tbuckley/cabot-search huggingface dataset:
Oligodendrocyte Progenitor Cells Promote Neovascularization in Glioma by Disrupting the Blood–Brain Barrier
Authors: Yujie Huang, Caitlin Hoffman, Prajwal Rajappa, Joon-Hyung Kim, Wenhuo Hu, Jason Huse, Zhongshu Tang, Xuri Li, Babette Weksler, Jacqueline Bromberg, David C. Lyden, Jeffrey P. Greenfield
Journal: Cancer Research (2013)

Enhanced platelet-derived growth factor (PDGF) signaling in glioma drives its development and progression. In this study, we define a unique role for stroma-derived PDGF signaling in maintaining tumor homeostasis within the glioma microenvironment. Large numbers of PDGF receptor-α (PDGFRα)-expressing stromal cells derived from oligodendrocytes progenitor cells (OPC) were discovered at the invasive front of high-grade gliomas, in which they exhibited a unique perivascular distribution. In PDGFRα-deficient host mice, in which orthotopic Gl261 tumors displayed reduced outgrowth, we found that tumor-associated blood vessels displayed smaller lumens and normalized vascular morphology, with tumors in host animals injected with the vascular imaging agent gadolinium also being enhanced less avidly by MRI. Notably, glioma-associated OPC promoted endothelial sprouting and tubule formation, in part by abrogating the inhibitory effect that perivascular astrocytes exert on vascular endothelial conjunctions. Stromal-derived PDGF-CC was crucial for the recruitment and activation of OPC, insofar as mice genetically deficient in PDGF-CC phenocopied the glioma/vascular defects observed in PDGFRα-deficient mice. Clinically, we showed that higher levels of PDGF-CC in glioma specimens were associated with more rapid disease recurrence and poorer overall survival. Our findings define a PDGFRα/PDGF-CC signaling axis within the glioma stromal microenvironment that contributes to vascular remodeling and aberrant tumor angiogenesis in the brain.
Molecular Biology of Steroid Hormone Synthesis*
Authors: WALTER L. MILLER
Journal: Endocrine Reviews (1988)

STEROID hormones are familiar clinically and physiologically as regulators of physiological processes. Five groups of steroid hormones are generally recognized according to their physiological behavior: mineralocorticoids, which instruct the renal tubules to retain sodium; glucocorticoids, which are named for their carbohydratemobilizing properties but have many other effects as well; estrogens, which induce female secondary sexual characteristics; progestins, which are essential for reproduction; and androgens, which induce male secondary sexual characteristics. These classes of steroid hormones are structurally similar and arise from a common series of pathways. They are distinguished by their actions on one or more specific steroid hormone receptors. The hormone/receptor complexes function as tissue-specific transcriptional regulators of distinct domains of genes and, consequently, exert their broad array of physiological effects. (For reviews, see Refs. 1 and 2.) The pathways by which these steroid hormones are produced from cholesterol were initially studied by studying the structures of the steroids themselves. Over the past 30 yr, studies of enzyme kinetics and of steroidal precursorproduct relationships have led to the widely held belief that a very large number of distinct enzymes are involved in the conversion of cholesterol and its esters to active steroid hormones. The application of modern protein chemistry and molecular biology to these questions has radically changed this view.
Intravenous Iron Optimizes the Response to Recombinant Human Erythropoietin in Cancer Patients With Chemotherapy-Related Anemia: A Multicenter, Open-Label, Randomized Trial
Authors: Michael Auerbach, Harold Ballard, J. Richard Trout, Marilyn McIlwain, Alan Ackerman, Huzefa Bahrain, Stefan Balan, Lance Barker, Jeevindra Rana
Journal: Journal of Clinical Oncology (2004)

Purpose Recombinant human erythropoietin (rHuEPO) is the standard of care for patients with chemotherapy-related anemia. Intravenous (IV) iron improves hemoglobin (Hb) response and decreases dosage requirements in patients with anemia of kidney disease, but its effect has not been studied in randomized trials in cancer patients. Methods This prospective, multicenter, open-label, randomized trial enrolled 157 patients with chemotherapy-related anemia (Hb ≤ 105 g/L, serum ferritin ≤ 450 pmol/L or ≤ 675 pmol/L with transferrin saturation ≤ 19%) receiving subcutaneously rHuEPO 40,000 U once weekly to: (1) no-iron; (2) oral iron 325 mg twice daily; (3) iron dextran repeated 100mg IV bolus; or (4) iron dextran total dose infusion (TDI). Hb and quality of life (QOL) were measured at baseline and throughout. Results All groups showed Hb (P &lt; .0001) increases from baseline. Mean Hb increases for both IV iron groups were greater (P &lt; .02) than for no-iron and oral iron groups. The percentage of patients with hematopoietic responses was higher (P &lt; .01) in both IV iron groups (each case 68%) compared with no-iron (25%) and oral iron (36%) groups. IV iron groups showed increases in energy, activity, and overall QOL from baseline, compared with a decrease in energy and activity for no-iron group and no change in activity or overall QOL for oral iron group. Conclusion rHuEPO increases Hb levels and improves QOL in patients with chemotherapy-related anemia. Magnitude of Hb increase and QOL improvement is significantly greater if IV iron is added.
Differential Effect of Bryostatin 1 and Phorbol 12-Myristate 13-Acetate on HOP-92 Cell Proliferation Is Mediated by Down-regulation of Protein Kinase Cδ
Authors: Sung Hee Choi, Tehila Hyman, Peter M. Blumberg
Journal: Cancer Research (2006)

Abstract Bryostatin 1 is currently in clinical trials as a cancer chemotherapeutic agent. Although bryostatin 1, like phorbol 12-myristate 13-acetate (PMA), is a potent activator of protein kinase C (PKC), it induces only a subset of those responses induced by PMA and antagonizes others. We report that, in the HOP-92 non–small cell lung cancer line, bryostatin 1 induced a biphasic proliferative response, with maximal proliferation at 1 to 10 nmol/L. This biphasic response mirrored a biphasic suppression of the level of PKCδ protein, with maximal suppression likewise at 1 to 10 nmol/L bryostatin 1. The typical phorbol ester PMA, in contrast to bryostatin 1, had no effect on the level of PKCδ and modest suppression of cell proliferation, particularly evident at later treatment times. Flow cytometric analysis revealed changes in the fraction of cells in the G0-G1 and S phases corresponding to the effects on proliferation. Cells overexpressing PKCδ exhibited a lower rate of cell proliferation compared with control untreated cells and showed neither a proliferative response nor a loss of PKCδ in response to bryostatin 1. Conversely, treatment with PKCδ small interfering RNA significantly increased the cellular growth compared with controls. We conclude that the differential effect on cellular proliferation induced by bryostatin 1 compared with PMA reflects the differential suppression of PKCδ. (Cancer Res 2006; 66(14): 7261-9)
High-Dose Atorvastatin Enhances the Decline in Inflammatory Markers in Patients With Acute Coronary Syndromes in the MIRACL Study
Authors: Scott Kinlay, Gregory G. Schwartz, Anders G. Olsson, Nader Rifai, Sally J. Leslie, William J. Sasiela, Michael Szarek, Peter Libby, Peter Ganz
Journal: Circulation (2003)

Inflammation promotes acute coronary syndromes and ensuing clinical complications. Although statins reduce inflammatory markers in asymptomatic adults or in patients with stable angina, the effect of statins on the markedly heightened inflammation in patients with acute coronary syndromes is unknown.We measured C-reactive protein (CRP), serum amyloid A (SAA), and interleukin 6 (IL-6) in 2402 subjects enrolled the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study. Subjects with unstable angina or non-Q-wave myocardial infarction were randomized to atorvastatin 80 mg/d or placebo within 24 to 96 hours of hospital admission and treated for 16 weeks. The effect of treatment on inflammatory markers was assessed by ANCOVA after adjustment for presenting syndrome, country, and initial level of marker. All 3 markers were markedly elevated at randomization and declined over the 16 weeks in both treatment groups. Compared with placebo, atorvastatin significantly reduced CRP, -83% (95% CI, -84%, -81%) versus -74% (95% CI, -75%, -71%) (P<0.0001) and SAA, -80% (95% CI, -82%, -78%) versus -77% (-79%, -75%) (P=0.0006) but not IL-6, -55% (95% CI, -57%, -53%) versus -53% (95% CI, -55%, -51%) (P=0.3). Reductions in CRP and SAA were observed in patients with unstable angina and non-Q-wave myocardial infarction, with initial LDL cholesterol <3.2 or > or =3.2 mmol/L (125 mg/dL), age > or =65 or <65 years, and in men and women. By 16 weeks, CRP was 34% lower with atorvastatin than with placebo.High-dose atorvastatin potentiated the decline in inflammation in patients with acute coronary syndromes. This supports the value of early statin therapy in these patients.
Expectations for Weight Loss and Willingness to Accept Risk Among Patients Seeking Weight Loss Surgery
Authors: Christina C. Wee, Mary Beth Hamel, Caroline M. Apovian, George L. Blackburn, Dragana Bolcic-Jankovic, Mary Ellen Colten, Donald T. Hess, Karen W. Huskey, Edward R. Marcantonio, Benjamin E. Schneider, Daniel B. Jones
Journal: JAMA Surgery (2013)

Weight loss surgery (WLS) has been shown to produce long-term weight loss but is not risk free or universally effective. The weight loss expectations and willingness to undergo perioperative risk among patients seeking WLS remain unknown.To examine the expectations and motivations of WLS patients and the mortality risks they are willing to undertake and to explore the demographic characteristics, clinical factors, and patient perceptions associated with high weight loss expectations and willingness to assume high surgical risk.We interviewed patients seeking WLS and conducted multivariable analyses to examine the characteristics associated with high weight loss expectations and the acceptance of mortality risks of 10% or higher.Two WLS centers in Boston.Six hundred fifty-four patients.Disappointment with a sustained weight loss of 20% and willingness to accept a mortality risk of 10% or higher with WLS.On average, patients expected to lose as much as 38% of their weight after WLS and expressed disappointment if they did not lose at least 26%. Most patients (84.8%) accepted some risk of dying to undergo WLS, but only 57.5% were willing to undergo a hypothetical treatment that produced a 20% weight loss. The mean acceptable mortality risk to undergo WLS was 6.7%, but the median risk was only 0.1%; 19.5% of all patients were willing to accept a risk of at least 10%. Women were more likely than men to be disappointed with a 20% weight loss but were less likely to accept high mortality risk. After initial adjustment, white patients appeared more likely than African American patients to have high weight loss expectations and to be willing to accept high risk. Patients with lower quality-of-life scores and those who perceived needing to lose more than 10% and 20% of weight to achieve "any" health benefits were more likely to have unrealistic weight loss expectations. Low quality-of-life scores were also associated with willingness to accept high risk.Most patients seeking WLS have high weight loss expectations and believe they need to lose substantial weight to derive any health benefits. Educational efforts may be necessary to align expectations with clinical reality.
Molecular Profiling of Gastric Cancer: Toward Personalized Cancer Medicine
Authors: Lincoln D. Nadauld, James M. Ford
Journal: Journal of Clinical Oncology (2013)

Gastric cancer is the fourth most common cancer worldwide and the second leading cause of global cancer deaths.The prognosis of patients diagnosed with gastric cancer continues to be dismal, despite improving surgical and adjuvant treatment approaches, with a 5-year overall survival less than 25%. 1,2The high disease incidence and poor outcomes continue to make gastric cancer a topic of active clinical and basic scientific research.Notwithstanding these efforts, relatively little is known about the molecular changes that contribute to the development of this deadly disease and how they may influence outcomes and therapeutic results.Gastric cancer can be considered a multifactorial disease because many inherited and environmental factors play a role in its carcinogenesis, including the genetic background of the host, infectious agents such as Helicobacter pylori, and dietary habits.Gastric cancer is a heterogeneous disorder that can be divided into at least the following two main histologic types on the basis of the Lauren classification: intestinal and diffuse types. 3These two types have distinct morphologic, clinical, and epidemiologic features and may also represent a different molecular mechanism of tumor development and progression.The identification of germline E-cadherin (CDH1) mutations in families with hereditary diffuse gastric cancer provided early insight into the initial changes that promote gastric tumorigenesis and established CDH1 as a bona fide tumor suppressor. 4Subsequent studies indicated that, although germline CDH1 mutations are common in hereditary gastric cancer of the diffuse, but not intestinal, type, somatic mutations in CDH1 are frequently identified in sporadic gastric cancer of both major histologic subtypes. 3In addition, somatic epigenetic alterations, such as CDH1 promoter hypermethylation, are present in diffuse-and intestinal-type tumors and result in gene silencing.This epigenetic silencing of CDH1 gene expression represents the "second hit" in approximately 50% of hereditary diffuse gastric cancers, 5 whereas the prevalence of CDH1 promoter hypermethylation in sporadic gastric cancers ranges in estimates from 11% to 46% depending on the histologic subtype. 6elatively small sample sizes and a focus on hereditary cancers or a single histologic subtype have hampered previous studies that evaluated the prevalence of CDH1 somatic mutations in gastric cancer overall.The current study by Corso et al 7 evaluated a large set of familial and sporadic gastric cancers to provide a more comprehensive analysis of the prevalence of CDH1 somatic mutations and their correlation with patient survival.The authors analyzed 246 patients with
Human Serum Dopamine-β-Hydroxylase: Relationship to Hypertension and Sympathetic Activity
Authors: DAVID HORWITX, R. WAYNE ALEXANDER, WALTER LOVENBERG, HARRY R. KEISER
Journal: Circulation Research (1973)

Serum dopamine-β-hydroxylase activity varied from 3 to 581 units/ml in a group of 168 untreated adults (90 normals, 78 with borderline or overt hypertension). Levels did not correlate with blood pressure or age, but mean values were significantly lower in blacks than they were in whites. Subjects with exceptionally low levels of serum dopamine-β-hydroxylase activity showed normal cardiovascular function and normal β-hydroxylation of an administered synthetic substrate, hydroxyamphetamine. Pronounced blood pressure reduction by antihypertensive drugs did not change serum dopamine-β-hydroxylase activity, and intensive bicycle exercise produced only small and variable increases. Two subjects with severe sympathetic dysfunction, i.e., orthostatic hypotension, showed normal levels of dopamine-β-hydroxylase activity (89-123 units/ml). Serum dopamine-β-hydroxylase activity varied from 450 to 950 units/ml in five subjects with pheochromocytomas and decreased to one-tenth the preoperative level in one subject who underwent curative surgery. Therefore, serum dopamine-β-hydroxylase activity is not a satisfactory index of sympathetic function; moreover, activity levels do not correlate with prevailing blood pressure. Subjects with pheochromocytomas, however, may show increased serum levels of the enzyme, which demonstrates that such tumors can release dopamine-β-hydroxylase.
Mediastinoscopy: An Endangered Species?
Authors: Valerie W. Rusch
Journal: Journal of Clinical Oncology (2005)

Accurate staging is a critical part of the management of newly diagnosed non-small-cell lung cancer (NSCLC), and of the decision to offer patients induction therapy.During the last decade, the introduction into clinical practice of positron emission tomography (PET) and of endoscopic ultrasound biopsy techniques has again raised the question of when mediastinoscopy, long the gold standard for determining the presence and extent of mediastinal nodal metastases, should be performed.In this edition of the Journal of Clinical Oncology, two articles address this issue.Pozo-Rodriguez et al 1 report a prospective study in 132 patients comparing the efficacy of helical computed tomography (CT) and PET in the mediastinal staging of NSCLC.They find that CT and PET have similar accuracies and, when combined, yield a negative predictive probability of .98.Conversely, they note that positive results of either test need to be confirmed pathologically.In the second article, Annema et al 2 evaluated endoscopic ultrasound-guided fine-needle aspiration (EUS FNA) in the diagnosis and staging of lung cancer in 242 consecutive patients for whom mediastinoscopy or exploratory thoracotomy were planned.EUS FNA prevented 70% of scheduled surgical procedures, and the accuracy of this procedure in mediastinal staging was found to be 93%.How does the practicing clinician incorporate this information into daily practice?First, it is important to note that these are not the first studies to highlight the utility of PET and EUS in the staging of NSCLC.4][5][6][7][8] Table 6 in the article by Pozo-Rodriguez et al 1 summarizes some of the most relevant articles published on CT and PET in NSCLC since 1980.However, the authors correctly point out that their trial was more stringently designed than many previous studies, and benefited from the readings of CT and PET being blinded and independent both of each other and of the reference tests.A long follow-up period allowed clinical confirmation of the study findings.Multiple articles already attest to the safety and accuracy of EUS FNA in detecting mediastinal lymph node metastases and mediastinal tumor invasion in NSCLC.
Pathophysiology of adenomyosis
Authors: A Ferenczy
Journal: Human Reproduction Update (1998)

Adenomyosis refers to endometrial glands and stroma located haphazardly deep within the myometrium. Similar histological alterations may be found in extra-uterine locations such as the rectovaginal septum. The aetiology and pathogenic mechanism(s) responsible for adenomyosis are poorly understood. Both human and experimental studies favour the theory of endomyometrial invagination of the endometrium, although the de-novo development of adenomyosis from Müllerian rests in an extrauterine location is a possibility. The prerequisite for adenomyosis may be triggered or facilitated by either a 'weakness of the smooth muscle tissue or an increased intrauterine pressure or both. Relatively high oestrogen concentrations and impaired immune-related growth control in ectopic endometrium may be necessary for the maintenance of adenomyosis. Smooth muscle cell hyperplasia and hypertrophy are a reflection of reactive change secondary to ectopic endometrial proliferation. Further studies are needed for insight into the precise aetiology and pathogenesis of adenomyosis. Adenomyosis is a relatively frequent endomyometrial pathology discovered in multiparous women between 40 and 50 years of age. About 2/3 of women are symptomatic with menorrhagia and dysmenorrhoea; 80% of adenomyotic cases are associated with leiomyomata uteri; and in women with endometrial adenocarcinoma, adenomyosis is relatively often seen. Definite diagnosis is made on hysterectomy specimens, although attempts are made at securing preoperative diagnosis by magnetic resonance imaging and myometrial biopsies. Definite treatment of symptomatic women is hysterectomy.
Studies on T cell maturation on defined thymic stromal cell populations in vitro.
Authors: E J Jenkinson, G Anderson, J J Owen
Journal: The Journal of Experimental Medicine (1992)

We describe an in vitro system in which positive selection of developing T cells takes place on defined stromal cell preparations, which include major histocompatibility complex class II+ epithelial cells but exclude cells of bone marrow origin. In this system, maturation of double-positive T cell receptor negative (TCR-), CD4+8+ thymocytes into single-positive TCR+, CD4+ and CD8+ cells takes place together with the development of functional competence. As in vivo, this maturation is associated with the upregulation of TCR levels as cells progress from double-positive to single-positive status. We also show that class II+ epithelial cells in these cultures are less efficient than dendritic cells in mediating the deletion (negative selection) of V beta 8+ cells by the superantigen staphylococcal enterotoxin B. For the first time, this approach provides a model in which the cellular interactions involved in both positive and negative selection can be studied under controlled in vitro conditions.
Influence of histological subtypes on the risk of an invasive recurrence in a large series of stage I borderline ovarian tumor including 191 conservative treatments
Authors: C. Uzan, M. Nikpayam, L. Ribassin-Majed, S. Gouy, S. Bendifallah, A. Cortez, A. Rey, P. Duvillard, E. Darai, P. Morice
Journal: Annals of Oncology (2014)
Differences in Parent-Provider Concordance Regarding Prognosis and Goals of Care Among Children With Advanced Cancer
Authors: Abby R. Rosenberg, Liliana Orellana, Tammy I. Kang, J. Russell Geyer, Chris Feudtner, Veronica Dussel, Joanne Wolfe
Journal: Journal of Clinical Oncology (2014)

Purpose Concordance between parents of children with advanced cancer and health care providers has not been described. We aimed to describe parent-provider concordance regarding prognosis and goals of care, including differences by cancer type. Patients and Methods A total of 104 pediatric patients with recurrent or refractory cancer were enrolled at three large children's hospitals. On enrollment, their parents and providers were invited to complete a survey assessing perceived prognosis and goals of care. Patients' survival status was retrospectively abstracted from medical records. Concordance was assessed via discrepancies in perceived prognosis, κ statistics, and McNemar's test. Distribution of categorical variables and survival rates across cancer type were compared with Fisher's exact and log-rank tests, respectively. Results Data were available from 77 dyads (74% of enrolled). Parent-provider agreement regarding prognosis and goals of care was poor (κ, 0.12 to 0.30). Parents were more likely to report cure was likely (P &lt; .001). The frequency of perceived likelihood of cure and the goal of cure varied by cancer type for both parents and providers (P &lt; .001 to .004). Relatively optimistic responses were more common among parents and providers of patients with hematologic malignancies, although there were no differences in survival. Conclusion Parent-provider concordance regarding prognosis and goals in advanced pediatric cancer is generally poor. Perceptions of prognosis and goals of care vary by cancer type. Understanding these differences may inform parent-provider communication and decision making.