tbuckley/cabot-search huggingface dataset:
Association of High-Level <i>MRP1</i> Expression With Poor Clinical Outcome in a Large Prospective Study of Primary Neuroblastoma
Authors: Michelle Haber, Janice Smith, Sharon B. Bordow, Claudia Flemming, Susan L. Cohn, Wendy B. London, Glenn M. Marshall, Murray D. Norris
Journal: Journal of Clinical Oncology (2006)

Purpose We have previously shown in a retrospective study that expression of the multidrug transporter gene MRP1 (ABCC1) is associated with outcome in neuroblastoma. We have now undertaken a prospective analysis to examine the independent prognostic significance of MRP1 expression in a large cohort of primary untreated neuroblastomas. Patients and Methods Two hundred nine diagnostic neuroblastoma samples from patients prospectively enrolled onto the Pediatric Oncology Group biology protocol 9047 were analyzed for expression of the MRP1, MDR1, MYCN, and TRKA genes using real-time polymerase chain reaction. Expression levels were correlated with established prognostic indicators and disease outcome. Results MRP1 expression was detected in all tumors analyzed, and levels were significantly higher in tumors with versus without MYCN amplification (P &lt; .0001). High levels of MRP1 were highly predictive of both event-free survival (EFS; P &lt; .001) and overall survival (OS; P &lt; .001). High-level MYCN and low-level TRKA were also predictive of poor outcome. MDR1 expression demonstrated no prognostic significance. After adjustment for the effect of statistically significant prognostic indicators in multivariate models, MRP1 expression retained significant prognostic value for both EFS (hazard ratio = 3.0; P = .0011) and OS (hazard ratio = 2.5; P = .0095), whereas MYCN amplification did not have prognostic significance. Conclusion The results of this prospective study confirm our earlier findings and support a clinically relevant role for MRP1 gene expression in neuroblastoma. These findings have implications for the biology, prognosis, and treatment of this disease and provide evidence that MRP1 is a bone fide molecular target for reversing chemotherapy resistance in aggressive drug-refractory neuroblastoma.
Social Epidemiology: Social Determinants of Health in the United States: Are We Losing Ground?
Authors: Lisa F. Berkman
Journal: Annual Review of Public Health (2009)

The United States ranks in the lower tiers of OECD countries in life expectancy, and recent studies indicate that socioeconomic inequalities in health have been widening in the past decades. Over this period, many rigorous longitudinal studies have identified important social, behavioral, and environmental conditions that might reduce health disparities if we could design effective interventions and make specific policy changes to modify them. Often, however, neither our policy changes nor our interventions are as effective as we hoped they would be on the basis of findings from observational studies. Reviewed here are issues related to causal inference and potential explanations for the discrepancy between observational and experimental studies. We conclude that more attention needs to be devoted to (a) identifying the correct etiologic period within a life-course perspective and (b) understanding the dynamic interplay between interventions and the social, economic, and environmental contexts in which interventions are delivered.
Serum Bilirubin and Ferritin Levels Link Heme Oxygenase-1 Gene Promoter Polymorphism and Susceptibility to Coronary Artery Disease in Diabetic Patients
Authors: Ying-Hwa Chen, Lee-Young Chau, Jaw-Wen Chen, Shing-Jong Lin
Journal: Diabetes Care (2008)

OBJECTIVE—Heme oxygenase (HO) leads to the generation of free iron, carbon monoxide, and bilirubin. A length polymorphism of GT repeats in the promoter of human HO-1 gene has been shown to modulate gene transcription. The aim of this study was to assess the association of the length of (GT)n repeats in the HO-1 gene promoter with serum bilirubin, markers of iron status, and the development of coronary artery disease (CAD). RESEARCH DESIGN AND METHODS—We screened the allelic frequencies of (GT)n repeats in the HO-1 gene promoter in 986 unrelated individuals who underwent coronary angiography. Serum bilirubin and markers of iron status were evaluated. RESULTS—The distribution of numbers of (GT)n repeats was divided into two subclasses: class S included shorter (&amp;lt;27) repeats, and class L included longer (≥27) repeats. Among those with diabetes, subjects with the L/L genotype had significantly lower bilirubin levels than those with S/S and S/L genotypes (0.70 ± 0.22 vs. 0.81 ± 0.24 mg/dl, P = 0.001) and higher serum ferritin values (4.76 ± 0.72 vs. 4.28 ± 1.05 μg/l for log ferritin, P = 0.001). Compared with those carrying the S allele, diabetic subjects with the L/L genotype had an almost threefold increase in CAD risk after controlling for conventional risk factors (odds ratio 2.81, [95% CI 1.22–6.47], P = 0.015). With adjustment for both serum bilirubin and ferritin, the effect of HO-1 promoter polymorphism on susceptibility to CAD disappeared. CONCLUSIONS—Length polymorphism in the HO-1 gene promoter is correlated with susceptibility to CAD in diabetic patients, and this effect might be conveyed through its influence on serum bilirubin and ferritin.
Phase I and Pharmacokinetic Study of Two Different Schedules of Oxaliplatin, Irinotecan, Fluorouracil, and Leucovorin in Patients With Solid Tumors
Authors: Matthew P. Goetz, Charles Erlichman, Anthony J. Windebank, Joel M. Reid, Jeffrey A. Sloan, Pamela Atherton, Alex A. Adjei, Joseph Rubin, Henry Pitot, Evanthia Galanis, Matthew M. Ames, Richard M. Goldberg
Journal: Journal of Clinical Oncology (2003)

Purpose: We sought to determine the maximum-tolerated dose (MTD) and evaluate the toxicities and clinical activity of two irinotecan (CPT-11), fluorouracil (FU), leucovorin (LV), and oxaliplatin schedules in patients with advanced solid tumors. Additionally, we investigated the effect of CPT-11 on oxaliplatin pharmacokinetics. Patients and Methods: Thirteen patients (cohort 1) received intravenous CPT-11 (infusion) and FU/LV (bolus) on days 1, 8, 15, and 22 and oxaliplatin (infusion) on days 1 and 15 every 6 weeks for a total 37 courses (median, three courses) at three dose levels. Twenty-two cohort 2 patients received intravenous CPT-11/oxaliplatin (infusion, day 1) and FU/LV (90-minute bolus infusion, days 2 to 5) every 3 weeks for a total of 122 courses (median, four courses) at three dose levels. Pharmacokinetic and neurotoxicity assessments were performed at the cohort 2 MTD. Results: Dose-limiting toxicity (DLT) seen in both cohorts at the starting dose required dose de-escalation. Cohort 1 DLT included diarrhea and neutropenia. In cohort 2, diarrhea, vomiting, dehydration, neutropenia, febrile neutropenia, and paresthesias were DLTs. Antitumor activity was seen in both cohorts. In cohort 2, the total platinum area under the curve of patients increased 17% in cycle 2 (P = .048), but objective neurotoxicity was not seen. Conclusion: The toxicities resulting from the addition of oxaliplatin to CPT-11/FU/LV are significant but manageable. The MTDs for the weekly schedule are CPT-11 (75 mg/m 2 ), oxaliplatin (50 mg/m 2 ), FU (320 mg/m 2 ), and LV (20 mg/m 2 ); and, for the 3-weekly schedule, the MTDs are CPT-11 (175 mg/m 2 ), oxaliplatin (85 mg/m 2 ), FU (240 mg/m 2 ), and LV (20 mg/m 2 ). Second-cycle platinum accumulation raises the possibility for enhanced cumulative neurotoxicity with CPT-11/oxaliplatin combinations.
Differences in Cardiovascular Risk Factors, Insulin Resistance, and Insulin Secretion in Individuals With Normal Glucose Tolerance and in Subjects With Impaired Glucose Regulation
Authors: Francisco J. Nóvoa, Mauro Boronat, Pedro Saavedra, Juan M. Díaz-Cremades, Valois F. Varillas, Fátima La Roche, María P. Alberiche, Armando Carrillo
Journal: Diabetes Care (2005)

OBJECTIVE—To assess the cardiovascular risk profile, the degree of insulin resistance, and β-cell secretion in a cohort of subjects with different categories of impaired glucose regulation (IGR): impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and combined IFG/IGT. RESEARCH DESIGN AND METHODS—We studied 902 nondiabetic subjects between 30 and 80 years of age, recruited from a cross-sectional population-based study in Telde, Gran Canaria Island, Spain. Categories of glucose tolerance were defined according to 2003 modified American Diabetes Association criteria. Risk factors for cardiovascular disease, the presence of the metabolic syndrome, and indirect measures of both insulin resistance and β-cell function were analyzed. RESULTS—A total of 132 (14.6%) participants had isolated IFG, 59 (6.5%) isolated IGT, and 48 (5.3%) combined IFG/IGT. Groups with normal glucose tolerance (NGT) and combined IFG/IGT had, respectively, the most favorable and unfavorable levels of cardiovascular risk factors, metabolic syndrome rates, and measures of insulin resistance. Subjects with IFG and IGT showed an intermediate profile between NGT and IFG/IGT categories. We found no significant differences between IFG and IGT in cardiovascular risk factors, metabolic syndrome prevalence, or insulin resistance. The IFG group exhibited a more impaired insulin secretion than those with IGT or IFG/IGT. CONCLUSIONS—Individuals with IGR, especially those with IFG/IGT, have increased values of cardiovascular risk factors and higher indexes of insulin resistance. Groups with isolated IFG and isolated IGT present similar cardiovascular risk profiles. Subjects with IFG are characterized by more defective β-cell function than other forms of IGR.
Barriers to Breast and Colorectal Cancer Survivorship Care: Perceptions of Primary Care Physicians and Medical Oncologists in the United States
Authors: Katherine S. Virgo, Catherine C. Lerro, Carrie N. Klabunde, Craig Earle, Patricia A. Ganz
Journal: Journal of Clinical Oncology (2013)

High-quality, well-coordinated cancer survivorship care is needed yet barriers remain owing to fragmentation in the United States health care system. This article is a nationwide survey of barriers perceived by primary care physicians (PCPs) and medical oncologists (MOs) regarding breast and colorectal cancer survivorship care beyond 5 years after treatment.The Survey of Physician Attitudes Regarding the Care of Cancer Survivors was mailed out in 2009 to a nationally-representative sample (n = 3,596) of US PCPs and MOs. Ten physician-perceived cancer survivorship care barriers/concerns were compared between the two provider types. Using weighted multinomial logistic regression, we modeled each barrier, adjusting for physician demographics, reimbursement, training, and practice characteristics.We received responses from 2,202 physicians (1,072 PCPs; 1,130 MOs; 65.1% cooperation rate). In adjusted patient-related barriers models, MOs were more likely than PCPs to report patient language barriers (odds ratio, [OR], 1.72; 95% CI, 1.22 to 2.42), insurance restrictions impeding test/treatment use (OR, 1.42; 95% CI, 1.03 to 1.96), and patients requesting more aggressive testing (OR, 4.08; 95% CI, 2.73 to 6.10). In adjusted physician-related barriers models, PCPs were more likely to report inadequate training (OR, 3.06; 95% CI, 2.03 to 4.61) and ordering additional tests/treatments because of malpractice concerns (OR, 1.87; 95% CI, 1.20 to 2.93). MOs were more likely to report uncertainty regarding general preventive care responsibility (often/always: OR, 1.97; 95% CI, 1.13 to 3.43; sometimes: OR, 2.16; 95% CI, 1.60 to 2.93).MOs and PCPs perceive different cancer follow-up care barriers/concerns to be problematic. Resolving inadequate training, malpractice-driven test ordering, and preventive-care responsibility concerns may require continuing education, explicit guidelines, and survivorship care plans. Reviewing care plans with survivors may also reduce patients' requests for unnecessary testing.
Clinics in neurology and neurosurgery of sport: lumbar spine. Sequestrated disc prolapse and disc bulge
Authors: G Davis, E Johnson, P C McCormick, E P Roger, K Ugokwe, E C Benzel, W R Sears, P McCrory
Journal: British Journal of Sports Medicine (2009)

Focal degenerative disc disease in the lumbar spine is broadly categorized into three clinical types: (1) asymptomatic disc degeneration, (2) degenerative disc disease resulting in low back pain (LBP) and (3) focal disc prolapse resulting in compression of the spinal nerve root producing the clinical picture of radiculopathy or sciatica. Whenever possible, non-surgical management is the favoured option, but when persistent nerve root compression does not respond to conservative measures, surgical decompression of the nerve root is required. A variety of operative procedures and approaches exists to deal with focal disc prolapse. Such procedures include open discectomy, microdiscectomy and endoscopic percutaneous discectomy. In some situations, in addition to discectomy, a vertebral fusion procedure is also required.

Although the fine details of surgical technique are beyond the scope of this paper, two cases have been selected for discussion because they represent common clinical scenarios encountered by the spinal surgeon, but there is limited published information specific to the athlete with such an injury. We have therefore addressed the issues specific to return to sport rather than focus on the myriad surgical procedures that can be performed on the lumbar spine.

A 29-year-old American footballer was tackled to the ground and instantly felt a “twinge” in his lower back. He got up from his fall, and over the next few hours the pain intensified and then radiated into his right thigh, calf and foot. Treatment over the following 4 weeks included physiotherapy, acupuncture, non-steroidal anti-inflammatory medication, and hydrotherapy. The leg pain intensified and MRI of the lumbar spine showed a right L5–S1 sequestrated disc prolapse (figs 1 and 2). A microdiscectomy was performed, with complete resolution of pain. He was discharged from hospital the day after surgery and has remained free of pain. You review him 6 weeks postoperatively and he is …
Type-specific immunogenicity of a chemically synthesized peptide fragment of type 5 streptococcal M protein.
Authors: J B Dale, J M Seyer, E H Beachey
Journal: The Journal of Experimental Medicine (1983)

We determined the antigenic specificity and protective immunogenicity of two chemically synthesized peptides of type 5 streptococcal M protein. The synthetic peptides, designated S-M5(1-20) and S-M5(20-40), represent the amino-terminal amino acid sequence of the native pepsin-extracted M5 molecule, which is known to contain at least one heart cross-reactive epitope. Initial studies showed that neither of the synthetic peptides was able to bind purified heart-reactive M5 antibodies. In addition, S-M5(1-20), but not S-M5(20-40), contained type-specific antigenic determinants as measured by enzyme-linked immunosorbent inhibition assays. When covalently linked to tetanus toxoid, S-M5(1-20), but not S-M5(20-40), evoked significant levels of type-specific, opsonic (and presumably protective) antibodies in rabbits without evoking heart cross-reactive antibodies.
A self-management programme for COPD: a randomised controlled trial
Authors: Katy E. Mitchell, Vicki Johnson-Warrington, Lindsay D. Apps, John Bankart, Louise Sewell, Johanna E. Williams, Karen Rees, Kate Jolly, Michael Steiner, Mike Morgan, Sally J. Singh
Journal: European Respiratory Journal (2014)

Studies of programmes of self-management support for chronic obstructive pulmonary disease (COPD) have been inconclusive. The Self-Management Programme of Activity, Coping and Education (SPACE) FOR COPD is a 6-week self-management intervention for COPD, and this study aimed to evaluate the effectiveness of this intervention in primary care. A single-blind randomised controlled trial recruited people with COPD from primary care and randomised participants to receive usual care or SPACE FOR COPD. Outcome measures were performed at baseline, 6 weeks and 6 months. The primary outcome was symptom burden, measured by the self-reported Chronic Respiratory Questionnaire (CRQ-SR) dyspnoea domain. Secondary outcomes included other domains of the CRQ-SR, shuttle walking tests, disease knowledge, anxiety, depression, self-efficacy, smoking status and healthcare utilisation. 184 people with COPD were recruited and randomised. At 6 weeks, there were significant differences between groups in CRQ-SR dyspnoea, fatigue and emotion scores, exercise performance, anxiety, and disease knowledge. At 6 months, there was no between-group difference in change in CRQ-SR dyspnoea. Exercise performance, anxiety and smoking status were significantly different between groups at 6 months, in favour of the intervention. This brief self-management intervention did not improve dyspnoea over and above usual care at 6 months; however, there were gains in anxiety, exercise performance, and disease knowledge.
Significance of plasma copper and caeruloplasmin concentrations in rheumatoid arthritis.
Authors: D P Bajpayee
Journal: Annals of the Rheumatic Diseases (1975)

To understand the role of copper in initiating protein alterations in rheumatoid arthritis (RA) as reported previously, concentrations of copper anc caeruloplasmin were determined in RA patients. The mean copper concentration of the RA population examined was 24.8 mumol/l (157.5 mug/100 ml), and the mean caeruloplasmin concentration in this RA population was 45.52 mg/100 ml. These values are not different from those reported by previous workers. However, when the RA population was divided into three groups according to sex and oestrogen therapy it was found that caeruloplasmin and copper concentrations in the group of female RA patients on oestrogens was significantly different from other groups (P less than 0.001). A highly significant (P less than 0.01) positive correlation was obtained between copper and caeruloplasmin concentrations (r = 0.91). Concentrations of copper and caeruloplasmin failed to explain the low sulphydryl content of plasma which was observed to be independent of these two parameters. Increased alpha2-globulin concentration, which was refractory to chrysotherapy but 'finger-printed' with a pure preparation of caeruloplasmin in electrophoresis, along with the absence of Kayser-Fleischer rings, supports the contention that copper is not present in a free ionic state in RA patients. This study shows that only a concurrent oestrogen therapy raises copper and caeruloplasmin concentration significantly in a female RA population. Past investigators appear to have overlooked this fact, and it could be that a disproportionate sex distribution (more female rheumatoid arthritics) could cause misleading results in RA studies. The role of oestrogens, copper, and caeruloplasmin in causing exacerbation of RA symptoms is discussed.
Alopecia Universalis Successfully Treated With Adalimumab
Authors: Loren Gorcey, Elizabeth A. Gordon Spratt, Marie C. Leger
Journal: JAMA Dermatology (2014)

IMPORTANCE Alopecia universalis is an uncommon form of alopecia areata (AA) involving hair loss over the entire scalp and body and is often difficult to treat. Tumor necrosis factor (TNF)inhibitors have been largely unsuccessful in treating AA and have been reported to induce or worsen AA in patients.We report herein a case of alopecia universalis successfully treated with adalimumab and discuss the possible mechanism.OBSERVATIONS A woman in her 30s with alopecia universalis, refractory to multiple treatment modalities, was successfully treated with adalimumab.CONCLUSIONS AND RELEVANCE Tumor necrosis factor has multiple important roles in the pathogenesis of AA, and its interplay with other cytokines, specifically interferons, may be responsible for the development of AA in patients treated with TNF inhibitors.Pharmacogenetics and the inherent physiologic levels of TNF may explain why TNF inhibitors cause AA in some individuals, while treating AA in others. These conclusions warrant further investigation on this subject.
An analysis of <i>ERBB2</i> alterations (amplifications and mutations) found by next-generation sequencing (NGS) in 2000+ consecutive solid tumor (ST) patients.
Authors: Gary A. Palmer, Kai Wang, Vincent A. Miller, Roman Yelensky, Phil Stephens, Jeffrey S. Ross, Doron Lipson
Journal: Journal of Clinical Oncology (2013)

11000 Background: Testing for ERBB2 amplification by FISH and IHC is routine in breast and gastro-esophageal cancer. There are 3 approved and multiple targeted therapies in clinical trials that rely on the results of these tests. ERBB2 amplification and activation by mutation/fusion has also been described in a wide variety of other ST. As these alterations are not routinely tested for but may predict response to anti-ERBB2 agents we sought to determine their frequency in an unselected cohort of specimens from advanced ST patients. Methods: We reviewed genomic profiles from the first 2,223 formalin-fixed, paraffin-embedded specimens received and analyzed by our CLIA-certified lab (Foundation Medicine) with our NGS platform. 3,230 exons in 182 cancer-related genes and 14 genes frequently rearranged were assayed for base pair substitutions, small insertions/deletions (indels), amplifications, and rearrangements. Results: 110/2,223 (4.9%) specimens had 116 ERBB2 alterations: 67 (58%) amplifications, 29 (25%) substitutions, 16 (14%) indels, 2 (2%) splice site variants and 2 (2%) translocations, including a potential fusion. Six samples (5%) had multiple alterations, and two had both ERBB2 substitution and amplification. 14 ST types had evidence of ERBB2 alterations including 29% of esophageal, 20% of uterine, 14% of breast, and 12% of stomach carcinomas. 6% of all lung cancer samples had ERBB2 alterations. Amplifications predominated, but lung specimens had predominantly indels. Durable responses exist to anti-ERBB2 agents in STs with activating ERBB2 mutations. Conclusions: Use of a broad NGS panel identifies an unprecedented number of actionable genomic changes including a significant rate of ERBB2 alterations across 14 different solid tumor types. The discovery of unanticipated ERBB2 amplifications and activating mutations in a wide variety of ST highlights the need to study a broad range of genes at a high level of sensitivity and specificity when searching for novel targets of therapy. Widespread use of this approach could provide more treatment options and enable more rapid accrual to ongoing and planned trials of agents targeting pathways under study.