tbuckley/cabot-search huggingface dataset:
Deletion of Chromosome 11q Predicts Response to Anthracycline-Based Chemotherapy in Early Breast Cancer
Authors: Joan Climent, Peter Dimitrow, Jane Fridlyand, Jose Palacios, Reiner Siebert, Donna G. Albertson, Joe W. Gray, Daniel Pinkel, Ana Lluch, Jose A. Martinez-Climent
Journal: Cancer Research (2007)

Abstract Despite the recent consensus on the eligibility of adjuvant systemic therapy in patients with lymph node–negative breast cancer (NNBC) based on clinicopathologic criteria, specific biological markers are needed to predict sensitivity to the different available therapeutic options. We examined the feasibility of developing a genomic predictor of chemotherapy response and recurrence risk in 185 patients with NNBC using assembled arrays containing 2,460 bacterial artificial chromosome clones for scanning the genome for DNA copy number changes. After surgery, 90 patients received anthracycline-based chemotherapy, whereas 95 did not. Tamoxifen was administered to patients with hormone receptor–positive tumors. The association of genomic and clinicopathologic data and outcome was computed using Cox proportional hazard models and multiple testing adjustment procedures. Analysis of NNBC genomes revealed a common genomic signature. Specific DNA copy number aberrations were associated with hormonal receptor status, but not with other clinicopathologic variables. In patients treated with chemotherapy, none of the genomic changes were significantly correlated with recurrence. In patients not receiving chemotherapy, deletion of eight bacterial artificial chromosome clones clustered to chromosome 11q was independently associated with relapse (disease-free survival at 10 years ± SE, 40% ± 14% versus 86% ± 6%; P &amp;lt; 0.0001). The 54 patients with deletion of 11q (29%) did not present more aggressive clinicopathologic features than those without 11q loss. The adverse influence of 11q deletion on clinical outcome was confirmed in an independent validation series of 88 patients with NNBC. Our data suggests that patients with NNBC with the 11q deletion might benefit from anthracycline-based chemotherapy despite other clinical, pathologic, or genetic features. However, these initial findings should be evaluated in randomized clinical trials. [Cancer Res 2007;67(2):818–26]
Nitric oxide mediated endothelium-dependent relaxation induced by glibenclamide in rat isolated aorta
Authors: W Chan
Journal: Cardiovascular Research (2000)

Objectives: Glibenclamide was found to act as both a selective ATP-sensitive K+ channel blocker and a vasorelaxant. The exact mechanisms underlying the relaxant effect of glibenclamide are unknown. The present study was designed to examine the role of endothelium/nitric oxide in glibenclamide-induced relaxation in rat isolated aortic rings. Methods: A combination of experimental approaches including isometric force measurement, cell culture, Ca2+ fluorescence measurement and radioimmunoassay were used to examine the vascular effect of glibenclamide. Results: Glibenclamide induced a concentration-dependent relaxation more effectively in rings with endothelium (IC50 of 32±4 μM) than those without endothelium (IC50 of 365±29 μM). Incubation with NG-nitro-l-arginine methyl ester (L-NAME) or methylene blue significantly reduced and l-arginine (3 mM) potentiated the glibenclamide-induced relaxation. l-Arginine (3 mM) partially antagonized the effect of L-NAME. Glibenclamide (100 μM) increased the cyclic GMP content of endothelium-intact tissues. Pretreatment with NG-nitro-l-arginine (100 μM) or removal of endothelium significantly suppressed the effect of glibenclamide on cyclic GMP production. Glibenclamide elevated the intracellular Ca2+ levels in cultured rat aortic endothelial cells. Glibenclamide also inhibited the endothelium-independent contractile response to 60 mM K+ (IC50 of 137±21 μM) and caused a rightward shift in the concentration–contraction curve for CaCl2. Besides, glibenclamide inhibited phorbol-12,13-diacetate (1 μM)-induced contraction in Ca2+-free Krebs solution. Conclusion: These results indicate that glibenclamide-induced endothelium-dependent relaxation involves nitric oxide release and this effect may be related to its stimulatory effect on endothelial Ca2+ levels. However, the glibenclamide-induced endothelium-independent relaxation may be associated with its inhibitory effect on Ca2+ influx through Ca2+ channels and on the protein kinase C-mediated contractile mechanism.
Treatment of Chronic Hyponatremia
Authors: Arthur Greenberg, Ruediger W. Lehrich
Journal: Journal of the American Society of Nephrology (2010)

Two vasopressin receptor antagonists (vaptans) are now available for treatment of euvolemic or hypervolemic hyponatremia in the United States. The Food and Drug Administration approved conivaptan, a combined V1a/V2 receptor antagonist, in December 2005. Although orally active, marketing was limited to a parenteral form intended for short-term hospital use because of concern for the drug's potency as a CYP3A4 inhibitor.1 Tolvaptan, a selective V2 receptor antagonist, was approved in May 2009. Like conivaptan, it has been shown in short-term studies to be effective in raising the serum sodium concentration in patients with diverse causes of hyponatremia.2 Until now, almost all of the published experience with vaptans in hyponatremia has come from studies of short duration, ranging from a single dose to 30 days of therapy.2,3 Longer term experience with conivaptan is convincing but anecdotal1; even a single study that used satavaptan to treat hyponatremia for up to 12 months had only 10 patients.4

In this issue of JASN , important data on the long-term use of vaptan therapy in a much larger cohort are presented by Berl et al. 5 Termed Safety and sodium Assessment of Long-term Tolvaptan With hyponatremia: A year-long, open-label Trial to gain Experience under Real-world conditions (SALTWATER), it was an open-label extension of the earlier Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT) in which SALT enrollees who previously received either tolvaptan or placebo for 30 days were given oral tolvaptan for up to 804 days.2 A total of 111 individuals participated in SALTWATER, and, over time, 64 discontinued the drug, 30 because of death or adverse reactions. The median time on …
The Tears of the Physician
Authors: William H. Frey
Journal: JAMA (1990)

To the Editor.—  Dr Krauser1presents both a thoughtful and an emotionprovoking discourse on physicians' emotional tears and their occurrence in the physician-patient relationship. The ability to excrete emotional tears is one of the few physiological functions that distinguish humans from other animals. I have theorized that emotional tearing evolved in the human being as an adaptive response to emotional stress and that perhaps the reason we feel better after crying is that we may be removing in our tears chemicals that build up as a result of stress. I have also suggested that women may cry more easily and more frequently than men because of hormonal differences between the sexes and because of societal conditioning against crying in men.2  It is unfortunate that tears are still viewed by some as a sign of weakness and loss of control. This view is certainly not held by all, however.
Cause-Specific Effects of Radiotherapy and Lymphadenectomy in Stage I–II Endometrial Cancer: A Population-Based Study
Authors: Loren K. Mell, Ruben Carmona, Sachin Gulaya, Tina Lu, John Wu, Cheryl C. Saenz, Florin Vaida
Journal: JNCI Journal of the National Cancer Institute (2013)

Radiotherapy and lymphadenectomy have been associated with improved survival in population-based studies of endometrial cancer, which is in contrast with findings from randomized trials and meta-analyses. The primary study aim was to estimate the cause-specific effects of adjuvant radiotherapy and lymphadenectomy on competing causes of mortality.We analyzed Surveillance, Epidemiology, and End Results (SEER) data from 1988 to 2006. The sample comprised 58172 patients with stage I and II endometrial adenocarcinoma. Patients were risk stratified by stage, grade, and age. Cumulative incidences and cause-specific hazards of competing causes of mortality were estimated according to treatment. All statistical tests were two-sided.Pelvic radiotherapy was associated with statistically significantly increased endometrial cancer mortality (hazard ratio [HR] = 1.66; 95% confidence interval [CI] = 1.52 to 1.82) in all stage I and II patients and decreased noncancer mortality in intermediate and high-risk stage I and II patients (HR = 0.82; 95% CI = 0.77 to 0.89). Lymphadenectomy was associated with increased endometrial cancer mortality in stage I patients (HR = 1.27; 95% CI = 1.16 to 1.39), decreased endometrial cancer mortality in stage II patients (HR = 0.61; 95% CI = 0.52 to 0.72), and decreased noncancer mortality in both stage I and II patients (HR = 0.84; 95% CI = 0.80 to 0.88). Effects of radiotherapy and lymphadenectomy on second cancer mortality varied according to risk strata.Radiotherapy and lymphadenectomy are associated with statistically significantly reduced noncancer mortality in stage I and II endometrial cancer. The improved overall survival associated with these treatments reported from SEER studies is largely attributable to their selective application in healthier patients rather than their effects on endometrial cancer.
High-Sensitivity Cardiac Troponin T Levels and Secondary Events in Outpatients With Coronary Heart Disease From the Heart and Soul Study
Authors: Alexis L Beatty, Ivy A Ku, Robert H Christenson, Christopher R DeFilippi, Nelson B Schiller, Mary A Whooley
Journal: JAMA Internal Medicine (2013)

Levels of high-sensitivity cardiac troponin T (hs-cTnT) predict secondary cardiovascular events in patients with stable coronary heart disease.To determine the association of hs-cTnT levels with structural and functional measures of heart disease and the extent to which these measures explain the relationship between hs-cTnT and secondary events.We measured serum concentrations of hs-cTnT and performed exercise treadmill testing with stress echocardiography in a prospective cohort study of outpatients with coronary heart disease who were enrolled from September 11, 2000, through December 20, 2002, and followed up for a median of 8.2 years.Twelve outpatient clinics in the San Francisco Bay Area.Nine hundred eighty-four patients with stable coronary heart disease.Cardiovascular events (myocardial infarction, heart failure, or cardiovascular death), determined by review of medical records and death certificates.Of 984 participants, 794 (80.7%) had detectable hs-cTnT levels. At baseline, higher hs-cTnT levels were associated with greater inducible ischemia and worse left ventricular ejection fraction, left atrial function, diastolic function, left ventricular mass, and treadmill exercise capacity. During follow-up, 317 participants (32.2%) experienced a cardiovascular event. After adjustment for clinical risk factors, baseline cardiac structure and function, and other biomarkers (N-terminal portion of the prohormone of brain-type natriuretic peptide and C-reactive protein levels), each doubling in hs-cTnT level remained associated with a 37% higher rate of cardiovascular events (hazard ratio, 1.37 [95% CI, 1.14-1.65]; P = .001).In outpatients with stable coronary heart disease, higher hs-cTnT levels were associated with multiple abnormalities of cardiac structure and function but remained independently predictive of secondary events. These findings suggest that hs-cTnT levels may detect an element of risk that is not captured by existing measures of cardiac disease severity.
CDK8 Maintains Tumor Dedifferentiation and Embryonic Stem Cell Pluripotency
Authors: Adam S. Adler, Mark L. McCleland, Tom Truong, Shari Lau, Zora Modrusan, Tim M. Soukup, Merone Roose-Girma, Elizabeth M. Blackwood, Ron Firestein
Journal: Cancer Research (2012)

CDK8 is a cyclin-dependent kinase that mediates transcriptional control of pathways linked to both cancer and stem cells. In this study, we show that CDK8 is required for both tumor growth and maintenance of tumor dedifferentiation in vivo and uncover a common role for CDK8 in controlling cancer and stem cell function. Acute CDK8 loss in vivo strongly inhibited tumor growth and promoted differentiation. Transcriptional profiling identified a set of embryonic stem cell-related genes that are activated by CDK8 in cancer. Consistent with this, we found that CDK8 expression correlated to the embryonic stem cell pluripotency state and loss of CDK8 caused embryonic stem cells to differentiate. This effect was, at least partially, mediated by the ability of CDK8 to regulate MYC protein and downstream MYC target gene expression. Similar regulation of MYC target genes by CDK8 was observed in colon tumor cells, and increased expression of a CDK8-regulated, embryonic stem cell MYC target gene signature was associated with loss of differentiation and poor outcome in primary human colon cancers. Together, these observations reveal that CDK8 acts, at least in part, through MYC to maintain both tumors and embryonic stem cells in an undifferentiated state. This raises the intriguing possibility that targeting CDK8 therapeutically may specifically inhibit the stem-like properties of cancer cells.
Combination Immunotherapy of B16 Melanoma Using Anti–Cytotoxic T Lymphocyte–Associated Antigen 4 (Ctla-4) and Granulocyte/Macrophage Colony-Stimulating Factor (Gm-Csf)-Producing Vaccines Induces Rejection of Subcutaneous and Metastatic Tumors Accompanied by Autoimmune Depigmentation
Authors: Andrea van Elsas, Arthur A. Hurwitz, James P. Allison
Journal: The Journal of Experimental Medicine (1999)

We examined the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade, alone or in combination with a granulocyte/macrophage colony-stimulating factor (GM-CSF)-expressing tumor cell vaccine, on rejection of the highly tumorigenic, poorly immunogenic murine melanoma B16-BL6. Recently established tumors could be eradicated in 80% (68/85) of the cases using combination treatment, whereas each treatment by itself showed little or no effect. Tumor rejection was dependent on CD8(+) and NK1.1(+) cells but occurred irrespective of the presence of CD4(+) T cells. Mice surviving a primary challenge rejected a secondary challenge with B16-BL6 or the parental B16-F0 line. The same treatment regimen was found to be therapeutically effective against outgrowth of preestablished B16-F10 lung metastases, inducing long-term survival. Of all mice surviving B16-BL6 or B16-F10 tumors after combination treatment, 56% (38/68) developed depigmentation, starting at the site of vaccination or challenge and in most cases progressing to distant locations. Depigmentation was found to occur in CD4-depleted mice, strongly suggesting that the effect was mediated by CTLs. This study shows that CTLA-4 blockade provides a powerful tool to enhance T cell activation and memory against a poorly immunogenic spontaneous murine tumor and that this may involve recruitment of autoreactive T cells.
The Psychiatrist's Effect on the Behavior and Interaction of Therapy Groups
Authors: BORIS M. ASTRACHAN, ARTHUR H. SCHWARTZ, ROBERT BECKER, MARTIN HARROW
Journal: American Journal of Psychiatry (1967)

The present study investigated which aspects of group behavior and interaction are influenced more by the particular psychotherapist and patients involved than by the type of group therapy session. Taped segments from three therapists' groups, with each group attending under three controlled conditions, were rated "blind" for 37 aspects of group emotion, behavior, and interaction. The style of behavior preferred by each group therapist influenced particular patterns of group interaction and the groups' characteristic response to stress.
Frasier Syndrome
Authors: LAURIE DEMMER, WILLIAM PRIMACK, VALERIE LOIK, ROSALIND BROWN, NICOLE THERVILLE, KEN MCELREAVEY
Journal: Journal of the American Society of Nephrology (1999)

Abstract. The description of Frasier syndrome until now has been restricted to XY females with gonadal dysgenesis, progressive glomerulopathy, and a significant risk of gonadoblastoma. Mutations in the donor splice site in intron 9 of the Wilms' tumor (WT1) gene have been shown to cause Frasier syndrome and are distinct from WT1 exon mutations associated with Denys-Drash syndrome. The WT1 gene, which is essential for normal kidney and gonadal development, encodes a zinc finger transcription factor. The intron 9 alternative splice donor site mutation seen in Frasier syndrome leads to loss of three amino acids (+KTS isoform), thus disrupting the normal ratio of the +KTS/-KTS isoforms critical for proper gonadal and renal development. This study examines two sisters with identical intron 9 mutations. The proband carries a classic diagnosis of Frasier syndrome with 46, XY gonadal dysgenesis, whereas her sister has progressive glomerulopathy but a 46, XX karyotype and normal female development. This indicates that the proper WT1 isoform ratio is critical for renal and testicular development, but apparently does not affect either ovarian development or function. It is proposed that the clinical definition of Frasier syndrome should be broadened to include 46,XX females with normal genital development and focal segmental glomerulosclerosis associated with a WT1 intron 9 donor splice site mutation. Nephrologists need to consider the possibility of this heritable syndrome in evaluation of females with focal segmental glomerulosclerosis and to consider their risk for gonadal malignancy, as well as the risk for kidney disease, gonadal dysgenesis, and malignancy in their offspring.
Electrical Compartmentalization in Dendritic Spines
Authors: Rafael Yuste
Journal: Annual Review of Neuroscience (2013)

Most excitatory inputs in the CNS contact dendritic spines, avoiding dendritic shafts, so spines must play a key role for neurons. Recent data suggest that, in addition to enhancing connectivity and isolating synaptic biochemistry, spines can behave as electrical compartments independent from their parent dendrites. It is becoming clear that, although spines experience voltages similar to those of dendrites during action potentials (APs), spines must sustain higher depolarizations than do dendritic shafts during excitatory postsynaptic potentials (EPSPs). Synaptic potentials are likely amplified at the spine head and then reduced as they invade the dendrite through the spine neck. These electrical changes, probably due to a combination of passive and active mechanisms, may prevent the saturation of dendrites by the joint activation of many inputs, influence dendritic integration, and contribute to rapid synaptic plasticity. The electrical properties of spines could enable neural circuits to harness a high connectivity, implementing a "synaptic democracy," where each input can be individually integrated, tallied, and modified in order to generate emergent functional states.
[<sup>18</sup>F]Fluorodeoxyglucose Positron Emission Tomography Correlates With Akt Pathway Activity but Is Not Predictive of Clinical Outcome During mTOR Inhibitor Therapy
Authors: Wen Wee Ma, Heather Jacene, Dongweon Song, Felip Vilardell, Wells A. Messersmith, Dan Laheru, Richard Wahl, Chris Endres, Antonio Jimeno, Martin G. Pomper, Manuel Hidalgo
Journal: Journal of Clinical Oncology (2009)

Purpose Positron emission tomography (PET) with [ 18 F]fluorodeoxyglucose (FDG-PET) has increasingly been used to evaluate the efficacy of anticancer agents. We investigated the role of FDG-PET as a predictive marker for response to mammalian target of rapamycin (mTOR) inhibition in advanced solid tumor patients and in murine xenograft models. Patients and Methods Thirty-four rapamycin-treated patients with assessable baseline and treatment FDG-PET and computed tomography scans were analyzed from two clinical trials. Clinical response was evaluated according to Response Evaluation Criteria in Solid Tumors, and FDG-PET response was evaluated by quantitative changes and European Organisation for Research and Treatment of Cancer (EORTC) criteria. Six murine xenograft tumor models were treated with temsirolimus. Small animal FDG-PET scans were performed at baseline and during treatment. The tumors were analyzed for the expression of pAkt and GLUT1. Results Fifty percent of patients with increased FDG-PET uptake and 46% with decreased uptake had progressive disease (PD). No objective response was observed. By EORTC criteria, the sensitivity of progressive metabolic disease on FDG-PET in predicting PD was 19%. Preclinical studies demonstrated similar findings, and FDG-PET response correlated with pAkt activation and plasma membrane GLUT1 expression. Conclusion FDG-PET is not predictive of proliferative response to mTOR inhibitor therapy in both clinical and preclinical studies. Our findings suggest that mTOR inhibitors suppress the formation of mTORC2 complex, resulting in the inhibition of Akt and glycolysis independent of proliferation in a subset of tumors. Changes in FDG-PET may be a pharmacodynamic marker for Akt activation during mTOR inhibitor therapy. FDG-PET may be used to identify patients with persistent Akt activation following mTOR inhibitor therapy.
HIV-associated nephropathy patients with and without apolipoprotein L1 gene variants have similar clinical and pathological characteristics
Authors: Mohamed G. Atta, Michelle M. Estrella, Michael Kuperman, Matthew C. Foy, Derek M. Fine, Lorraine C. Racusen, Gregory M. Lucas, George W. Nelson, Andrew C. Warner, Cheryl A. Winkler, Jeffrey B. Kopp
Journal: Kidney International (2012)
A homozygous mutation in the integrin alpha6 gene in junctional epidermolysis bullosa with pyloric atresia.
Authors: L Ruzzi, L Gagnoux-Palacios, M Pinola, S Belli, G Meneguzzi, M D'Alessio, G Zambruno
Journal: Journal of Clinical Investigation (1997)

The alpha6 integrin subunit participates in the formation of both alpha6beta1 and alpha6beta4 laminin receptors, which have been reported to play an important role in cell adhesion and migration and in morphogenesis. In squamous epithelia, the alpha6beta4 heterodimer is the crucial component for the assembly and stability of hemidesmosomes. These anchoring structures are ultrastructurally abnormal in patients affected with junctional epidermolysis bullosa with pyloric atresia (PA-JEB), a recessively inherited blistering disease of skin and mucosae characterized by an altered immunoreactivity with antibodies specific to integrin alpha6beta4. In this report, we describe the first mutation in the alpha6 integrin gene in a PA-JEB patient presenting with generalized skin blistering, aplasia cutis, and defective expression of integrin alpha6beta4. The mutation (791delC) is a homozygous deletion of a single base (C) leading to a frameshift and a premature termination codon that results in a complete absence of alpha6 polypeptide. We also describe the DNA-based prenatal exclusion of the disease in this family at risk for recurrence of PA-JEB. Our results demonstrate that, despite the widespread distribution of the alpha6 integrin subunit, lack of expression of the alpha6 integrin chain is compatible with fetal development, and results in a phenotype indistinguishable from that caused by mutations in the beta4 chain, which is expressed in a more limited number of tissues.