tbuckley/cabot-search huggingface dataset:
Pathologic Reassessment of Prostate Cancer Surgical Specimens Before Molecular Retrospective Studies
Authors: Gaelle Fromont, Pierre Validire, Dominique Prapotnich, François Rozet, Guy Vallancien, Olivier Cussenot, Xavier Cathelineau
Journal: Clinical Cancer Research (2010)

The retrospective use of prostate cancer tissue is crucial to design tumor marker prognostic studies. We hypothesize that comparison between recent and more historical cases could introduce biases due to stage and grade migration upon time.We reviewed 544 margin-free specimens from patients treated for clinically localized prostate cancer by radical prostatectomy between 2000 and 2005. One hundred and ninty-two patients that underwent biochemical recurrence after surgery were matched with 352 patients without progression, according to pretreatment prostate specific antigen, Gleason score, pathologic stage, and follow-up duration (at least 36 months).The reassessment led to histopathologic reclassification of standard prognostic variables in 15% of cases, including modifications in the Gleason score (n = 63), pathologic stage (n = 12), and margin status (n = 30). Most discrepancies with the initial reports are explained either by differences in the scoring system upon time, or by the exam of additional tissues sections. The impact of reclassification led to increase adverse prognostic factors more frequently in the group of patients with progression (Chi(2), P < 0.0001).Careful reassessment of prostate cancer samples should be mandatory before molecular prognostic studies to ensure a more uniform pathologic evaluation, and might be reported in the "recommendations for tumor markers prognostic studies" (REMARK).
Expression of myeloperoxidase in acute myeloid leukemia blasts mirrors the distinct DNA methylation pattern involving the downregulation of DNA methyltransferase DNMT3B
Authors: H Itonaga, D Imanishi, Y-F Wong, S Sato, K Ando, Y Sawayama, D Sasaki, K Tsuruda, H Hasegawa, Y Imaizumi, J Taguchi, H Tsushima, S Yoshida, T Fukushima, T Hata, Y Moriuchi, K Yanagihara, Y Miyazaki
Journal: Leukemia (2014)
Differences in Bone Quality in Low- and High-Turnover Renal Osteodystrophy
Authors: Hartmut H. Malluche, Daniel S. Porter, Marie-Claude Monier-Faugere, Hanna Mawad, David Pienkowski
Journal: Journal of the American Society of Nephrology (2011)

Abnormal bone turnover is common in CKD, but its effects on bone quality remain unclear. We qualitatively screened iliac crest bone specimens from patients on dialysis to identify those patients with low (n=18) or high (n=17) bone turnover. In addition, we obtained control bone specimens from 12 healthy volunteers with normal kidney function. In the patient and control specimens, Fourier transform infrared spectroscopy and nanoindentation quantified the material and mechanical properties of the specimens, and we used bone histomorphometry to assess parameters of bone microstructure and bone formation and resorption. Compared with high or normal turnover, bone with low turnover had microstructural abnormalities such as lower cancellous bone volume and reduced trabecular thickness. Compared with normal or low turnover, bone with high turnover had material and nanomechanical abnormalities such as reduced mineral to matrix ratio and lower stiffness. These data suggest that turnover-related alterations in bone quality may contribute to the diminished mechanical competence of bone in CKD, albeit through different mechanisms. Therapies tailored specifically to low- or high-turnover bone may treat renal osteodystrophy more effectively.
Surgical resection of lung cancer England: more operations but no trials to test their effectiveness
Authors: Tom Treasure, Christopher Russell, Dion Morton, Fergus Macbeth, Martin Utley
Journal: Thorax (2012)

Ten years ago a joint working group of The British Thoracic Society and the Society for Thoracic Surgery in Great Britain in Ireland published its findings, concluding that there was ‘critical under-provision of Thoracic Surgery in the UK’.1 ,2 The situation has improved according to Lung Cancer Data (LUCADA),3 the National Lung Cancer Audit,4 and the English Cancer Repository Dataset reported in this number of Thorax .5 The English Cancer Repository Dataset study found that the proportion of patients with non-small cell lung cancer undergoing surgery has risen to 10.6% from 8.8% in 1998, the situation that prompted the formation of the working party. The data provide evidence that there is now better access to thoracic surgery in the management of lung cancer and that the drive by professional societies to achieve this has met with success. The critical question now is whether, on existing evidence, it is reasonable to believe that simply increasing lung cancer resection rates will result in overall better outcomes for future patients with lung cancer.

Overall survival for lung cancer remains extremely poor. In bowel cancer, 5-year survival has steadily increased from around 20% to 50% (figure 1) while that for lung cancer remains under 10% with negligible improvement over 40 years (figure 2). The lung cancer patients who have surgery are, by selection, the most favourable decile, yet fewer than one in four operated patients were alive 5 years later according to data in the National Lung Cancer Audit,4 the same as in patients operated on between 1949 and 1983.6 In the intervening 30 years, there have been fundamental changes in endoscopy, imaging, staging and the …
X-Tile
Authors: Robert L. Camp, Marisa Dolled-Filhart, David L. Rimm
Journal: Clinical Cancer Research (2004)

Abstract The ability to parse tumors into subsets based on biomarker expression has many clinical applications; however, there is no global way to visualize the best cut-points for creating such divisions. We have developed a graphical method, the X-tile plot that illustrates the presence of substantial tumor subpopulations and shows the robustness of the relationship between a biomarker and outcome by construction of a two dimensional projection of every possible subpopulation. We validate X-tile plots by examining the expression of several established prognostic markers (human epidermal growth factor receptor-2, estrogen receptor, p53 expression, patient age, tumor size, and node number) in cohorts of breast cancer patients and show how X-tile plots of each marker predict population subsets rooted in the known biology of their expression.
MESO-2,3-Dimercaptosuccinic Acid: Chemical, Pharmacological and Toxicological Properties of an Orally Effective Metal Chelating Agent
Authors: H V Aposhian, M M Aposhian
Journal: The Annual Review of Pharmacology and Toxicology (1990)

Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe2+, carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed cell death. The mechanism ...Read More
Clinical Outcomes and CD4 Cell Response in Children Receiving Antiretroviral Therapy at Primary Health Care Facilities in Zambia
Authors: Carolyn Bolton-Moore, Mwangelwa Mubiana-Mbewe, Ronald A. Cantrell, Namwinga Chintu, Elizabeth M. Stringer, Benjamin H. Chi, Moses Sinkala, Chipepo Kankasa, Craig M. Wilson, Catherine M. Wilfert, Albert Mwango, Jens Levy, Elaine J. Abrams, Marc Bulterys, Jeffrey S. A. Stringer
Journal: JAMA (2007)

The Zambian Ministry of Health provides pediatric antiretroviral therapy (ART) at primary care clinics in Lusaka, where, despite scale-up of perinatal prevention efforts, many children are already infected with the human immunodeficiency virus (HIV).To report early clinical and immunologic outcomes of children enrolled in the pediatric treatment program.Open cohort assessment using routinely collected clinical and outcome data from an electronic medical record system in use at 18 government primary health facilities in Lusaka, Zambia. Care was provided primarily by nurses and clinical officers ("physician extenders" akin to physician assistants in the United States). Patients were children (<16 years of age) presenting for HIV care between May 1, 2004, and June 29, 2007.Three-drug ART (zidovudine or stavudine plus lamivudine plus nevirapine or efavirenz) for children who met national treatment criteria.Survival, weight gain, CD4 cell count, and hemoglobin response.After enrollment of 4975 children into HIV care, 2938 (59.1%) started ART. Of those initiating ART, the median age was 81 months (interquartile range, 36-125), 1531 (52.1%) were female, and 2087 (72.4%) with World Health Organization stage information were in stage III or IV. At the time of analysis, 158 children (5.4%) had withdrawn from care and 382 (13.0%) were at least 30 days late for follow-up. Of the remaining 2398 children receiving ART, 198 (8.3%) died over 3018 child-years of follow-up (mortality rate, 6.6 deaths per 100 child-years; 95% confidence interval [CI], 5.7-7.5); of these deaths, 112 (56.6%) occurred within 90 days of therapy initiation (early mortality rate, 17.4/100 child-years; post-90-day mortality rate, 2.9/100 child-years). Mortality was associated with CD4 cell depletion, lower weight-for-age, younger age, and anemia in multivariate analysis. The mean CD4 cell percentage at ART initiation among the 1561 children who had at least 1 repeat measurement was 12.9% (95% CI, 12.5%-13.3%) and increased to 23.7% (95% CI, 23.1%-24.3%) at 6 months, 27.0% (95% CI, 26.3%-27.6%) at 12 months, 28.0% (95% CI, 27.2%-28.8%) at 18 months, and 28.4% (95% CI, 27.4%-29.4%) at 24 months.Care provided by clinicians such as nurses and clinical officers can result in good outcomes for HIV-infected children in primary health care settings in sub-Saharan Africa. Mortality during the first 90 days of therapy is high, pointing to a need for earlier intervention.
Combined exposure to Maneb and Paraquat alters transcriptional regulation of neurogenesis-related genes in mice models of Parkinson’s disease
Authors: Paula Desplats, Pruthul Patel, Kori Kosberg, Michael Mante, Christina Patrick, Edward Rockenstein, Masayo Fujita, Makoto Hashimoto, Eliezer Masliah
Journal: Molecular Neurodegeneration (2012)

Parkinson's disease (PD) is a multifactorial disease where environmental factors act on genetically predisposed individuals. Although only 5% of PD manifestations are associated with specific mutations, majority of PD cases are of idiopathic origin, where environment plays a prominent role. Concurrent exposure to Paraquat (PQ) and Maneb (MB) in rural workers increases the risk for PD and exposure of adult mice to MB/PQ results in dopamine fiber loss and decreased locomotor activity. While PD is characterized by neuronal loss in the substantia nigra, we previously showed that accumulation of α-synuclein in the limbic system contributes to neurodegeneration by interfering with adult neurogenesis. We investigated the effect of pesticides on adult hippocampal neurogenesis in two transgenic models: Line 61, expressing the human wild type SNCA gene and Line LRRK2(G2019S), expressing the human LRRK2 gene with the mutation G2019S. Combined exposure to MB/PQ resulted in significant reduction of neuronal precursors and proliferating cells in non-transgenic animals, and this effect was increased in transgenic mice, in particular for Line 61, suggesting that α-synuclein accumulation and environmental toxins have a synergistic effect. We further investigated the transcription of 84 genes with direct function on neurogenesis. Overexpresion of α-synuclein resulted in the downregulation of 12% of target genes, most of which were functionally related to cell differentiation, while LRRK2 mutation had a minor impact on gene expression. MB/PQ also affected transcription in non-transgenic backgrounds, but when transgenic mice were exposed to the pesticides, profound alterations in gene expression affecting 27% of the studied targets were observed in both transgenic lines. Gene enrichment analysis showed that 1:3 of those genes were under the regulation of FoxF2 and FoxO3A, suggesting a primary role of these proteins in the response to genetic and environmental cues. We report that adult neurogenesis is highly susceptible to multiple "risk factors" for PD, including α-synuclein accumulation, LRRK2 G2019 mutation and exposure to environmental toxins. We identified specific groups of genes that are responsive to each stressor, while uncovering a novel function for Fox transcription factors in PD.
Clinical Studies of Histone Deacetylase Inhibitors
Authors: H. Miles Prince, Mark J. Bishton, Simon J. Harrison
Journal: Clinical Cancer Research (2009)

Abstract Over the last 5 years, a plethora of histone deacetylase inhibitors (HDACi) have been evaluated in clinical trials. These drugs have in common the ability to hyperacetylate both histone and nonhistone targets, resulting in a variety of effects on cancer cells, their microenvironment, and immune responses. To date, responses with single agent HDACi have been predominantly observed in advanced hematologic malignancies including T-cell lymphoma, Hodgkin lymphoma, and myeloid malignancies. Therefore, in this review we focus upon hematologic malignancies. Generally HDACi are well tolerated with the most common acute toxicities being fatigue, gastrointestinal, and transient cytopenias. Of note, few patients have been treated for prolonged periods of time and little is known about long-term toxicities. The use of the biomarker of histone hyperacetylation has been useful as a guide to target specificity, but generally does not predict for response and the search for more clinically relevant biomarkers must continue.
Airway Surface Dehydration in Cystic Fibrosis: Pathogenesis and Therapy
Authors: Richard C. Boucher
Journal: Annual Review of Medicine (2007)

Cystic fibrosis (CF) lung disease reflects the failure of airways defense against chronic bacterial infection. Studies of CF cultures, transgenic mice, and CF patients suggest that the initiating event in CF airways disease pathogenesis is reduced airway surface liquid (ASL) volume, i.e., dehydration. CF ASL volume regulation depends on a single extracellular signaling system, ATP, which renders CF airways more vulnerable to disease-causing insults (e.g., viruses) than are normal airways, which regulate ASL volume by dual ATP and adenosine signaling pathways. Clinical studies have explored the hypothesis that treating the dehydration of CF airways will be therapeutically beneficial. Inhaled hypertonic saline osmotically draws water onto airway surfaces, improves mucus clearance and pulmonary function, and reduces acute exacerbations in CF patients. Thus, rehydration therapies may slow the progression of CF lung disease in patients with established bacterial infection and may prevent the onset of CF lung disease if initiated early in life.
Primary Care–Relevant Interventions to Prevent Falling in Older Adults: A Systematic Evidence Review for the U.S. Preventive Services Task Force
Authors: Yvonne L. Michael, Evelyn P. Whitlock, Jennifer S. Lin, Rongwei Fu, Elizabeth A. O'Connor, Rachel Gold
Journal: Annals of Internal Medicine (2010)

Background: Falls among older adults are both prevalent and preventable. Purpose: To describe the benefits and harms of interventions that could be used by primary care practitioners to prevent falling among community-dwelling older adults. Data Sources: The reviewers evaluated trials from a good-quality systematic review published in 2003 and searched MEDLINE, the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL from the end of that review's search date to February 2010 to identify additional English-language trials. Study Selection: Two reviewers independently screened 3423 abstracts and 638 articles to identify randomized, controlled trials (RCTs) of primary care–relevant interventions among community-dwelling older adults that reported falls or fallers as an outcome. Trials were independently critically appraised to include only good- or fair-quality trials; discrepancies were resolved by a third reviewer. Data Extraction: One reviewer abstracted data from 61 articles into standardized evidence tables that were verified by a second reviewer. Data Synthesis: Overall, the included evidence was of fair quality. In 16 RCTs evaluating exercise or physical therapy, interventions reduced falling (risk ratio, 0.87 [95% CI, 0.81 to 0.94]). In 9 RCTs of vitamin D supplementation, interventions reduced falling (risk ratio, 0.83 [CI, 0.77 to 0.89]). In 19 trials involving multifactorial assessment and management, interventions with comprehensive management seemed to reduce falling, although overall pooled estimates were not statistically significant (risk ratio, 0.94 [CI, 0.87 to 1.02]). Limited evidence suggested that serious clinical harms were no more common for older adults in intervention groups than for those in control groups. Limitations: Interventions and methods of fall ascertainment were heterogeneous. Data on potential harms of interventions were scant and often not reported. Conclusion: Primary care–relevant interventions exist that can reduce falling among community-dwelling older adults. Primary Funding Source: Agency for Healthcare Research and Quality.
A first or dominant immunization. II. Induced immunoglobulin carries transforming growth factor beta and suppresses cytolytic T cell responses to unrelated alloantigens.
Authors: R M Stach, D A Rowley
Journal: The Journal of Experimental Medicine (1993)

Fresh sera from mice immunized by bearing an immunogenic tumor or by repeated injections of allogeneic spleen cells or xenogeneic erythrocytes powerfully suppress cytolytic T cell responses in one-way mixed lymphocyte cultures. Suppression is not antigen specific, though is mediated by immunoglobulin (Ig)G specific for the immunizing antigen. Suppression caused by IgG mimics that caused by active transforming growth factor beta (TGF-beta). IgG associates with or carries latent TGF-beta; however, suppression caused by the complex of IgG-TGF-beta requires macrophages (M phi), whereas active TGF-beta alone does not. Also, IgG dissociated from TGF-beta does not cause suppression, suggesting that M phi may take up Ig-TGF-beta, process the complex, and deliver active TGF-beta to lymphocytes. Indeed, suppression by immune serum was prevented by antibody to Fc receptors, by saturating Fc receptors with heterologous IgGs, and by antibodies against TGF-beta. The overall findings reveal a previously unrecognized regulatory circuit whereby IgG produced in response to one antigen nonspecifically downregulates cytolytic T lymphocyte responses to unrelated antigens. The findings introduce the intriguing possibility that TGF-beta delivered by IgG and processed by M phi may mediate important biological effects in processes such as wound healing, tumor growth, and some autoimmune diseases.
A phase II study of sorafenib (BAY 43–9006) in recurrent diffuse large B cell lymphoma: an eastern cooperative oncology group study (E1404)
Authors: Daniel R Greenwald, Hailun Li, Selina M Luger, Ronald S Go, David King, Taral Patel, Randy D Gascoyne, Jill Kolesar, Brad S Kahl, Sandra Horning
Journal: Journal of Hematology & Oncology (2013)

Patients with diffuse large B cell lymphoma (DLBCL) who are not candidates for or recur after autologous stem cell transplant have a poor overall prognosis. We conducted a phase II study of sorafenib (formerly BAY 43–9006) in the treatment of relapsed DLBCL. Fourteen patients were enrolled and assessed for response. Median number of cycles administered was 3 (range, 1–12). Common grade 3 toxicities included fatigue (29%), rash/desquamation (21%) and diarrhea (14%). One complete response (CR) was observed (the 14th patient enrolled). Response rate was 7% (90% CI, 0.4 – 30%). Duration of response was 6 months. Median progression-free survival (PFS) was 2 months (90% CI, 1 – 5 months). Median overall survival (OS) was 9 months (90% CI, 5 – 16 months). Although sorafenib has demonstrated activity in solid malignancies it demonstrated low single agent activity in treatment of DLBCL.
Mechanisms of dyspnoea and its language in patients with asthma
Authors: P. Laveneziana, P. Lotti, C. Coli, B. Binazzi, L. Chiti, L. Stendardi, R. Duranti, G. Scano
Journal: European Respiratory Journal (2006)

This study hypothesises that regardless of the global score of dyspnoea intensity, different descriptors may be selected by asthmatic patients during short cardiopulmonary exercise test (sCPET) and methacholine (Mch) inhalation. It also examines whether different qualitative dyspnoea sensations can help explain the underlying mechanisms of the symptom. Minute ventilation (V'E), tidal volume (VT) and inspiratory capacity (IC) were measured in 22 stable asthmatic patients, and the sensation of dyspnoea during Mch inhalation and sCPET was quantitatively (Borg scale) and qualitatively (descriptors) assessed. The work rate and oxygen uptake (V'O2) were also measured during sCPET. Airway obstruction and hyperinflation, as measured by IC reduction, were the best correlates for dyspnoea with Mch. During sCPET, changes in WR, V'O2, V'E and VT significantly correlated with Borg score, with V'E being the best predictor of dyspnoea; IC decreased in eight patients. Furthermore, chest tightness (68%) was the highest reported descriptor during Mch inhalation, whereas work/effort (72%) was the highest during sCPET. In conclusion, obstruction/hyperinflation and work rate are highly reliable predictors of Borg rating of dyspnoea during methacholine inhalation and short cardiopulmonary exercise testing, respectively. Regardless of the global score of intensity dyspnoea, different descriptors may be selected by patients during short cardiopulmonary exercise testing and methacholine inhalation. Various qualities of dyspnoea result from different pathophysiological abnormalities.
<i>DPC4</i>/Smad4 Expression and Outcome in Pancreatic Ductal Adenocarcinoma
Authors: Andrew V. Biankin, Adrienne L. Morey, C.-Soon Lee, James G. Kench, Sandra A. Biankin, Henry C. Hook, Darren R. Head, Thomas B. Hugh, Robert L. Sutherland, Susan M. Henshall
Journal: Journal of Clinical Oncology (2002)

Prognostic indicators in pancreatic cancer (PC) are poorly defined and difficult to quantify preoperatively, hence they may lead to inappropriate patient selection for treatment. We examined the protein expression of key cell-cycle regulatory and cell-signaling molecules that occur at high frequency in PC and assessed their relationship to clinicopathologic parameters, response to operative resection, and outcome.We identified 348 patients with pancreatic ductal adenocarcinoma and assessed the influence of reported clinicopathologic prognostic factors and the expression of the cell-cycle regulatory genes p21(WAF1/CIP1) (CDKN1A), cyclin D1 (CCND1), p53, and p16(INK4A) (CDKN2) and the cell-signaling molecule DPC4/Smad4 (MADH4) using immunohistochemistry in a subgroup of 129 patients.Independent prognostic factors in resected patients were tumor size greater than 45 mm (P =.0015), involvement of surgical margins (P <.0001), and perineural invasion (P =.014). Loss of DPC4/Smad4 expression cosegregated with resectability (P <.0001) and was associated with improved survival after resection (P <.0001), whereas resection did not improve survival in patients whose tumor expressed DPC4/Smad4 (P =.5). Aberrant expression of p21(WAF1/CIP1), cyclin D1, p53, or p16(INK4A) was not associated with a difference in survival.Tumor size (> 45 mm), resection margin involvement, and perineural invasion were independent prognostic factors. Preoperative assessment of DPC4/Smad4 expression has potential as a prognostic indicator in patients with PC since resection did not benefit those patients whose cancers expressed DPC4/Smad4 and accurate assessment of DPC4/Smad4 expression, unlike tumor size, margin status, and perineural invasion, does not require resection.