tbuckley/cabot-search huggingface dataset:
Iron in sickle cell disease: A review why less is better
Authors: Prasad Rao Koduri
Journal: American Journal of Hematology (2003)

Abstract Sickle cell anemia (SCA) is an inherited disorder of hemoglobin synthesis that is characterized by life‐long severe hemolytic anemia, attacks of pain crisis, and chronic organ system damage. A third of the hemolysis in SCA is intravascular and the resulting urinary losses of iron may lead to iron deficiency. There is no evidence of iron overload in SCA and iron deficiency may be more common than suspected, especially in men. Absence of bone marrow iron remains a gold standard for the diagnosis of iron deficiency in these patients. Although low serum ferritin is highly specific for the diagnosis of iron deficiency, its sensitivity is quite low in SCA because of non‐specific elevation due to increased red cell turnover. The kinetics of sickling is strongly concentration dependent such that small decreases in the mean corpuscular deoxyhemoglobin‐S concentration (MCHC‐S) cause a substantial delay in sickle hemoglobin polymerization. Prolongation of the ‘delay time of gelation’ in excess of the capillary transit time may allow the erythrocyte to traverse the capillary bed to escape to the arterial side before there is rheologic impairment of the erythrocyte from polymerization of sickle hemoglobin. Overt iron deficiency lowers the MCHC‐S and thereby decreases the sickling tendency and the severity of hemolysis. The clinical improvement in SCA following the induction of iron deficient erythropoiesis by repeated phlebotomies or by erythrocytapheresis has been reported. Prospective controlled studies are needed to evaluate further, the therapeutic strategy of inducing controlled iron‐deficient erythropoiesis in selected patients witb SCA. Am. J. Hematol. 73:59–63, 2003. © 2003 Wiley‐Liss, Inc.
P254 Once-daily Tiotropium And Olodaterol Fixed-dose Combination Via The Respimat(R) Improves Outcomes Versus Mono-components In Copd In Two 1-year Studies
Authors: R. Buhl, E. Derom, G. Ferguson, E. Pizzichini, J. Reid, H. Watz, L. Gronke, A. Hamilton, K. Tetzlaff, L. Korducki, H. Huisman, S. Waitere-Wijker, F. Maltais
Journal: Thorax (2014)

<h3>Introduction</h3> Tiotropium (T), a once-daily long-acting muscarinic antagonist, is a well-established first-line maintenance treatment in chronic obstructive pulmonary disease (COPD); olodaterol (O) is a once-daily long-acting β<sub>2</sub>-agonist that has recently gained approval in several countries. Two Phase III replicate pivotal studies assessed the efficacy and safety of fixed-dose combinations of T and O (T+O) delivered via Respimat<sup>®</sup> Soft Mist™ inhaler in patients with GOLD 2–4 COPD. <h3>Methods</h3> Two 52-week, double-blind, parallel-group studies randomised 5162 patients to O 5 µg, T 2.5 µg, T 5 µg, T+O 2.5/5 µg or T+O 5/5 µg. Primary efficacy end points were trough forced expiratory volume in 1 second (FEV<sub>1</sub>) response (ie change from baseline), FEV<sub>1</sub> area under the curve from 0–3 h and St George’s Respiratory Questionnaire (SGRQ) total score after 24 weeks. Pooled data from the two studies are presented here; lung function from the individual studies will subsequently be provided. <h3>Results</h3> All treatments resulted in clinically relevant improvements in lung function, with significant increases with both T+O doses over the individual components (p1 responses were 0.055 L (O 5 µg), 0.073 L (T 2.5 µg), 0.080 L (T 5 µg), 0.118 L (T+O 2.5/5 µg) and 0.140 L (T+O 5/5 µg). SGRQ total scores improved by 5.1 (O 5 µg), 5.7 (T 2.5 µg), 5.6 (T 5 µg), 6.2 (T+O 2.5/5 µg) and 6.8 points (T+O 5/5 µg); differences between T+O 5/5 µg and O 5 µg and T 5 µg were statistically significant (p <h3>Conclusions</h3> T+O 5/5 µg significantly improved lung function and provided symptomatic benefit over O 5 µg and T 5 µg.
T-cell migration into allografts.
Authors: A K Bhan, C L Reinisch, R H Levey, R T McCluskey, S F Schlossman
Journal: The Journal of Experimental Medicine (1975)

The ability of T and B lymphocytes to migrate into skin allografts undergoing rejection was studied in mice. Spleen cells from CBA/J mice sensitized to transplantation antigens of A/J or C57BL/6 mice were separated on immunabsorbent columns into purified populations of T and B cells, labeled in vitro with 3H-uridine and injected intravenously into CBA/J mice with 7-day old skin iso and allografts (A/J or C57BL/6). The mice were sacrificed 24 h later and studied by autoradiography. After transfer of either unfractionated spleen cells or T cells, large numbers of labeled cells were found in the cellular infiltrate of allografts, whereas extremely few were seen in isografts. In contrast, after transfer of B cells, almost no labeled cells were detected either in the allografts or the isografts, although they, like T cells, homed normally to lymphoid tissue.
Inhibition of 7,12-Dimethylbenz(<i>a</i>)anthracene-Induced Skin Tumorigenesis in C57BL/6 Mice by Sulforaphane Is Mediated by Nuclear Factor E2–Related Factor 2
Authors: Changjiang Xu, Mou-Tuan Huang, Guoxiang Shen, Xiaoling Yuan, Wen Lin, Tin Oo Khor, Allan H. Conney, Ah-Ng Tony Kong
Journal: Cancer Research (2006)

Sulforaphane, a dietary isothiocyanate, possesses potent chemopreventive effects through the induction of cellular detoxifying/antioxidant enzymes via the transcription factor nuclear factor E2-related factor 2 (Nrf2). To investigate carcinogenesis mechanisms related to the regulation of Nrf2, we examined the tumor incidence and tumor numbers per mouse in Nrf2 wild-type (+/+) and Nrf2 knockout (-/-) mice. 7,12-Dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate treatments resulted in an increase in the incidence of skin tumors and tumor numbers per mouse in both genotypes; however, both indices were markedly higher in Nrf2(-/-) mice as compared with Nrf2(+/+) mice. Western blot analysis revealed that Nrf2 as well as heme oxygenase-1, a protein regulated by Nrf2 were not expressed in skin tumors from mice of either genotype, whereas expression of heme oxygenase-1 in Nrf2(+/+) mice was much higher than that in Nrf2(-/-) mice in nontumor skin samples. Next, we examined the chemopreventive efficacy of sulforaphane in mice with both genotypes. Topical application of 100 nmol of sulforaphane once a day for 14 days prior to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate applications decreased the incidence of skin tumor in the Nrf2(+/+) mice when compared with the vehicle-treated group. Importantly, there was no chemoprotective effect elicited by sulforaphane pretreatment in the Nrf2(-/-) mice group. Taken together, our results show for the first time that Nrf2(-/-) mice are more susceptible to skin tumorigenesis and that the chemopreventive effects of sulforaphane are mediated, at least in part, through Nrf2.
Efficacy and safety of combination etanercept and methotrexate versus etanercept alone in patients with rheumatoid arthritis with an inadequate response to methotrexate: the ADORE study
Authors: P L C M van Riel, A J Taggart, J Sany, M Gaubitz, H W Nab, R Pedersen, B Freundlich, D MacPeek
Journal: Annals of the Rheumatic Diseases (2006)

To evaluate the efficacy and safety of etanercept (ETN) monotherapy compared with combination ETN and methotrexate (MTX) treatment in patients with rheumatoid arthritis who had an inadequate response to MTX monotherapy. (The response was defined by the presence of Disease Activity Score-28 joint count (DAS28) >or=3.2 or a combination of >or=5 swollen joints, >or=5 painful joints and erythrocyte sedimentation rate >or=10 mm/h.)
Abstract A53: Bayesian Network Inference Modeling Reveals Novel Regulators of Cell Cycle Progression and Survival
Authors: Rina Gendelman, Heming Xing, Preeti Sarde, Olga K. Mirzoeva, Heidi Feiler, Joe W. Gray, Paul McDonagh, Iya Khalil, W. Michael Korn
Journal: Clinical Cancer Research (2012)

Abstract Molecular networks governing responses to targeted therapies in cancer cells are complex dynamic systems that demonstrate non-intuitive behaviors. We applied a novel computational strategy to decipher causal relationships between signaling network components. Gene networks were constructed from global gene expression profiles to model G1-S cell cycle arrest as a consequence of inhibition of MEK, a key component of the oncogenic RAF-MEK-ERK signal transduction pathway. Simulation of causally driven models generated a ranked list of 12 testable hypotheses, which confirmed role of known cell cycle regulators (CCND1, CCNE2, and CDC25A) and identified novel drivers of G1-S transition (IER2, TRIB1, C14ORF133). Validation confirmed 11 out 12 predictions. Second model which inferred causal relationships between genes lead to discovery of TRIB1 (tribbles homolog of Drosophila) as a regulator of NFkB-dependent gene expression. TRIB1 also mediates cross-talk to the NFκB pathway by enhancing p100 and IκBα-phosphorylation and degradation thus regulating cell survival and expression of cytokines crucial for tumor-stroma interaction. In agreement with this, knock-down of TRIB1 results in induction of apoptosis and sensitizes cells to cell killing induced by the death-receptor agonist TRAIL via upregulation of TRAIL receptor, DR5. Thus TRIB1 is a central regulator of cell cycle and survival and represents a potential therapeutic target. Therefore, applying REFS (Reverse Engineering Forward Simulation) to analyze gene expression profiles maximizes our ability to extract knowledge from experimental data.
Sociopathy and sociobiology: Biological units and behavioral units
Authors: Carl J. Erickson
Journal: Behavioral and Brain Sciences (1995)

Abstract Behavioral biologists have long sought to link behavioral units (e.g., aggression, depression, sociopathy) with biological units (e.g., genes, neurotransmitters, hormones, neuroanatomical loci). These units, originally contrived for descriptive purposes, often lead to misunderstandings when they are reified for purposes of causal analysis. This genetic and biochemical explanation for sociopathy reflects such problems.
Vision of the Aging Patient
Authors: Albert E. Sloane
Journal: JAMA (1962)

Fifteen authors combine to make this book a worthwhile addition to every ophthalmological library. The contributors include Ph.D.'s and optometrists. All have in common a background of extensive teaching and academic interest. Since this book is optometrically slanted, there will be those who will disagree with many points, but the indisputable worth of the book outbalances the dissension. The section on pathology of the eye is sparse which is to be expected when one tries to condense this subject into 2 short chapters. An excellent general introduction including social implications paves the way for interesting chapters on physiology, visual acuity, refraction, and accommodation aspects of the aging. There is a section on partial vision and optical aids. The special problem of adjusting spectacles is considered. Contact lenses are discussed as well as the problems and opportunities for rehabilitation. In all, there are 17 chapters and a bibliography. The reader cannot
Stem-Cell Politics
Authors: Susan Okie
Journal: New England Journal of Medicine (2006)

Interview with former Senator John Danforth on the politics of stem-cell research. (05:20)Download In Missouri this election season, former Republican Senator John Danforth, an Episcopal priest and abortion opponent, is citing the New Testament in support of a state constitutional amendment protecting the legality of human embryonic stem-cell research. "I find nothing in the Bible that tells me that cells in a lab dish are people," said Danforth, who lost a brother to amyotrophic lateral sclerosis and believes that the research will lead to new treatments for diseases. "What I do find in the Gospels is an emphasis on healing — relieving people of their suffering."In Wisconsin, where human embryonic stem cells . . .
Hyperglycemic Crises in Adult Patients With Diabetes: A Consensus Statement From the American Diabetes Association
Authors: Abbas E. Kitabchi, Guillermo E. Umpierrez, Mary B. Murphy, Robert A. Kreisberg
Journal: Diabetes Care (2007)

In response to the comments by Dr. Rosival (1), we point out that impaired mental status is present in 52% of adult patients with diabetic ketoacidosis (DKA) and 74% of patients with hyperglycemic hyperosmolar syndrome (HHS) (2). Although most patients are lethargic or stuporous on arrival, 13% of admissions for DKA and 23% for HHS present with loss of consciousness. In previous reports (3–6), we evaluated the relationship between the initial biochemical data and level of consciousness in adult patients with DKA (4). In 1980, we reported that age, admission plasma …
Optimizing Prostate Cancer Treatment by Combining Local Radiation Therapy with Systemic Vaccination
Authors: Howard L. Kaufman, Chaitanya R. Divgi
Journal: Clinical Cancer Research (2005)

Prostate cancer is the most common malignancy in men and recurs in up to 30% to 40% of patients within 10 years of diagnosis despite initial treatment by prostatectomy or radiation therapy ([1][1]). This suggests that primary treatment may be limited by failing to address occult metastatic disease
Urinary Tract Infection in Male Veterans
Authors: Dimitri M. Drekonja, Thomas S. Rector, Andrea Cutting, James R. Johnson
Journal: JAMA Internal Medicine (2012)

Lengthier antimicrobial therapy is associated with increased costs, antimicrobial resistance, and adverse drug events. Therefore, establishing minimum effective antimicrobial treatment durations is an important public health goal. The optimal treatment duration and current treatment patterns for urinary tract infection (UTI) in men are unknown. We used Veterans Affairs administrative data to study male UTI treatment and outcomes.Male UTI episodes in the Veterans Affairs system (fiscal year 2009) were identified by combining International Classification of Diseases, Ninth Revision codes with UTI-relevant antimicrobial prescriptions. Episodes were categorized as index, early recurrence (<30 days), or late recurrence (≥30 days) cases. Drug name, treatment duration, and outcomes (recurrence and Clostridium difficile infection during 12 months) were recorded for index cases. Demographic, clinical, and treatment characteristics were assessed for associations with outcomes in univariate and multivariate analyses.Among 4 854 765 outpatient male veterans, 39 149 UTI episodes involving 33 336 unique patients were identified, including 33 336 index cases (85.2%), 1772 early recurrences (4.5%), and 4041 late recurrences (10.3%). Highest-use antimicrobial agents were ciprofloxacin (62.7%) and trimethoprim-sulfamethoxazole (26.8%); 35.0% of patients received shorter-duration treatment (≤7 days), and 65.0% of patients received longer-duration treatment (>7 days). Of the index cases, 4.1% were followed by early recurrence and 9.9% by late recurrence. Longer-duration treatment was not associated with a reduction in early or late recurrence but was associated with increased late recurrence compared with shorter-duration treatment (10.8% vs 8.4%, P < .001), including in multivariate analysis (odds ratio, 1.20; 95% CI, 1.10-1.30). In addition, C difficile infection risk was significantly higher with longer-duration vs shorter-duration treatment (0.5% vs 0.3%, P = .02) and exhibited a similar suggestive trend in multivariate analysis (odds ratio, 1.42; 95% CI, 0.97-2.07).Longer-duration treatment (>7 days) for male UTI in the outpatient setting was associated with no reduction in early or late recurrence.
Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett's oesophagus
Authors: S J Leedham, S L Preston, S A C McDonald, G Elia, P Bhandari, D Poller, R Harrison, M R Novelli, J A Jankowski, N A Wright
Journal: Gut (2008)

Current models of clonal expansion in human Barrett's oesophagus are based upon heterogenous, flow-purified biopsy analysis taken at multiple segment levels. Detection of identical mutation fingerprints from these biopsy samples led to the proposal that a mutated clone with a selective advantage can clonally expand to fill an entire Barrett's segment at the expense of competing clones (selective sweep to fixation model). We aimed to assess clonality at a much higher resolution by microdissecting and genetically analysing individual crypts. The histogenesis of Barrett's metaplasia and neo-squamous islands has never been demonstrated. We investigated the oesophageal gland squamous ducts as the source of both epithelial sub-types.Individual crypts across Barrett's biopsy and oesophagectomy blocks were dissected. Determination of tumour suppressor gene loss of heterozygosity patterns, p16 and p53 point mutations were carried out on a crypt-by-crypt basis. Cases of contiguous neo-squamous islands and columnar metaplasia with oesophageal squamous ducts were identified. Tissues were isolated by laser capture microdissection and genetically analysed.Individual crypt dissection revealed mutation patterns that were masked in whole biopsy analysis. Dissection across oesophagectomy specimens demonstrated marked clonal heterogeneity, with multiple independent clones present. We identified a p16 point mutation arising in the squamous epithelium of the oesophageal gland duct, which was also present in a contiguous metaplastic crypt, whereas neo-squamous islands arising from squamous ducts were wild-type with respect to surrounding Barrett's dysplasia.By studying clonality at the crypt level we demonstrate that Barrett's heterogeneity arises from multiple independent clones, in contrast to the selective sweep to fixation model of clonal expansion previously described. We suggest that the squamous gland ducts situated throughout the oesophagus are the source of a progenitor cell that may be susceptible to gene mutation resulting in conversion to Barrett's metaplastic epithelium. Additionally, these data suggest that wild-type ducts may be the source of neo-squamous islands.
GENDER SPECIFIC ROLE OF HABITUAL PHYSICAL ACTIVITY ON VENTRICULAR REPOLARIZATION AMONG MIDDLE AGED AND ELDERLY INDIVIDUALS. THE IKARIA STUDY
Authors: Evangelos Oikonomou, Christina Chrysohoou, Dimitris Tsiachris, Gerasimos Siasos, Georgia Vogiatzi, Elias Gialafos, Dimitris Maragiannis, Kyriakos Dimitriadis, Christos Pitsavos, Christodoulos Stefanadis
Journal: Journal of the American College of Cardiology (2011)
Surgical treatment of colorectal metastases to the liver
Authors: Y. Fong, L. H. Blumgart, A. M. Cohen
Journal: CA A Cancer Journal for Clinicians (1995)

Up to one fourth of patients diagnosed with colorectal cancer present with liver metastases, and by the time of death, up to 70 percent of patients with colorectal cancer have metastatic disease to the liver. At present, surgical excision is the standard therapy for resectable liver metastases from colorectal primaries. This article reviews the natural history of colorectal metastases to the liver and results of studies of systemic chemotherapy, surgical resection, and alternative surgical approaches.
Abstract 1379: The role of PERK and the unfolded protein response in the development of resistance to antiangiogenic agents in renal cell carcinoma
Authors: Shudong Zhu, David J. Panka, James W. Mier, Daniel C. Cho
Journal: Cancer Research (2012)

Abstract Introduction: Intrinsic and delayed resistance of renal cell carcinoma (RCC) towards agents targeting VEGF-signaling remains a major therapeutic problem. The initial regression of RCC metastases observed in many patients treated with VEGFR2 antagonists is due to the hypoxia and diminished supply of nutrients resulting from the involution of tumor microvasculature. However, hypoxia also elicits a series of adaptive responses in tumor cells that enhance their survival, including activation of the unfolded protein response. To investigate the role of the unfolded protein response in the resistance of RCC to antiangiogenic agents, we assessed the effects of suppressing PERK in RCC cell lines. Experimental Design: A 786-O cell line was generated which was transfected with tetracycline-regulable shRNA targeting PERK. The 786-0 PERK shRNA cell line was exposed to hypoxia (0.5% O2) and glucose deprivation both in the presence and absence of doxycycline. Cells thus treated were lysed after 24 hours for western blot analysis for PERK, LC3, phospho-ACC, BIP, and phopsho-eIF2α. Similarly treated cells were also analyzed after 48 hours for viability by propidium iodide staining. Xenografts were generated from 786-O PERK snRNA cells in nude beige mice and grown to 10mm in size. Mice were then treated with saline, doxycycline (2mg/ml in drinking water), sunitinib (50mg/kg) once daily by gavage, or the combination of both doxycline and sunitinib. Results: Treatment of 786-O PERK shRNA cells with doxycycline suppressed expression level of PERK by approximately 80%. Knockdown of PERK significantly increased cell death resulting from exposure of cell lines to hypoxia and nutrient deprivation in vitro associated with diminished expression of LC3. Treatment of mice bearing 786-0 PERK snRNA xenografts with doxycycline or sunitnib alone had little effect on tumor growth compared with saline treated mice. However, the combination of both sorafenib and doxycline resulted in a sustained tumor growth arrest. Conclusions: These data suggested that PERK and the unfolded protein response have a critical role in the ability of tumor cells to survive the insult of hypoxia and nutrient deprivation caused by the diminished vasculature induced by antiangiogenic therapy. Therapeutic strategies to oppose to unfolded protein response may be promising adjuncts to antiangiogenc agents in RCC. 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 1379. doi:1538-7445.AM2012-1379
Dialysis and transplantation: the national picutre over the next five years.
Authors: S C Farrow, D J Fisher, D B Johnson
Journal: BMJ (1972)

which seems unlikely to change radically for many years, it seems hard to believe that any major decline in the incidence or severity of acute rheumatic fever and its consequences is im minent. If anything increasing urbanization, school attendance, and group organization may aggravate the situation further. If rheumatic fever is different in the tropics it is in terms of incidence and severity, and this may be entirely a function of the streptococcus or it may, in addition, relate to host susceptibility. It is these two facets, the streptococcus and host susceptibility, which deserve a major investment in research time and public health money. The rewards may be of universal benefit and not limited to the tropics.
Left-Sided Colonoscopy in Screening Programs. What Preparation?
Authors: V. Pugliese, P. Bruzzi, H. Aste
Journal: Endoscopy (1982)

In order to limit patients' refusal to undergoing colorectal cancer endoscopic screening procedures, traditional cleansing enemas were compared with a new simpler oral cleansing preparation by means of a randomized controlled trial. Ninety-three patients were evaluated both for compliance and effectiveness of the two modalities tested. No difference in acceptability or effectiveness was detected. The authors discuss more rigorous cleansing techniques routinely used in diagnostic schedules which cannot be considered for preparation for colonoscopy in screening programs.