the radioactive Auger-electron-emitter (AEE) [125I]5-Iodo-2'-deoxyuridine (125I-UdR). This drug incorporates into DNA of dividing cells and upon decay emission of Auger-electrons causes clusters of double strand breaks leading to cell death. METHODS: In vitro, cells from two GBM spheroid cultures (T78 & T87) were exposed to either 125I-UdR or 127I-UdR (non-radioactive analogue) and tumor cell viability and migration were measured. In vivo, nude rats were implanted orthotopically with T87 cells and after tumor formation micro infusion pumps were implanted enabling direct intratumoral convection-enhanced delivery (CED). Animals were divided into three groups (I-III). Group I (n = 8) was treated with 127I-UdR by CED, group II (n = 7) with neoadjuvant methotrexate (MTX) + 125I-UdR by CED and group III with neoadjuvant MTX + 125I-UdR by CED and concomitant systemic temozolomide (TMZ). Rats were followed for 180 days post-treatment with repeated [11C]methylaminoisobutyric acid ([11C]MeAIB) positron emission tomography scans and blood sampling. Single photon emission computed tomography/computed tomography (SPECT/CT) scans were performed to evaluate 125I-UdR distribution. Additionally, post-mortem histological examination of brain, liver, kidneys and thyroid gland was performed. RESULTS: In vitro, 125I-UdR significantly decreased GBM cell viability and migration. In group I, no animals (8/8) survived longer than 23 days after treatment start. In group II, 4/7 animals survived the entire observation period of 180 days. In group III, all animals (8/8) survived the entire observation period. SPECT/CT showed a widespread intracerebral distribution of 125I-UdR, while blood samples and post-mortem histology revealed no signs of dose-limiting adverse effects. CONCLUSIONS: The novel therapeutic approach with CED of MTX and the AEE-compound 125I-UdR in combination with systemic TMZ seemed safe and very efficient in the orthotopic GBM model.
Mixing of Cr <sup>51</sup> -Labeled Red Cells in Patients with Congestive Heart Failure and Controls
Authors: ROBERT K. FUNKHOUSER
Journal: Circulation Research (1957)

Composite time-concentration curves of labeled erythrocytes in venous blood constructed by pooling data from 11 patients without circulatory failure showed a curve of mixing lasting 25 min. Data from 9 patients in congestive heart failure showed variable mixing lasting at least as long as in the control patients.
Mismatches at the HLA-DR and HLA-B Loci Are Risk Factors for Acute Rejection after Lung Transplantation
Authors: LARRY L. SCHULMAN, ALAN D. WEINBERG, CARLTON McGREGOR, MARK E. GALANTOWICZ, NICOLE M. SUCIU-FOCA, SILVIU ITESCU
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Early high-grade acute rejections (pathologic grade A2 or A3) in recipients of lung allografts are a major risk factor for the subsequent development of obliterative bronchiolitis (OB). We analyzed the risk factors for high-grade acute rejections in 152 recipients of single (100) or bilateral (52) lung allografts transplanted at our institution between 1990 and 1996. Using Kaplan-Meier product limit estimate analysis, there was a 50% probability of grade A2 or A3 rejection by 1 yr after transplant. By univariate analysis, the only significant predictor of early high-grade rejections was the presence of one or more mismatches at the HLA-DR locus (p = 0.038). This association was confirmed using the Cox proportional hazards model for multivariable analysis, with HLA-DR locus mismatch being the only risk factor identified for high-grade rejection (p = 0.036). Using repeated rejection analysis, recipients with one or more matches at the HLA-DR locus had a lower cumulative rate of grade A2 or A3 rejections during the first year compared with recipients with no matches at the HLA-DR locus (0.73 versus 1.32). In addition, recipients with one or more HLA-B locus matches had a lower cumulative rate of grade A2 or A3 rejections in the first year than did recipients with no matches at the HLA-B locus (0.59 versus 1.30). These results indicate that mismatches between donors and recipients at the HLA-DR and HLA-B loci are important risk factors for early high-grade rejections after lung transplantation. Immunosuppressive protocols that are more effective in preventing recipient T-cell activation by donor alloantigens are likely to reduce the rate of high-grade acute rejections in recipients of lung transplants, and may directly impact on the time to onset of OB.
Extreme Outlier Analysis Identifies Occult Mitogen-Activated Protein Kinase Pathway Mutations in Patients With Low-Grade Serous Ovarian Cancer
Authors: Rachel N. Grisham, Brooke E. Sylvester, Helen Won, Gregory McDermott, Deborah DeLair, Ricardo Ramirez, Zhan Yao, Ronglai Shen, Fanny Dao, Faina Bogomolniy, Vicky Makker, Evis Sala, Tara E. Soumerai, David M. Hyman, Nicholas D. Socci, Agnes Viale, David M. Gershenson, John Farley, Douglas A. Levine, Neal Rosen, Michael F. Berger, David R. Spriggs, Carol A. Aghajanian, David B. Solit, Gopa Iyer
Journal: Journal of Clinical Oncology (2015)

No effective systemic therapy exists for patients with metastatic low-grade serous (LGS) ovarian cancers. BRAF and KRAS mutations are common in serous borderline (SB) and LGS ovarian cancers, and MEK inhibition has been shown to induce tumor regression in a minority of patients; however, no correlation has been observed between mutation status and clinical response. With the goal of identifying biomarkers of sensitivity to MEK inhibitor treatment, we performed an outlier analysis of a patient who experienced a complete, durable, and ongoing (> 5 years) response to selumetinib, a non-ATP competitive MEK inhibitor.Next-generation sequencing was used to analyze this patient's tumor as well as an additional 28 SB/LGS tumors. Functional characterization of an identified novel alteration of interest was performed.Analysis of the extraordinary responder's tumor identified a 15-nucleotide deletion in the negative regulatory helix of the MAP2K1 gene encoding for MEK1. Functional characterization demonstrated that this mutant induced extracellular signal-regulated kinase pathway activation, promoted anchorage-independent growth and tumor formation in mice, and retained sensitivity to selumetinib. Analysis of additional LGS/SB tumors identified mutations predicted to induce extracellular signal-regulated kinase pathway activation in 82% (23 of 28), including two patients with BRAF fusions, one of whom achieved an ongoing complete response to MEK inhibitor-based combination therapy.Alterations affecting the mitogen-activated protein kinase pathway are present in the majority of patients with LGS ovarian cancer. Next-generation sequencing analysis revealed deletions and fusions that are not detected by older sequencing approaches. These findings, coupled with the observation that a subset of patients with recurrent LGS ovarian cancer experienced dramatic and durable responses to MEK inhibitor therapy, support additional clinical studies of MEK inhibitors in this disease.
Molecular Detection of Cancer Cells by Competitive Reverse Transcription-Polymerase Chain Reaction Analysis of Specific CD44 Variant RNAs
Authors: Isamu Okamoto, Ji-ichiro Sasaki, Tetsuro Morisaki, Hideyuki Saya, Hideaki Miyake, Mitsuhiro Matsumoto, Moritaka Suga, Masayuki Ando
Journal: JNCI Journal of the National Cancer Institute (1998)

Background: CD44 is a cell surface glycoprotein implicated in such diverse biologic processes as lymphocyte activation and homing, extracellular matrix adhesion, and cellular migration. Primary transcripts of the CD44 gene can be alternatively spliced to produce a variety of messenger RNA (mRNA) species. The standard form of CD44 mRNA contains sequences from at least 20 genomic exons; variant mRNAs contain sequences from one or more additional exons (v1-10). Predominant expression of a specific CD44 variant, i.e., CD44v8-10, in several human carcinomas has been described previously. In this study, we developed a novel molecular approach for detecting cancer cells that overexpress CD44v8-10 mRNA. Methods: After finding that CD44v8-10 was pre-dominantly expressed in non-small-cell lung and bladder carcinomas and that CD44v10 was predominantly expressed in leukocytes, we developed a competitive reverse transcription-polymerase chain reaction assay (CC-RT-PCR) that allows quantification of the relative expression of these two mRNA species in clinical specimens (i.e., determination of a v8-10/v10 ratio). CC-RT-PCR analysis was applied to pleural effusion specimens from patients with benign or malignant lung diseases as well as to spontaneously voided urine samples from patients with benign or malignant urologic diseases. Results: Fifty two of 54 samples from patients with benign diseases expressed CD44v10 predominantly (v8-10/v10 ratio ⩽0.65), whereas 46 of 61 samples from patients with malignant diseases expressed CD44v8-10 predominantly (v8-10/v10 ratio >1.00) (two-sided P<.001). CC-RT-PCR detected predominant expression of CD44v8-10 in cytologically negative samples from 11 patients who were later diagnosed with malignant disease. Conclusions: CC-RT-PCR analysis of CD44v8-10 expression could be an important adjunct to cytologic examination in cancer diagnosis, especially in detecting exfoliated cancer cells in pleural effusions and urine.
Benign cutaneous polyarteritis nodosa in children below 10 years of age--a clinical experience.
Authors: L Kumar, B R Thapa, B Sarkar, B N Walia
Journal: Annals of the Rheumatic Diseases (1995)

To report 10 children younger than 10 years of age with benign cutaneous polyarteritis nodosa (BCPAN).Ten children aged 1.25-10 years (mean 4.7 years; M:F = 7:3) were admitted with an unusual vasculitis. The clinical features, laboratory investigations, treatment and follow up data were analysed.Clinical features of these patients included: fever (10), peripheral gangrene (eight), livido reticularis (four), ulceration, nodules and vesiculobullous lesions alone or in combination (10), black necrotic patches over limbs and trunk (three), and arthralgia or swelling of large joints (seven). Cryoglobulinaemia was transient in three children, lasting for eight months in one of them. Histopathology of the skin lesions revealed vasculitis of small and occasionally medium sized blood vessels in nine of the 10 children. Possible association of BCPAN was noted with diphtheria-pertussistetanus immunisation (one), drugs (two), streptococcal infection (two), wasp sting (one), and falciparum malaria (one). The clinical course was interspersed with remissions and exacerbations. Response to corticosteroids alone occurred in seven patients, while three children needed cytotoxic drugs in addition. In a follow up of 5.6 years (mean) no evidence of systemic involvement was noted.A rare form of vasculitis, BCPAN, is reported in children. The features that distinguished our patients from those reported earlier were onset in the first decade of life and higher incidence of peripheral gangrene.
The fusion gene Cbfb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia
Authors: Lucio H. Castilla, Lisa Garrett, Neeraj Adya, Donald Orlic, Amalia Dutra, Stacie Anderson, Jennie Owens, Michael Eckhaus, David Bodine, P. Paul Liu
Journal: Nature Genetics (1999)