tbuckley/cabot-search huggingface dataset:
Elective surgery for gastrointestinal tumours in the elderly
Authors: R.A. Audisio, P. Veronesi, L. Ferrario, C. Cipolla, B. Andreoni, M. Aapro
Journal: Annals of Oncology (1997)

The geriatric population is expanding and clinical decision-making is often complicated by the effects of ageing. Age should not be the only parameter considered when addressing medical problems. Elderly subjects have been denied surgery because of their presumed higher mortality and morbidity. The present review summarises the physiology of the aged and discusses operative risks, mortality and morbidity rates as well as therapeutic results for the different gastrointestinal sites when affected by cancer. Reports on surgical treatments are revisited and compared to the same procedures delivered to younger patients in the context of the ethical issue of offering the best care to every patient. Elective operations by surgical oncologists are found to be safe with the exception of major liver resections. Complication rates and mean hospital stay do not differ between the two age groups provided the procedure is conducted with the best-known technique in expert hands. A drop in operative morbidity has occurred in the past three decades. Several investigators have emphasised the marked increase in morbidity and mortality experienced by elderly patients when undergoing emergency procedures. Associated diseases have to be properly assessed, as the elderly have a frail physiological balance with a reduced capacity for recovery from traumatic events including major surgical procedures. Careful preoperative evaluation, intraoperative conduct and postoperative care are presently achieved in almost every major hospital. Good clinical practice is based on the balance between probability of cure and toxic effects. Treatment of the elderly should no longer be based on untested beliefs and personal opinions. The elderly should be accrued for prospective clinical evaluation and should not be denied optimal surgical treatment.
A First-in-Human Phase I Study of MORAb-004, a Monoclonal Antibody to Endosialin in Patients with Advanced Solid Tumors
Authors: Luis A. Diaz, Christina M. Coughlin, Susan C. Weil, Jean Fishel, Mrinal M. Gounder, Susan Lawrence, Nilofer Azad, Daniel J. O'Shannessy, Luigi Grasso, Jason Wustner, Wolfgang Ebel, Richard D. Carvajal
Journal: Clinical Cancer Research (2014)

Endosialin (TEM-1, CD248) is a protein expressed on the surface of activated mesenchymal cells, including certain subsets of tumors. Preclinical models suppressing endosialin function have shown antitumor activity. A humanized monoclonal antibody, MORAb-004, was engineered to target endosialin and is the first agent in clinical development for this mesenchymal cell target.This first-in-human, open-label, phase I study recruited patients with treatment-refractory solid tumors. MORAb-004 was administered intravenously once weekly in 4-week cycles. Objectives included determination of the safety of multiple infusions of MORAb-004, identification of the maximum tolerated dose (MTD), pharmacokinetic modeling, detection of any anti-human antibody response, and assessment of objective radiographic response to therapy.Thirty-six patients were treated at 10 dose levels of MORAb-004, ranging from 0.0625 to 16 mg/kg. Drug-related adverse events were primarily grade 1-2 infusion toxicities. Dose-limiting toxicity of grade 3 vomiting was observed at 16 mg/kg. Eighteen of 32 evaluable patients across all doses achieved disease stability, with minor radiographic responses observed in 4 patients (pancreatic neuroendocrine, hepatocellular, and sarcoma tumor types). Pharmacokinetics showed MORAb-004 accumulation beginning at 4 mg/kg and saturable elimination beginning at 0.25 mg/kg. Exposure increased in a greater-than-dose-proportional manner with terminal half-life increasing proportionally with dose. The MTD was identified as 12 mg/kg.Preliminary antitumor activity was observed. Safety profile, pharmacokinetics, and early antitumor activity suggest that MORAb-004 is safe at doses up to 12 mg/kg and should be studied further for efficacy.
Nutritional assessment with bioelectrical impedance analysis in maintenance hemodialysis patients.
Authors: G M Chertow, E G Lowrie, D W Wilmore, J Gonzalez, N L Lew, J Ling, M S Leboff, M N Gottlieb, W Huang, B Zebrowski
Journal: Journal of the American Society of Nephrology (1995)

Protein energy malnutrition is common among persons with ESRD and contributes substantially to morbidity and mortality. The usual methods of nutritional assessment, such as anthropometry, can be misleading because of altered tissue hydration. Bioelectrical impedance analysis (BIA) has been recommended by some as a practical nutritional assessment tool but has not been validated in patients with ESRD. Thirty-three stable patients on maintenance hemodialysis were evaluated in an ambulatory clinical research center with simultaneous BIA, dual-energy x-ray absorptiometry, and deuterium oxide (D2O) and sodium bromide (NaBr) isotope dilution studies. Standard determinations of total body water (TBW) and body cell mass (BCM) were obtained and compared with values estimated by BIA. Two separate outpatient BIA measurements were also obtained approximately 2 wk before and after the clinical research center evaluation. BCM estimated by BIA was directly correlated (r = 0.92, P < 0.0001) with BCM determined by DEXA and NaBr. TBW estimated by BIA was directly correlated (r = 0.96, P < 0.0001) with TBW determined by deuterium oxide dilution. The reactance to resistance ratio (Xc/R) derived from BIA was inversely correlated (r = -0.73, P < 0.0001) with the extracellular water/TBW ratio determined by NaBr/D2O. Bland-Altman analyses showed that for TBW, BIA was in excellent agreement with D2O dilution. BCM was modestly underestimated by BIA compared with the dual-energy x-ray absorptiometry/NaBr standard and was adjusted by linear regression. The coefficients of variation on repeated BIA measurements were below 4%, demonstrating test-retest reliability. BIA is a valid and reliable method of nutritional assessment in maintenance hemodialysis patients.
Proteolysis in the lung
Authors: S.D. Shapiro
Journal: European Respiratory Journal (2003)

Pulmonary emphysema is a major component of the morbidity and mortality of chronic obstructive pulmonary disease (COPD), a condition that has become the fourth leading cause of death in the USA, and is becoming epidemic worldwide. Emphysema is defined as enlargement of peripheral airspaces of the lung including respiratory bronchioles, alveolar ducts and alveoli, accompanied by destruction of the walls of these structures. The pathogenesis of emphysema can be dissected into three interrelated events: 1) chronic exposure to cigarette smoke may lead to inflammatory cell recruitment within the terminal airspaces of the lung; 2) these inflammatory cells release elastolytic proteinases that damage the extracellular matrix of the lung; and 3) ineffective repair of elastin and perhaps other extracellular matrix components result in pulmonary emphysema.

Inherited deficiency of α1‐antitrypsin (α1‐AT), the primary inhibitor of neutrophil elastase (NE), predisposes individuals to early onset emphysema, and intrapulmonary instillation of elastolytic enzymes in experimental animals causes emphysema. Together, these findings led to the elastase/antielastase hypothesis for the pathogenesis of emphysema, which was proposed ∼40 yrs ago and remains the prevailing concept today. While the capacity of NE to initiate emphysema in patients deficient in α1‐AT is clear, the proteinases involved in the pathogenesis of the common form of emphysema associated with cigarette smoking is more complicated. In addition to NE, neutrophil primary granules contain other elastolytic serine proteinases including, cathepsin G and proteinase 3, and secondary granules possess matrix metalloproteinases; MMP‐8, a collagenase and MMP‐9, a 92 kDa gelatinase. While, macrophages are prominent inflammatory cells in smokers' lungs, the capacity of macrophages to degrade elastin was controversial until cysteine proteinases including cathepsins S and L were identified (K the most potent elastase has not been identified in lung macrophages). The author's group identified several MMPs produced by alveolar and interstitial …
Serum Level of Endogenous Secretory Receptor for Advanced Glycation End Products and Other Factors in Type 2 Diabetic Patients With Mild Cognitive Impairment
Authors: Gang Chen, Liangchun Cai, Bin Chen, Jixing Liang, Fenhui Lin, Liantao Li, Lixiang Lin, Jin Yao, Junping Wen, Huibin Huang
Journal: Diabetes Care (2011)

Determine the serum levels of endogenous secretory receptor for advanced glycation end products (esRAGEs) in patients with type 2 diabetes and mild cognitive impairment (MCI) and in control patients with type 2 diabetes but no MCI, and examine the relationship of esRAGE and MCI with other clinical factors.A total of 101 patients with type 2 diabetes who were hospitalized in the Department of Endocrinology at Fujian Provincial Hospital between January 2010 and January 2011 were enrolled. There were 58 patients with MCI and 43 patients without MCI (control). Serum levels of esRAGE were measured using an enzyme-linked immunosorbent assay (ELISA). Other clinical parameters were also measured.Type 2 diabetic patients with MCI had a longer duration of diabetes; elevated HbA(1c), total cholesterol (CHOL), LDL cholesterol (LDL-C), triglyceride (TG), intima-media thickness, C-reactive protein (CRP), and brachial-ankle pulse wave velocity (ba-PWV); and lower ankle brachial index (ABI) and esRAGE relative to the control group. Among patients with MCI, the Montreal Cognitive Assessment (MoCA) score was positively correlated with serum esRAGE but negatively correlated with CHOL. Spearman rank correlation analysis indicated that esRAGE was positively correlated with MoCA score and ABI but negatively correlated with ba-PWV, CHOL, TG, and CRP in all subjects.Our results suggest that esRAGE may be a potential protective factor for dyslipidemia, atherosclerosis, and MCI in patients with type 2 diabetes.
Induction of Apoptosis in Leukemic Cells by Homovanillic Acid Derivative, Capsaicin, through Oxidative Stress
Authors: Keisuke Ito, Tomonori Nakazato, Kenji Yamato, Yoshitaka Miyakawa, Taketo Yamada, Nobumichi Hozumi, Kaoru Segawa, Yasuo Ikeda, Masahiro Kizaki
Journal: Cancer Research (2004)

Abstract Capsaicin (N-vanillyl-8-methyl-1-nonenamide) is a homovanillic acid derivative found in pungent fruits. Several investigators have reported the ability of capsaicin to inhibit events associated with the promotion of cancer. However, the effects of capsaicin on human leukemic cells have never been investigated. We investigated the effects of capsaicin on leukemic cells in vitro and in vivo and further examined the molecular mechanisms of capsaicin-induced apoptosis in myeloid leukemic cells. Capsaicin suppressed the growth of leukemic cells, but not normal bone marrow mononuclear cells, via induction of G0-G1 phase cell cycle arrest and apoptosis. Capsaicin-induced apoptosis was in association with the elevation of intracellular reactive oxygen species production. Interestingly, capsaicin-sensitive leukemic cells were possessed of wild-type p53, resulting in the phosphorylation of p53 at the Ser-15 residue by the treatment of capsaicin. Abrogation of p53 expression by the antisense oligonucleotides significantly attenuated capsaicin-induced cell cycle arrest and apoptosis. Pretreatment with the antioxidant N-acetyl-l-cystein and catalase, but not superoxide dismutase, completely inhibited capsaicin-induced apoptosis by inhibiting phosphorylation of Ser-15 residue of p53. Moreover, capsaicin effectively inhibited tumor growth and induced apoptosis in vivo using NOD/SCID mice with no toxic effects. We conclude that capsaicin has potential as a novel therapeutic agent for the treatment of leukemia.
Methicillin-Resistant<i>S. aureus</i>Infections among Patients in the Emergency Department
Authors: Gregory J. Moran, Anusha Krishnadasan, Rachel J. Gorwitz, Gregory E. Fosheim, Linda K. McDougal, Roberta B. Carey, David A. Talan
Journal: New England Journal of Medicine (2006)

Methicillin-resistant Staphylococcus aureus (MRSA) is increasingly recognized in infections among persons in the community without established risk factors for MRSA.We enrolled adult patients with acute, purulent skin and soft-tissue infections presenting to 11 university-affiliated emergency departments during the month of August 2004. Cultures were obtained, and clinical information was collected. Available S. aureus isolates were characterized by antimicrobial-susceptibility testing, pulsed-field gel electrophoresis, and detection of toxin genes. On MRSA isolates, we performed typing of the staphylococcal cassette chromosome mec (SCCmec), the genetic element that carries the mecA gene encoding methicillin resistance.S. aureus was isolated from 320 of 422 patients with skin and soft-tissue infections (76 percent). The prevalence of MRSA was 59 percent overall and ranged from 15 to 74 percent. Pulsed-field type USA300 isolates accounted for 97 percent of MRSA isolates; 74 percent of these were a single strain (USA300-0114). SCCmec type IV and the Panton-Valentine leukocidin toxin gene were detected in 98 percent of MRSA isolates. Other toxin genes were detected rarely. Among the MRSA isolates, 95 percent were susceptible to clindamycin, 6 percent to erythromycin, 60 percent to fluoroquinolones, 100 percent to rifampin and trimethoprim-sulfamethoxazole, and 92 percent to tetracycline. Antibiotic therapy was not concordant with the results of susceptibility testing in 100 of 175 patients with MRSA infection who received antibiotics (57 percent). Among methicillin-susceptible S. aureus isolates, 31 percent were USA300 and 42 percent contained pvl genes.MRSA is the most common identifiable cause of skin and soft-tissue infections among patients presenting to emergency departments in 11 U.S. cities. When antimicrobial therapy is indicated for the treatment of skin and soft-tissue infections, clinicians should consider obtaining cultures and modifying empirical therapy to provide MRSA coverage.
Dysregulation of the type I interferon system in adult‐onset clinically amyopathic dermatomyositis has a potential contribution to the development of interstitial lung disease
Authors: W.C. Sun, Y.C. Sun, H. Lin, B. Yan, G.X. Shi
Journal: British Journal of Dermatology (2012)

It has been speculated that viral infection might be one of the potential aetiologies for adult-onset clinically amyopathic dermatomyositis (CADM). The molecular pathogenesis remains largely unknown.To explore whether dysregulation of the type I interferon (IFN) system is involved in the pathogenesis of CADM.We studied 16 patients with CADM and compared them with healthy control subjects (n = 20) and patients with classic dermatomyositis (DM, n = 16) and polymyositis (PM, n = 16). Expressions of mRNA for serial toll-like receptor genes (TLR2, TLR3, TLR4, TLR7, TLR8 and TLR9) and type I IFN-regulated genes (IRF7, ISG15 and MxA) in peripheral blood leucocytes (PBL) were detected by real-time polymerase chain reaction analysis. The level of IFN-α in blood was tested by enzyme-linked immunosorbent assay.The mRNA expressions of TLR7, TLR9 and IRF7 were greatly elevated in the PBL from patients with CADM compared with controls. Upregulation of the ISG15 and MxA genes was detected in the PBL from patients with CADM, as well as from patients with classic DM. Among the four study groups, the overproduction of IFN-α in blood was most significant in the CADM group. Especially, IFN-α level was obviously high in the clinical interstitial lung disease (ILD) subgroup of patients with CADM. Positive correlations were found between IFN-α concentration and other unfavourable prognostic factors of CADM-associated ILD.Our data suggest that the dysregulation of the type I IFN system may be implicated in CADM pathogenesis. IFN-α may be a useful biomarker for assessing the disease severity of CADM-associated ILD.
ERG Is a Critical Regulator of Wnt/LEF1 Signaling in Prostate Cancer
Authors: Longtao Wu, Jonathan C. Zhao, Jung Kim, Hong-Jian Jin, Cun-Yu Wang, Jindan Yu
Journal: Cancer Research (2013)

Chromosomal translocations juxtaposing the androgen-responsive TMPRSS2 promoter with the ETS-family transcription factor ERG result in aberrant ERG upregulation in approximately 50% of prostate cancers. Studies to date have shown important roles of ERG in inducing oncogenic properties of prostate cancer. Its molecular mechanisms of action, however, are yet to be fully understood. Here, we report that ERG activates Wnt/LEF1 signaling cascade through multiple mechanisms. ERG bound to the promoters of various Wnt genes to directly increase ligand expression. Consequently, ERG overexpression increased active β-catenin level in the cells and enhanced TCF/LEF1 luciferase reporter activity, which could be partially blocked by WNT-3A inhibitor IWP-2. Most importantly, our data defined LEF1 as a direct target of ERG and that LEF1 inhibition fully abolished ERG-induced Wnt signaling and target gene expression. Furthermore, functional assays showed that Wnt/LEF1 activation phenocopied that of ERG in inducing cell growth, epithelial-to-mesenchymal transition, and cell invasion, whereas blockade of Wnt signaling attenuated these effects. Concordantly, LEF1 expression is significantly upregulated in ERG-high human prostate cancers. Overall, this study provides an important mechanism of activation of Wnt signaling in prostate cancer and nominates LEF1 as a critical mediator of ERG-induced tumorigenesis. Wnt/LEF1 pathway might provide novel targets for therapeutic management of patients with fusion-positive prostate cancer.
Abstract 1168: Identification of CNA signatures in prostate cancer: Narrowing chromosome regions related with occurrence, prognosis and recurrence after treatment
Authors: Tatiane C. Rodrigues, Felipe Carvalho, Ana C. V. Krepischi, Sergio Verjovski-Almeida, Carla Rosenberg
Journal: Cancer Research (2012)

Abstract Prostate cancer is the most common cancer in males and, despite its high incidence, only limited data are available on which genes or chromosome regions are specifically involved in its initiation and progression. We studied 72 prostate tumor samples by array-CGH, using a platform containing 60.000 oligonucleotides spread over the whole genome (60K Agilent Technologies). No chromosome alterations (CNA) were detected in 13 samples. The array-CGH profiles of the remaining samples showed losses at 8p and gains on 8q, often with narrow peaks of amplification, in ∼50% of the tumors. Additionally, losses at 6q, 13q and 16q were observed in ∼25% of the samples. Although these results are in general agreement with the location of alterations described earlier, the altered chromosome segments are often several megabases long. Mapping of minimum regions altered in several tumors, or pronounced copy number changes in smaller segments, permits a more precise definition of the relevant chromosome regions that are relevant for tumor development and progression. Current prognostic variables include prostatic specific antigen (PSA), the pathologically defined Gleason score (GS) and T-category (of the TNM staging). There is a great heterogeneity within the intermediate risk group and further genetic markers are needed to refine disease diagnosis and prognosis. So, we analyzed the copy number alteration signatures for the intermediate risk group, Gleason 7. In the comparison between samples related as GS 6 versus GS 7, we found that losses on 5q21.1 and gains on 7q11.21 are more frequent in GS 7. In other hand, losses on 22q13.33 are more frequent in GS 7 than in GS 8 and 9, while losses on 6q21 and 18q21 are correlated with GS 8 and 9. Additionally, we have medical follow-up of only 46 of the 72 samples. Fifteen of these patients had present recurrence after treatment. We analyzed this group versus the group with no recurrence. Losses at 2p21, 6q12, 7q36.3 and 16q13 are more frequent in the group of patients in which there is recurrence of the tumor. This suggests that these alterations could also be hallmarks for recurrence. Further studies with array-CGH of prostate tumors samples will ultimately lead to defining much smaller regions of overlap than at present, which in turn will indicate which specific individual genes and/or combinations of genes are the real “drivers” in prostate cancer or could act as hallmarks for prognosis and recurrence. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1168. doi:1538-7445.AM2012-1168
Human endothelial cell-lymphocyte interaction. Endothelial cells function as accessory cells necessary for mitogen-induced human T lymphocyte activation in vitro.
Authors: E R Ashida, A R Johnson, P E Lipsky
Journal: Journal of Clinical Investigation (1981)

Mitogen-stimulated human T cell activation is absolutely dependent on the participation of a nonresponding accessory cell. In populations of human peripheral blood mononuclear cells, monocytes function as the requisite accessory cells. The possibility that cultured endothelial cells (EC) might also function as accessory cells was studied by examining the potential of endothelial cells to restore mitogen responsiveness to monocyte-depleted human T cells. Highly purified T cells were prepared by isolating cells rosetting with sheep erythrocytes and removing monocyte contamination by glass adherence and nylon wool column passage. When cultured at low cell density, T cells failed to respond to stimulation with various mitogenic lectins, whereas co-culture with monocytes restored responsiveness. Similarly, EC obtained from umbilical vein, pulmonary artery, and ovarian vein restored the capacity of T cells to respond to mitogens. Mitogen-stimulated T cell activation required viable endothelial cells. Moreover, effective endothelial T cell cooperation appeared to involve the establishment of cell-to-cell contact between EC and responding T cells. Accessory cell function was not a nonspecific property of all tissue culture cells as evidenced by the finding that human foreskin fibroblasts, lung fibroblasts, and HeLa cells were unable to restore responsiveness to monocyte-depleted T cells. These observations indicate that endothelial cells can support the induction of mitogen-induced T cell activation and suggest that cells lining blood vessels may play an active role in the initiation of immune responses in vivo.