tbuckley/cabot-search huggingface dataset:
Hemoglobin Variability in Anemia of Chronic Kidney Disease
Authors: Kamyar Kalantar-Zadeh, George R. Aronoff
Journal: Journal of the American Society of Nephrology (2009)

Hemoglobin levels in individuals with chronic kidney disease fluctuate frequently above or below the recommended target levels within short periods of time even though the calculated mean hemoglobin remains within the target range of 11 to 12 g/dl. Both pharmacologic features and dosing of erythropoiesis-stimulating agents may lead to cyclic pattern of hemoglobin levels within the recommended range. Several longitudinal studies highlight the complexity of maintaining stable hemoglobin levels over time. As a consequence, patients may risk increased hospitalization and mortality, because both low and high hemoglobin levels are associated with increased cardiovascular events and death. The duration of time that hemoglobin remains higher or lower than the target thresholds may be important to adverse outcomes. It is not clear whether adverse effects of hemoglobin variability are because of the therapy with erythropoiesis-stimulating agents and/or iron or despite such a therapy. Several factors affect hemoglobin variability, including those that are drug related, such as pharmacokinetic parameters, patient-related differences in demographic characteristics, and factors affecting clinical status, as well as clinical practice guidelines, treatment protocols, and reimbursement policies. Strategies that consider each of these factors and reduce hemoglobin variability may be associated with improved clinical outcomes.
Sox11 Prevents Tumorigenesis of Glioma-Initiating Cells by Inducing Neuronal Differentiation
Authors: Takuichiro Hide, Tatsuya Takezaki, Yuka Nakatani, Hideo Nakamura, Jun-ichi Kuratsu, Toru Kondo
Journal: Cancer Research (2009)

Abstract Recent findings have shown that malignant tumors contain cancer-initiating cells (CIC), which self-renew and are tumorigenic. However, CICs have not been characterized properly due to lack of specific markers. We recently established a mouse glioma cell line, NSCL61, by overexpressing an oncogenic HRasL61 in p53-deficient neural stem cells. Using limiting dilution assays, we show that only 2 of 24 NSCL61 clones retained their tumorigenicity in vivo, although the others also expressed oncogenic HRasL61 and could proliferate in culture. A comparison of the gene expression profiles of tumorigenic and nontumorigenic clones showed that the tumorigenic clones had lost Sox11 expression. We show that overexpression of sox11 prevented tumorigenesis of NSCL61s by inducing their neuronal differentiation accompanied with decreased levels of plagl1. We also show that overexpression of plagl1 abolished neuronal commitment of nontumorigenic cells and induced them to become tumorigenic. Moreover, we show that human glioma-initiating cells lost sox11 expression, and overexpression of sox11 prevented their tumorigenesis in vivo. Together with the clinical evidence showing that downregulation of sox11 mRNA correlates with a significant decrease in survival, these findings suggest that Sox11 prevents gliomagenesis by blocking the expression of oncogenic plagl1. [Cancer Res 2009;69(20):7953–9]
Plasma B-Type Natriuretic Peptide Levels Predict Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Surgery
Authors: Oussama M. Wazni, David O. Martin, Nassir F. Marrouche, Ahmed Abdel Latif, Khaled Ziada, Mustaphasahim Shaaraoui, Soufian Almahameed, Robert A. Schweikert, Walid I. Saliba, A. Marc Gillinov, W. H. Wilson Tang, Roger M. Mills, Gary S. Francis, James B. Young, Andrea Natale
Journal: Circulation (2004)

Background— Postoperative (postop) atrial fibrillation (AF) occurs in up to 60% of patients after cardiac surgery, leading to longer hospital stays and increased healthcare costs. Recently, B-type natriuretic peptide (BNP) has been reported to predict occurrence of nonpostoperative AF. This study evaluates whether elevated preoperative (preop) plasma BNP levels predict the occurrence of postop AF. Methods and Results— One hundred eighty-seven patients with no history of atrial arrhythmia who had a preoperative BNP level and had undergone cardiac surgery were identified. Their records were reviewed, and postoperative ECG and telemetry strips were analyzed for AF until the time of discharge. Postop AF was documented in 80 patients (42.8%). AF patients were older (68±11 versus 64±14 years, P =0.04), but there was no difference in sex distribution, hypertension, left ventricular (LV) function, LV hypertrophy (LVH), left atrial size, history of coronary artery disease (CAD), or β-blocker use. Preop plasma BNP levels were higher in the postop AF patients (615 versus 444 pg/mL, P =0.005). After adjustment for age, sex, type of surgery, hypertension, LV function, LVH, left atrial size, CAD, and β-blocker use, the odds ratios of postop AF according to increasing quartiles, compared with patients with lowest quartile, were 1.8, 2.5, and 3.7 ( P trend =0.03). Conclusions— An elevated preop plasma BNP level is a strong and independent predictor of postop AF. This finding has important implications for identifying patients at higher risk of postop AF who could be considered for prophylactic antiarrhythmic or β-blocker therapy.
BET Protein Inhibitor JQ1 Attenuates Myc-Amplified MCC Tumor Growth <i>In Vivo</i>
Authors: Qiang Shao, Aarthi Kannan, Zhenyu Lin, Brendan C. Stack, James Y. Suen, Ling Gao
Journal: Cancer Research (2014)

Abstract Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin currently with no cure. In this study, we have first demonstrated that c-Myc overexpression is common in MCC. By targeting c-Myc, bromodomain inhibitors have demonstrated antitumor efficacy in several preclinical human cancer models. Thus, we interrogated the role of c-Myc inhibition in MCC with c-Myc amplification by using the BET inhibitor JQ1. We have uncovered that c-Myc can be regulated by JQ1 in MCC cells with pathologic c-Myc activation. Moreover, JQ1 potently abrogates c-Myc expression in MCC cells and causes marked G1 cell-cycle arrest. Mechanistically, JQ1-induced cell-cycle arrest coincides with downregulation of cyclin D1 and upregulation of p21, p27, and p57, whereas JQ1 exerts no effect on apoptosis in MCC cells. Further knockdown of p21, p27, or p57 by shRNA partially protects cells from JQ1-induced cell-cycle arrest. In addition, c-Myc knockdown by shRNA generates significant cell-cycle arrest, suggesting that c-Myc overexpression plays a role in MCC pathogenesis. Most importantly, JQ1 significantly attenuates tumor growth in xenograft MCC mouse models. Our results provide initial evidence, indicating the potential clinical utility of BET protein inhibitors in the treatment of MCC with pathologic activation of c-Myc. Cancer Res; 74(23); 7090–102. ©2014 AACR.
Oral Anticancer Drugs: How Limited Dosing Options and Dose Reductions May Affect Outcomes in Comparative Trials and Efficacy in Patients
Authors: Vinay Prasad, Paul R. Massey, Tito Fojo
Journal: Journal of Clinical Oncology (2014)

Historically, cancer medicine has avoided the problem of unequal dosing by comparing maximum-tolerated doses of intravenous regimens with proportionate dose reductions for toxicity. However, in recent years, with the development of numerous oral anticancer agents, dosing options are arbitrarily and increasingly limited by the size of pills. We contend that an underappreciated consequence of pill size is unequal dosing in comparative clinical trials and that this can have an impact on outcomes. We discuss how comparative effectiveness trials can be unbalanced and how the use of doses that are not sustainable might affect outcomes, especially marginal ones. We further argue that because of their poor tolerability and their limited dosing options, which often result in large dose adjustments in response to toxicity, the real-world clinical effectiveness of oral anticancer agents may be diminished and may not emulate results achieved in registration trials.
Home parenteral nutrition related complications are no more common in patients with malignant disease than other patients
Authors: R. E. Andrews, A. J. Brooks, K. E. Evans, K. Page, M. E. McAlindon
Journal: Gut (2011)

<h3>Introduction</h3> The demand for home parenteral nutrition (HPN) in advanced malignancy is increasing. This coincides with recent guidance recommending an explanation of the benefits, burden and risks of clinically assisted nutrition or hydration towards the end of life with patient and family.1 Furthermore, a 2nd expert opinion is required if clinically assisted nutrition is withdrawn or not commenced in end of life care. HPN related complications might be greater in malignant disease due to impaired immunity and prothrombotic tendency. The benefits and risks of HPN in malignant disease are currently unknown. <h3>Methods</h3> To compare HPN and non-HPN related complications and outcomes in patients receiving HPN for malignant indications (MI) compared to non-malignant indications (non-MI). A retrospective case note review was undertaken from a comprehensive database from 1995 to 2010. Data collected included indication for HPN, time on HPN, cause and duration of hospital readmissions (HPN related defined as catheter-related sepsis, line blockage or thrombus) and reason for discontinuation. Data was standardised by presenting complication rates and days per year on HPN. <h3>Results</h3> A total of 88 patients were identified. Fifty-one (58%) case notes were retrieved, of which 15(29%) had a MI and 36 (71%) non-MI. The median age of the cohort was 50 years (range 19–82); 23 (45%) male. The median time on HPN for MI was 164 days (range13–1089) which did not differ from non-MI; 156 days (range3–1117) (p=0.75). The number of HPN related complications did not differ in MI compared to non-MI; 5 and 3.6 per HPN year respectively (p=0.33). There was a trend towards increased mean time in hospital due to HPN related complications per HPN year; MI 18 days (range 0–84) and non-MI 6 days (range 0–75) (p=0.06). There was no difference detected in mean time in hospital per HPN year due to non-HPN related complications; non-MI 26days (range 0–156) compared with non-MI 37 days (range 0–365). HPN was discontinued in patients with MI due to; palliative care 9 (60%), death 3 (20%), enteral feed (13%). This did not differ significantly to non-MI; surgery 12 (33%), enteral feed 9 (25%) and death 5 (19%). Significantly fewer (5.6%) patients with non-MI were referred to palliative compared to MI (p=&lt;0.001). <h3>Conclusion</h3> Patients with advanced malignancy spend similar time on HPN and do not have greater complication rates compared to patients on HPN for non-MI. This suggests that HPN should be considered in end of life care as a result of advanced malignancy. A better understanding of the effects of HPN on quality of life in this setting is needed.
Geographic Determinants of Access to Pediatric Deceased Donor Kidney Transplantation
Authors: Peter P. Reese, Hojun Hwang, Vishnu Potluri, Peter L. Abt, Justine Shults, Sandra Amaral
Journal: Journal of the American Society of Nephrology (2014)

Children receive priority in the allocation of deceased donor kidneys for transplantation in the United States, but because allocation begins locally, geographic differences in population and organ supply may enable variation in pediatric access to transplantation. We assembled a cohort of 3764 individual listings for pediatric kidney transplantation in 2005-2010. For each donor service area, we assigned a category of short (<180 days), medium (181-270 days), or long (>270 days) median waiting time and calculated the ratio of pediatric-quality kidneys to pediatric candidates and the percentage of these kidneys locally diverted to adults. We used multivariable Cox regression analyses to examine the association between donor service area characteristics and time to deceased donor kidney transplantation. The Kaplan-Meier estimate of median waiting time to transplantation was 284 days (95% confidence interval, 263 to 300 days) and varied from 14 to 1313 days across donor service areas. Overall, 29% of pediatric-quality kidneys were locally diverted to adults. Compared with areas with short waiting times, areas with long waiting times had a lower ratio of pediatric-quality kidneys to candidates (3.1 versus 5.9; P<0.001) and more diversions to adults (31% versus 27%; P<0.001). In multivariable regression, a lower kidney to candidate ratio remained associated with longer waiting time (hazard ratio, 0.56 for areas with <2:1 versus reference areas with ≥5:1 kidneys/candidates; P<0.01). Large geographic variation in waiting time for pediatric deceased donor kidney transplantation exists and is highly associated with local supply and demand factors. Future organ allocation policy should address this geographic inequity.
Granulocyte-macrophage colony stimulating factor exacerbates collagen induced arthritis in mice
Authors: I. K Campbell, A. Bendele, D. A Smith, J. A Hamilton
Journal: Annals of the Rheumatic Diseases (1997)

<h3>OBJECTIVE</h3> To examine the effect of granulocyte-macrophage colony stimulating factor (GM-CSF) on disease progression in the collagen induced arthritis (CIA) model in mice. <h3>METHODS</h3> DBA/1 mice were primed for a suboptimal CIA response by intradermal injection of chick type II collagen without a secondary immunisation. Three weeks after immunisation the mice were given four to five consecutive daily intraperitoneal injections of recombinant murine GM-CSF (15 μg; 5 × 10<sup>5</sup> U), or vehicle, and arthritis development was monitored by clinical scoring of paws and calliper measurements of footpad swelling. At approximately six to eight weeks after immunisation mice were killed, their limbs removed and processed for histological analyses of joint pathology. <h3>RESULTS</h3> Control animals receiving a single immunisation with collagen exhibited a varied CIA response both in terms of incidence and severity. Mice treated with GM-CSF at 20 to 25 days after immunisation with collagen had a consistently greater incidence and more rapid onset of disease than the vehicle treated control mice, based on clinical assessment. GM-CSF treated mice showed higher average clinical scores and greater paw swelling than controls. Histological analyses of joints reflected the clinical scores with GM-CSF treated mice displaying more pronounced pathology (synovitis, pannus formation, cartilage and bone damage) than control mice. <h3>CONCLUSION</h3> GM-CSF is a potent accelerator of the pathological events leading to chronic inflammatory polyarthritis in murine CIA supporting the notion that GM-CSF may play a part in inflammatory polyarthritis, such as rheumatoid arthritis.
Problem-Solving Therapy and Supportive Therapy in Older Adults With Major Depression and Executive Dysfunction
Authors: Patricia A. Areán, Patrick Raue, R. Scott Mackin, Dora Kanellopoulos, Charles McCulloch, George S. Alexopoulos
Journal: American Journal of Psychiatry (2010)

Objective: The purpose of this study was to determine whether problem-solving therapy is an effective treatment in older patients with depression and executive dysfunction, a population likely to be resistant to antidepressant drugs. Method: Participants were adults age 60 and older with major depression and executive dysfunction. Problem-solving therapy was modified to be accessible to this population. Participants were randomly assigned to 12 weekly sessions of problem-solving therapy or supportive therapy and assessed at weeks 3, 6, 9, and 12. Results: Of the 653 individuals referred for this study, 221 met selection criteria and were enrolled in the study. Reduction of depressive symptom severity was comparable for the two treatment groups during the first 6 weeks of treatment, but at weeks 9 and 12 the problem-solving therapy group had a greater reduction in symptom severity, a greater response rate, and a greater remission rate than the supportive therapy group (response rates at week 9: 47.1% and 29.3%; at week 12:56.7% and 34.0%; remission rates at week 9: 37.9% and 21.7%; at week 12: 45.6% and 27.8%). Problem-solving therapy yielded one additional response or remission over supportive therapy for every 4.4–5.6 patients by the end of the trial. Conclusions: These results suggest that problem-solving therapy is effective in reducing depressive symptoms and leading to treatment response and remission in a considerable number of older patients with major depression and executive dysfunction. The clinical value of this finding is that problem-solving therapy may be a treatment alternative in an older patient population likely to be resistant to pharmacotherapy.
A cDNA clone expressed in natural killer and T cells that likely encodes a secreted protein.
Authors: T Yabe, C McSherry, F H Bach, J P Houchins
Journal: The Journal of Experimental Medicine (1990)

We have isolated a series of cross-hybridizing cDNA clones, as a group designated as NKG5, from a human natural killer (NK) cell clone cDNA library. These clones show a high degree of homology with a previously described gene, 519, which was thought to be T cell specific. A comparison of the full-length cDNA sequence of NKG5 and the published sequence of 519 shows that NKG5 lacks a 242-base segment that is found in 519 and that this deletion leads to the use of a different putative translational start codon. Unlike 519, the predicted NKG5 polypeptide has an NH2-terminal sequence that is strongly hydrophobic, characteristic of a signal peptide, and lacks any additional hydrophobic regions in the remainder of the peptide, suggesting that NKG5 encodes a secreted protein. Both NKG5 and 519 are expressed in NK and T cells but not in a variety of other hematopoietic cell lines. NKG5 is an abundant transcript and its level of expression is about 40 times that of 519 in NK and T cells. Southern blot and DNA sequence analyses suggest that NKG5 and 519 mRNAs are transcripts from a single gene that has allelic polymorphism.
Combined phospholamban ablation and SERCA1a overexpression result in a new hyperdynamic cardiac state
Authors: W Zhao
Journal: Cardiovascular Research (2002)

Phospholamban ablation or ectopic expression of SERCA1a in the heart results in significant increases in cardiac contractile parameters. The aim of the present study was to determine whether a combination of these two genetic manipulations may lead to further augmentation of cardiac function.Transgenic mice with cardiac specific overexpression of SERCA1a were mated with phospholamban deficient mice to generate a model with SERCA1a overexpression in the phospholamban null background (SERCA1(OE)/PLB(KO)). The cardiac phenotype was characterized using quantitative immunoblotting, sarcoplasmic reticulum calcium uptake and single myocyte mechanics and calcium kinetics.Quantitative immunoblotting revealed an increase of 1.8-fold in total SERCA level, while SERCA2 was decreased to 50% of wild types. Isolated myocytes indicated increases in the maximal rates of contraction by 195 and 125%, the maximal rates of relaxation by 200 and 124%, while the time for 80% decay of the Ca(2+)-transient was decreased to 43 and 75%, in SERCA1(OE)/PLB(KO) hearts, compared to SERCA1a overexpressors and phospholamban knockouts, respectively. These mechanical alterations reflected parallel alterations in V(max) and EC(50) for Ca(2+) of the sarcoplasmic reticulum Ca(2+) transport system. Furthermore, there were no significant cardiac histological or pathological alterations, and the myocyte contractile parameters remained enhanced, up to 12 months of age.These findings suggest that a combination of SERCA1a overexpression and phospholamban ablation results in further enhancement of myocyte contractility over each individual alteration.
The relative roles of calcium, phosphorus, and parathyroid hormone in glucose- and tolbutamide-mediated insulin release.
Authors: H R Harter, J V Santiago, W E Rutherford, E Slatopolsky, S Klahr
Journal: Journal of Clinical Investigation (1976)

The relative contributions of Ca++, phosphorus, and parathyroid hormone (PTH) on insulin secretion were evaluated in three groups of dogs. Dogs were studied with glucose infusions (group I) or standard intravenous glucose tolerance tests (IVGTT) (group II) before and after the development of diet-induced hypophosphatemia. Mean serum phosphorus levels for both groups fell from 4.1 to 1.1 mg/100 ml. Animals in group I demonstrated a fall in glucose disappearance rates (Kg) from 5.3+/-0.6% min to 3.5+/-0.5% after induction of hypophosphatemia (P less than 0.001). Mean insulin response was significantly greater in the hypophosphatemic animals than in controls in this group. In group II animals, mean insulin areas obtained during the IVGTT increased from 1,426+/-223 to 2,561+/-141 muU/ml/60 min after induction of hypophosphatemia, and were unaffected by Ca++ or PTH administration. Ca++ administration, but not hypophosphatemia or PTH infusion, increased significantly the mean insulin response to tolbutamide. Secondary hyperparathyroidism was induced by dietary manipulation in four dogs (group III). Mean PTH values increased from 71.4+/-2.1 to 3,012+/-372 pg/ml (P less than 0.001). Mean insulin response to an IVGTT was similar to group III animals, but increased from 1,352+/-128 to 1,894+/-360 muU/ml/60 min after the excessive dietary phosphorus was reduced for 3 mo, and plasma phosphorus fell from 3.2+/-0.1 to 2.8+/-0.3 mg/100 ml. PTH values decreased to 647+/-53 pg/ml. The insulin response to tolbutamide was comparable to that in group II animals, but increased significantly after calcium administration. Immunoreactive insulin disappearance rates were unaffected by hypophosphatemia or diet-induced secondary hyperparathyroidism. These data demonstrate that hypophosphatemia is associated with an augmented glucose-stimulated insulin release, without any effect on tolbutamide-stimulated insulin release. Hypercalcemia produces an augmented tolbutamide-stimulated insulin release with no apparent effect on glucose-stimulated insulin release. Finally, PTH does not appear to be an insulin antagonist and has no apparent effect on either glucose- or tolbutamide-stimulated insulin release in animals with dietary-induced secondary hyperparathyroidism.