tbuckley/cabot-search huggingface dataset:
A Phase I Biological Study of MG98, an Oligodeoxynucleotide Antisense to DNA Methyltransferase 1, in Patients with High-Risk Myelodysplasia and Acute Myeloid Leukemia
Authors: Rebecca B. Klisovic, Wendy Stock, Spero Cataland, Marko I. Klisovic, Shujun Liu, William Blum, Margaret Green, Olatoyosi Odenike, Lucy Godley, Jennifer Vanden Burgt, Emily Van Laar, Michael Cullen, A. Robert Macleod, Jeffrey M. Besterman, Gregory K. Reid, John C. Byrd, Guido Marcucci
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Epigenetic silencing via aberrant promoter DNA hypermethylation of normal genes has been described as a leukemogenic mechanism in myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). We hypothesized that MG98, an oligonucleotide antisense to DNA methyltransferase 1 (DNMT1), could reverse malignant phenotypes by down-regulating DNMT1 and inducing reexpression of hypermethylated genes. This phase I study was conducted to determine a biologically effective dose and describe the safety of MG98 in MDS/AML. Experimental Design: Twenty-three patients with MDS (n = 11) and AML (n = 12) were enrolled. Biologically effective dose was defined as the dose at which ≥50% of patients experienced &amp;gt;50% reduction in DNMT1 expression with acceptable toxicity. Escalating doses of MG98 were administered according to two schedules (2-hour i.v. bolus followed by 5-day continuous i.v. infusion every 14 days, or 14-day continuous i.v. infusion every 21 days). Results: DNMT1 down-regulation was observed in 8 patients. However, biologically effective dose was not reached. Reexpression of target genes (P15, WIT1, and ER) was observed in 12 patients but did not correlate with DNMT1 down-regulation. Escalation was stopped due to dose-limiting toxicities (bone pain, nausea, and fever). No objective clinical response was observed. Disease stabilization occurred in 6 (26%) patients. Conclusions: No pharmacodynamic or clinical activity was observed at MG98 doses and schedules administered. Despite this, pursuing DNMT1 down-regulation remains a sound approach for targeting aberrant epigenetics in AML/MDS. Future studies with different formulation and/or doses and schedules will be required to ensure efficient MG98 intracellular uptake and fully evaluate its therapeutic potential.
1375 SPLEEN STIFFNESS MEASUREMENT USING FIBROSCAN AND A MODIFIED CALCULATION ALGORITHM INCREASES THE DIAGNOSIS PERFORMANCE OF LARGE ESOPHAGEAL VARICES IN CIRRHOTIC PATIENTS
Authors: H. Stefanescu, C. Bastard, M. Lupsor, D. Feier, V. Miette, L. Sandrin, R. Badea
Journal: Journal of Hepatology (2011)
Widespread Recombination Throughout Wolbachia Genomes
Authors: Laura Baldo, Seth Bordenstein, Jennifer J Wernegreen, John H Werren
Journal: Molecular Biology and Evolution (2005)

Evidence is growing that homologous recombination is a powerful source of genetic variability among closely related free-living bacteria. Here we investigate the extent of recombination among housekeeping genes of the endosymbiotic bacteria Wolbachia. Four housekeeping genes, gltA, dnaA, ftsZ, and groEL, were sequenced from a sample of 22 strains belonging to supergroups A and B. Sequence alignments were searched for recombination within and between genes using phylogenetic inference, analysis of genetic variation, and four recombination detection programs (MaxChi, Chimera, RDP, and Geneconv). Independent analyses indicate no or weak intragenic recombination in ftsZ, dnaA, and groEL. Intragenic recombination affects gltA, with a clear evidence of horizontal DNA transfers within and between divergent Wolbachia supergroups. Intergenic recombination was detected between all pairs of genes, suggesting either a horizontal exchange of a genome portion encompassing several genes or multiple recombination events involving smaller tracts along the genome. Overall, the observed pattern is compatible with pervasive recombination. Such results, combined with previous evidence of recombination in a surface protein, phage, and IS elements, support an unexpected chimeric origin of Wolbachia strains, with important implications for Wolbachia phylogeny and adaptation of these obligate intracellular bacteria in arthropods.
Dilution Curves of Simultaneously Administered 1 <sup>131</sup> -Human Serum Albumin and Cr <sup>51</sup> -Labeled Erythrocytes in Patients with Various Types of Edema
Authors: JOHN TUCKMAN, FRANK A. FINNERTY
Journal: Circulation Research (1961)

Detailed indicator-dilution curves of simul taneously administered 1 131 -HSA and Cr 51 -RBC in six of eight edematous patients with congestive heart failure demonstrate that, as in normal patients, a significant quantity of 1 does not escape the intravascular space during the first several minutes post injection. It would seem, therefore, that cap illary permeability to albumin was not an im portant manifestation in these patients. De tailed indicator-dilution curves in five of six patients with edema not associated with con gestive heart failure differ from those derived from normal patients and from the edematous patients with congestive heart failure. These data do not exclude the possibility that capillary permeability to albumin might be a sig nificant concomitant of edema associated with chronic glomerulonephritis, disseminated lupus erythematosis, toxemia of pregnancy. car cinomatosis, and Kimmelstiel-Wilson syndrome.
Screening and diagnosis of gestational diabetes mellitus: critical appraisal of the new International Association of Diabetes in Pregnancy Study Group recommendations on a national level. Diabetes Care 2012;35:1894–1896
Authors: O Kalter-Leibovici, LS Freedman, L Olmer, N Liebermann, A Heymann, O Tal, L Lerner-Geva, N Melamed, M Hod
Journal: Diabetes Care (2012)

Kalter-Leibovici O, Freedman LS, Olmer L, Liebermann N, Heymann A, Tal O, Lerner-Geva L, Melamed N, Hod M. Screening and …
Physical Dependence on Nicotine in Gum
Authors: John R. Hughes
Journal: JAMA (1986)

To test whether ex-smokers become physically dependent on nicotine in gum, we entered eight ex-smokers who were using nicotine gum into a randomized, double-blind, placebo-substitution trial. When placebo was substituted, seven of the eight subjects were observed to have withdrawal symptoms and two relapsed to smoking or nicotine gum. This result suggests that physical dependence (ie, withdrawal) may be a cause of behavioral dependence on nicotine gum (ie, use of gum beyond the recommended period) and physicians should emphasize the need for gradual reduction of nicotine gum.
A147: Engaging Patients and Families in the Pediatric Rheumatology Care and Outcomes Improvement Network
Authors: Esi Morgan DeWitt, Kay Fricke, Lindsey Bergheger, Nancy Griffin, Ronald M. Laxer, Karla B. Jones, Beth S. Gottlieb, Janalee Taylor, Catherine C. Mims, Lisa M. Robbins, Daniel J. Lovell, Laura Noonan
Journal: Arthritis & Rheumatology (2014)

Background/Purpose:

The Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) is a multi-site quality improvement learning network that aims to improve outcomes for children and adolescents with juvenile idiopathic arthritis. In addition to addressing variations in care practices, PR-COIN has incorporated guidance and tangible contributions from patients and families to its national organizational and governance structure to drive improvement in JIA outcomes. PR-COIN aims to grow this initiative to bring care providers, patients and family members together as co-producers in improving care and outcomes.



Methods:

Various methods supporting family engagement are employed. PR-COIN teams invite interested parents at their respective clinical sites to bring the parent perspective and priorities into local improvement work. To assure a reliable structure, a parent engagement specialist was employed to develop a platform for bringing families and care providers together. National conference calls facilitated by the specialist establish relationships across site representatives and begin goal setting for this group. Parents contribute to shared decision making project efforts. PR-COIN's public website encourages family awareness and involvement in the network's improvement efforts.



Results:

7 of 11 sites have welcomed parent contributions to their improvement efforts (e.g. focus groups, advisory activities, etc.). Parents and patients have participated in PR-COIN's biannual conferences, sharing the family perspective and needs associated with JIA care. One parent brings a unique background and skillset as both a pediatrician with QI experience and the parent of a teen with JIA. This distinction prompted appointment to PR-COIN's governing body. We incorporate patient perspectives into clinic process improvements (e.g. pain management, optimizing physical functioning), enhanced and refined PR-COIN's Shared Decision Making tool, supporting stronger, more informed medication choice, and are developing best practices optimizing use of these materials in clinic. Finally our engaged parents are encouraging others to contribute ideas supportive of PR-COIN structure, growth, strategy and improvement efforts.



Conclusion:

Parents and patients bring unique talents, insight and skills to the operation of quality improvement networks making efforts more relevant to the self-identified needs of JIA families.
Electron probe analysis of sodium and other elements in hypertrophied and sodium-loaded smooth muscle.
Authors: J L Junker, A J Wasserman, P F Berner, A P Somlyo
Journal: Circulation Research (1984)

The composition of normal, hypertrophied, or sodium-loaded rabbit portal anterior mesenteric vein and of normal and sodium-loaded guinea pig taenia coli smooth muscle was measured in cryosections with electron probe analysis, and the effects of wash with cold sodium-free (Lithium) solutions were determined. There was no significant difference in the cytoplasmic, nuclear, or mitochondrial concentrations of any of the measured elements (sodium, potassium, chloride, magnesium, calcium, phosphorus, sulfur) between hypertrophied, sham-operated, or control veins. The cytoplasmic potassium:sodium:chloride ratio in rabbit portal anterior mesenteric vein was 1:0.26:0.46, and the average sodium concentration (198 mmol/kg dry cytoplasmic weight) was nearly twice as high as estimated from ion flux measurements. The cytoplasmic sodium concentration of normal guinea pig taenia coli was 61 mmol/kg dry weight. The existence of a rapidly exchanging, relatively low affinity, and temperature-insensitive component of cytoplasmic sodium efflux was indicated by the reduction in cytoplasmic sodium after washout in cold, sodium-free (lithium or Tris-substituted) solutions. This reduction, by 62% in normal, 71% in sodium-loaded portal anterior mesenteric vein, and 36% in sodium-loaded guinea pig taenia coli smooth muscle, suggests that the lithium wash method can underestimate cell sodium. In sodium-loaded guinea pig taenia coli and portal anterior mesenteric vein smooth muscles, the cytoplasmic sodium analyzed in individual cells showed a bimodal distribution; in cryosections, the cells having the highest sodium and lowest potassium and phosphorus content also had a more electronlucent (light cell) appearance.
Antiemetics: American Society of Clinical Oncology Focused Guideline Update
Authors: Paul J. Hesketh, Kari Bohlke, Gary H. Lyman, Ethan Basch, Maurice Chesney, Rebecca Anne Clark-Snow, Michael A. Danso, Karin Jordan, Mark R. Somerfield, Mark G. Kris
Journal: Journal of Clinical Oncology (2015)

Purpose To update a key recommendation of the American Society of Clinical Oncology antiemetic guideline. This update addresses the use of the oral combination of netupitant (a neurokinin 1 [NK 1 ] receptor antagonist) and palonosetron (a 5-hydroxytryptamine-3 [5-HT 3 ] receptor antagonist) for the prevention of acute and delayed nausea and vomiting in patients receiving chemotherapy. Methods An update committee conducted a targeted systematic literature review and identified two phase III clinical trials and a randomized phase II dose-ranging study. Results In one phase III trial, the oral combination of netupitant and palonosetron was associated with higher complete response rates (no emesis and no rescue medications) compared with palonosetron alone in patients treated with anthracycline plus cyclophosphamide chemotherapy (74% v 67% overall; P = .001). In another phase III trial, the oral combination of netupitant and palonosetron was safe and effective across multiple cycles of moderately or highly emetogenic chemotherapies. In the phase II dose-ranging study, each dose of netupitant (coadministered with palonosetron 0.50 mg) produced higher complete response rates than palonosetron alone among patients receiving cisplatin-based chemotherapy. The highest dose of netupitant (ie, 300 mg) was most effective. Recommendations All patients who receive highly emetogenic chemotherapy regimens (including anthracycline plus cyclophosphamide) should be offered a three-drug combination of an NK 1 receptor antagonist, a 5-HT 3 receptor antagonist, and dexamethasone. The oral combination of netupitant and palonosetron plus dexamethasone is an additional treatment option in this setting. The remaining recommendations from the 2011 ASCO guideline are unchanged pending a full update. Additional information is available at www.asco.org/guidelines/antiemetics and www.asco.org/guidelineswiki .
Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small-cell lung cancer: a pooled analysis of three randomised trials
Authors: Massimo Di Maio, Cesare Gridelli, Ciro Gallo, Frances Shepherd, Franco Vito Piantedosi, Silvio Cigolari, Luigi Manzione, Alfonso Illiano, Santi Barbera, Sergio Federico Robbiati, Luciano Frontini, Elena Piazza, Giovanni Pietro Ianniello, Enzo Veltri, Federico Castiglione, Francesco Rosetti, Vittorio Gebbia, Lesley Seymour, Paolo Chiodini, Francesco Perrone
Journal: The Lancet Oncology (2005)
Muscle-specific creatine kinase gene polymorphism and running economy responses to an 18-week 5000-m training programme
Authors: D Q Zhou, Y Hu, G Liu, L Gong, Y Xi, L Wen
Journal: British Journal of Sports Medicine (2006)

To investigate the association between muscle-specific creatine kinase (CKMM) gene polymorphism and the effects of endurance training on running economy.102 biologically unrelated male volunteers from northern China performed a 5000-m running programme, with an intensity of 95-105% ventilatory threshold. The protocol was undertaken three times per week and lasted for 18 weeks. Running economy indexes were determined by making the participants run on a treadmill before and after the protocol, and the A/G polymorphism in the 3' untranslated region of CKMM was detected by polymerase chain reaction-restricted fragment length polymorphism (NcoI restriction enzyme).Three expected genotypes for CKMM-NcoI (AA, AG and GG) were observed in the participants. After training, all running economy indexes declined markedly. Change in steady-state consumption of oxygen, change in steady-state consumption of oxygen by mean body weight, change in steady-state consumption of oxygen by mean lean body weight and change in ventilatory volume in AG groups were larger than those in AA and GG groups.The findings indicate that the CKMM gene polymorphism may contribute to individual running economy responses to endurance training.
Influenza in children. Relationship to other respiratory agents
Authors: W. P. Glezen
Journal: JAMA (1980)

During the 1975-1976 respiratory disease season, influenza A/Victoria virus exceeded respiratory syncytial (RS) virus as a cause of lower respiratory tract disease (LRD) in children admitted to the hospital. This was a reversal of their usual roles in the etiology of LRD; however, the importance of influenza viruses in causing serious disease in children has been underestimated because of failure to appreciate the full spectrum of disease associated with influenza virus infections. In addition to those with LRD, several children were hospitalized with nonspecific febrile illnesses or CNS involvement. Furthermore, in the ambulatory care setting, influenza viruses were the most important cause of illness that necessitated children's being brought for medical care during a three-year period. During the peak of epidemics, influenza viruses appeared to interfere with the spread of other major respiratory viruses--particularly RS virus.
The Local and Systemic Inflammatory Transcriptome after Acute Kidney Injury
Authors: Dmitry N. Grigoryev, Manchang Liu, Heitham T. Hassoun, Chris Cheadle, Kathleen C. Barnes, Hamid Rabb
Journal: Journal of the American Society of Nephrology (2008)

Studies in humans and animal models have demonstrated that acute kidney injury (AKI) has a significant effect on the function of extrarenal organs. The combination of AKI and lung dysfunction is associated with 80% mortality; the lung, because of its extensive capillary network, is a prime target for AKI-induced effects. The study presented here tested the hypothesis that AKI leads to a vigorous inflammatory response and produces distinct genomic signatures in the kidney and lung. In a murine model of ischemic AKI, prominent global transcriptomic changes and histologic injury in both kidney and lung tissues were identified. These changes were evident at both early (6 h) and late (36 h) timepoints after 60-min bilateral kidney ischemia and were more prominent than similar timepoints after sham surgery or 30 min of ischemia. The inflammatory transcriptome (109 genes) of both organs changed with marked similarity, including the innate immunity genes Cd14, Socs3, Saa3, Lcn2, and Il1r2. Functional genomic analysis of these genes suggested that IL-10 and IL-6 signaling was involved in the distant effects of local inflammation, and this was supported by increased serum levels of IL-10 and IL-6 after ischemia-reperfusion. In summary, this is the first comprehensive analysis of concomitant inflammation-associated transcriptional changes in the kidney and a remote organ during AKI. Functional genomic analysis identified potential mediators that connect local and systemic inflammation, suggesting that this type of analysis may be a useful discovery tool for novel biomarkers and therapeutic drug development.
Adherence to Medication
Authors: Lars Osterberg, Terrence Blaschke
Journal: New England Journal of Medicine (2005)

The full benefit of many effective medications will be achieved only if patients adhere to prescribed treatment regimens. Unfortunately, applying terms such as "noncompliant" and "nonadherent" to patients who do not consume every pill at the desired time can stigmatize them in their future relationships with health care providers. This article on medication adherence (or compliance) reviews strategies to assess and enhance this important aspect of patient care.
EVIDENCE FOR A CONGENITAL FACTOR IN MALADJUSTMENT AND DELINQUENCY
Authors: D. H. STOTT
Journal: American Journal of Psychiatry (1962)

A congenital factor in behaviour disturbance, including those types thereof related to delinquency, was inferred from data drawn from two sources. A recomputation was made of the delinquency proneness of boys by year of birth, as published by Wilkins. This showed that when limited to those committing offences between their 8th and 14th birthdays, the proneness was highly specific to those boys born during the early war years. This wartime peak closely resembled that for children dying from congenital malformation in the first 4 weeks of life. There was no such tendency among those commtting offences after their 14th birthday. Among Glasgow boys put on probation in 1957 and non-delinquent controls, a close relationship was found between a number of physical conditions—respiratory and other ailments, physical defects, bad eyesight and abnormality of growth—and indications of behaviour disturbance as recorded on the Bristol Social Adjustment Guides. With the exception of bad eyesight among the controls, the incidence of these conditions was never less than twice as high among the maladjusted compared with stable group; and among probationers and controls combined the difference was signficant for all 5 conditions at a risk of chance of less than 1 in a 1000. Three possible alternatives were considered to the hypothesis of a congenital factor common to the physical conditions and the behaviour disturbance. Inadequate living standards could not be the explanation since the associations held good among those probationers coming from adequate standard homes. Compensation for feelings of inferiority or frustration was similarly ruled out, because boys showing this type of behaviour disturbance had lower than average physical illness or defect. Finally a psychosomatic explanation—that the maladjustment produced exhaustion which undermined health—was rejected, first because the associations held good when the depressed children were excluded, and second because it could not feasibly account for the defects as distinct from the illnesses. It was consequently argued that the only explanation known which could account for the associations was that of congenital insult which in some cases was seen both somatically and in impairment of that part of the nervous system controlling behaviour. The latter might induce a greater delinquency proneness by reducing resistance to stress, and thus more frequent breakdown under adverse environmental conditions.
Roscovitine Modulates DNA Repair and Senescence: Implications for Combination Chemotherapy
Authors: Elvira Crescenzi, Giuseppe Palumbo, Hugh J.M. Brady
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Treatment of tumor cells by chemotherapy activates a series of responses ranging from apoptosis to premature senescence and repair. Survival responses are characterized by inhibition of cyclin-dependent kinases. Because inhibition of cyclin-dependent kinases represents a distinctive feature of DNA damage–induced prosurvival responses, we investigated the possibility that the cyclin-dependent kinase inhibitor roscovitine modulates drug-induced responses in human adenocarcinoma cells, favoring cell survival. Experimental Design: Sublethal concentrations of doxorubicin were used to induce premature senescence in human adenocarcinoma cells. The effect of the cyclin-dependent kinase inhibitor roscovitine on the doxorubicin-dependent cell cycle checkpoint activation and DNA repair pathways was evaluated. Results: Roscovitine reinforces doxorubicin-dependent G1 checkpoint in A549 and HEC1B cells leading to decreased frequency of double-strand breaks and to the preferential induction of senescence and enhanced clonogenic survival. However, in other tumor cell lines, such as HCT116 and H1299, combined treatment with doxorubicin and roscovitine increases the frequency of double-strand breaks and dramatically sensitizes to doxorubicin. This unexpected effect of roscovitine depends on a novel ability to inhibit DNA double-strand break repair processes and requires inactivation of the pRb pathway. Conclusions: Roscovitine, by hindering DNA repair processes, has the potential to inhibit recovery of mildly damaged tumor cells after doxorubicin treatment and to increase the susceptibility of tumor cells to chemotherapy. However, in some tumor cells, the cell cycle inhibitory function of roscovitine prevails over the DNA repair inhibitory activity, favoring premature senescence and clonogenic growth. These data indicate a novel mechanism underlying combined chemotherapy, which may have wide application in treatment of carcinomas.