tbuckley/cabot-search huggingface dataset:
Cellular Response to Injury in Membranous Nephropathy
Authors: Masaomi Nangaku, Stuart J. Shankland, William G. Couser
Journal: Journal of the American Society of Nephrology (2005)

The pathogenesis of membranous nephropathy (MN) involves in situ formation of subepithelial immune deposits that produce glomerular injury by damaging and/or activating podocytes through complement-dependent processes. C5b-9 formation and insertion into podocyte cell membranes causes glomerular injury in MN. C5b-9 in sublytic quantities stimulates podocytes to produce proteases, oxidants, prostanoids, extracellular matrix components, and cytokines including TGF-β. C5b-9 also causes alterations of the cytoskeleton that lead to abnormal distribution of slit diaphragm protein and detachment of viable podocytes that are shed into Bowman's space. These events result in disruption of the functional integrity of the glomerular basement membrane and the protein filtration barrier of podocytes with subsequent development of massive proteinuria. Complement components in proteinuric urine also induce tubular epithelial cell injury and mediate progressive interstitial disease in MN. Measurements of urinary C5b-9 or podocyte excretion in the urine may be useful in the diagnosis of MN and as measures of disease activity and response to therapy. Recent studies of cell-cycle proteins and DNA damage in podocytes have clarified why podocytes fail to proliferate in response to C5b-9–mediated injury and podocyte loss in MN, resulting in the development of glomerular sclerosis and renal failure. Improved understanding of the role of complement in the pathogenesis of MN and of the cellular response to C5b-9 attack creates several new opportunities for therapeutic intervention that may benefit patients with MN in the future.
Triterpenoid CDDO-Methyl Ester Inhibits the Janus-Activated Kinase-1 (JAK1)→Signal Transducer and Activator of Transcription-3 (STAT3) Pathway by Direct Inhibition of JAK1 and STAT3
Authors: Rehan Ahmad, Deepak Raina, Colin Meyer, Donald Kufe
Journal: Cancer Research (2008)

Abstract The C-28 methyl ester of the oleane triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me) induces apoptosis of human cancer cells by disrupting redox balance and is in clinical trials. CDDO-Me contains α,β-unsaturated carbonyl groups that form reversible adducts with thiol nucleophiles. The present studies show that CDDO-Me blocks interleukin-6 (IL-6)–induced and constitutive activation of the Janus-activated kinase 1 (JAK1) in cells. In support of a direct mechanism, CDDO-Me forms adducts with JAK1 at Cys1077 in the kinase domain and inhibits JAK1 activity. In concert with these results, CDDO-Me blocked IL-6–induced and constitutive activation of signal transducer and activator of transcription 3 (STAT3). Moreover, we show that CDDO-Me (a) binds directly to STAT3 by a mechanism dependent on the alkylation of Cys259 and (b) inhibits the formation of STAT3 dimers. These findings indicate that CDDO-Me inhibits activation of the JAK1→STAT3 pathway by forming adducts with both JAK1 and STAT3. [Cancer Res 2008;68(8):2920–6]
Prospective Evaluation of the Pharmacokinetics and Toxicity Profile of Docetaxel in the Elderly
Authors: Albert J. ten Tije, Jaap Verweij, Michael A. Carducci, Wilfried Graveland, Theresa Rogers, Tatjana Pronk, M.P. Verbruggen, Fitzroy Dawkins, Sharyn D. Baker
Journal: Journal of Clinical Oncology (2005)

To prospectively study the pharmacokinetics and toxicity profile of docetaxel in elderly patients with cancer.Docetaxel was administered at a dose 75 mg/m(2) once every 3 weeks to 25 elderly cancer patients aged >/= 65 years and 26 cancer patients aged younger than 65 years. Pharmacokinetic studies and toxicity assessments were performed during the first cycle of therapy.Of 51 patients treated, 20 aged >/= 65 years (median, 71 years; range, 65 to 80 years) and 20 aged younger than 65 years (median, 53 years; range, 26 to 64 years) were assessable for pharmacokinetic studies, and 39 were assessable for toxicity. Patient characteristics were similar (P >/= .15) between the two cohorts. Mean docetaxel clearance was not altered in the elderly versus younger patients: 30.1 L/h (standard deviation [SD] 18.3 L/h) v 30.0 L/h (SD, 14.8 L/h; P = .98). The percentage of patients with grade 4 and febrile neutropenia was higher in the elderly (63% and 16%, respectively) versus younger (30% and 0%, respectively) cohort, although this observation did not reach a level of statistical significance (P = .056). From logistic regression analysis, the odds ratio for a patient aged 65 years was 1.98 for developing grade 4 neutropenia compared with a patient aged 50 years (P = .091).Docetaxel plasma pharmacokinetics are unaltered in elderly patients. Patients aged >/= 65 years appear to be more sensitive to docetaxel-induced neutropenia.
A Rare Cause of Cachexia and Chronic Diarrhea
Authors: Jen-Fu Huang, Chien-Hung Liao, Ta-Sen Yeh
Journal: JAMA Surgery (2014)

A54-year-oldwomanpresentedwitha6-monthhistoryofwaterydiarrheaandseverehalitosis. She also lost more than 30 kg of weight during this period. Physical examination revealedacutecachexiawithconjunctivalpallorandan immobile nontendermass in the left upper abdomen.Her laboratory test results revealedamicrocytic anemiaand hypoalbuminemia. Abdominal computed tomography was performed (Figure 1). The patient was scheduled for exploratory laparotomy and resection. Quiz at jamasurgery.com Figure 1. A large central necrotic mass is shown in this computed tomography image of the abdomen.
False-negative results using Neisseria gonorrhoeae porA pseudogene PCR - a clinical gonococcal isolate with an N. meningitidis porA sequence, Australia, March 2011
Authors: D M Whiley, A Limnios, N J Moon, N Gehrig, N Goire, T Hogan, A Lam, K Jacob, S B Lambert, M D Nissen, T P Sloots
Journal: Eurosurveillance (2011)

The gonococcal porA pseudogene is a popular target for in-house Neisseria gonorrhoeae PCR methods. With this study we present two novel findings: the first case of an N. gonorrhoeae porA pseudogene PCR false-negative result caused by sequence variation, and in the same organism, the first description of a clinical N. gonorrhoeae strain harbouring an N. meningitidis porA sequence.
Synergism and Lack of Cross-resistance Between Short-term and Continuous Exposure to Fluorouracil in Human Colon Adenocarcinoma Cells
Authors: A. F. Sobrero, C. Aschele, A. P. Guglielmi, A. M. Mori, G. G. Melioli, R. Rosso, J. R. Bertino
Journal: JNCI Journal of the National Cancer Institute (1993)

Our recent findings in vitro in the human colon adenocar-cinoma cell line HCT-8 suggest that resistance to fluorouracil (5-FU) in patients with advanced colorectal cancer might be overcome by use of a different treatment schedule. We tested the hypothesis that HCT-8 cells resistant to short-term 5-FU exposure retain sensitivity to continuous exposure and studied interactions between the two schedules. Methods: HCT-8 cell lines resistant to short-term (pulse) treatment with 5-FU or to continuous exposure were obtained by six exposures to different concentrations of 5-FU for 4 hours or 7 days. We used a monolayer clonogenic assay to determine 5-FU-induced cell kill in resistant HCT-8 cells and sensitive parent cells. Parent cells were exposed to different concentrations of 5-FU for 1, 4, or 24 hours (short term), for 7 days (continuous exposure), or in a combination of both types of schedules. In astudy of the mechanism of interaction between short-term and continuous exposure in parent cells, we performed flow cytometric DNA analysis to determine the percentage of cells in S phase and assays of thymidylate synthase inhibition in intact cells and of incorporation of [6- 3 H]5-FU nucleotides into nucleic acids. Sensitive HCT-8 cells became fully resistant to 5-FU within five or six treatments, and low-dose continuous exposure almost immediately produced resistant clones. HCT-8 cells resistant to 5-FU given every 4 hours retained full sensitivity to continuous exposure, suggesting lack of cross-resistance between the two schedules, but cells resistant to continuous exposure were cross-resistant to short-term treatment Parent cells showed a statistically significant (synergistic) enhancement of the cytotoxic activity for 5-FU exposure for 1 hour (100,300, or 500 μ M ) followed by continuous exposure (0.5, 1, or 2 μ M ) or 4 hours (10, 30, or 60 μ M ) followed by continuous exposure (1 or 2 μ M ). Short-term plus continuous exposure produced a marked increase in percentage of S-phase cells, compared with the percentage for each schedule alone. The combination of 1-hour exposure and continuous exposure (1000 and 2 μ M , respectively) produced a marked accumulation of cells in S phase at 24 hours (59%), which lasted up to 96 hours (53%). The combination of the two schedules produced only additive enhancement of thymidylate synthase inhibition as well as incorporation of [6- 3 H]5-FU nucleotides into nucleic acids of HCT-8 cells. Our findings provide a rationale for the use of bolus 5-FU and continuous infusion 5-FU in sequence. Implications : We are conducting a clinical trial of bolus methotrexate followed by continuous-infusion 5-FU plus leu-covorin. [J Natl Cancer Inst 85:1937–1944, 1993]
A rash starting on the palms and soles
Authors: Vinod E Nambudiri, Navya S Nambudiri, Rosalynn M Nazarian, Sandy S Tsao
Journal: BMJ (2015)

A 23 year old man presented with a rash eight weeks after emigrating to the United States. One week after immigration he had a sore throat, dysphagia, and mild subjective fevers, which resolved in 10 days. Two weeks later, he developed a papular eruption starting on his hands and feet. He had no arthralgia, myalgia, or systemic symptoms. He took no drugs, had no allergies, no family history of skin eruptions, and no close contacts with a similar rash.

He was evaluated at an urgent care clinic one week after the eruption started. The rash was mainly on his palms and soles but was spreading to the arms and legs. Blood was sent for antibodies to Rocky Mountain spotted fever (RMSF) and coxsackievirus. Given the life threatening nature of RMSF, he was treated empirically with seven days of doxycycline without improvement; both tests were negative.

Over the next two weeks the rash spread diffusely, becoming mildly pruritic, and he presented to our institution for evaluation. His vital signs were within normal limits and he had no erythema of the oral mucosa or lymphadenopathy. Hundreds of pink papules with silvery scale measuring 2-3 mm in diameter were noted on his face, palms and dorsal hands, arms, trunk, legs, and feet (fig 1⇓). Linear lesions in areas of excoriation were seen in the right antecubital fossa. …
Short-term exposure to second hand smoke induces vascular dysfunction in normocholesterolemic rabbits
Authors: A.E.M. Browne, Y.-P. Sun, B.-Q. Zhu, S.J. Hutchison, T.M. Chou, S.A. Glantz, K. Chatterjee, W.W. Parmley, K. Sudhir
Journal: Journal of the American College of Cardiology (1998)
Biochemical and Mechanical Dysfunction in a Mouse Model of Desmin-Related Myopathy
Authors: Alina Maloyan, Hanna Osinska, Jan Lammerding, Richard T. Lee, Oscar H. Cingolani, David A. Kass, John N. Lorenz, Jeffrey Robbins
Journal: Circulation Research (2009)

An R120G mutation in alphaB-crystallin (CryAB(R120G)) causes desmin-related myopathy (DRM). In mice with cardiomyocyte-specific expression of the mutation, CryAB(R120G)-mediated DRM is characterized by CryAB and desmin accumulations within cardiac muscle, mitochondrial deficiencies, activation of apoptosis, and heart failure (HF). Excessive production of reactive oxygen species (ROS) is often a hallmark of HF and treatment with antioxidants can sometimes prevent the progression of HF in terms of contractile dysfunction and cardiomyocyte survival. It is unknown whether blockade of ROS is beneficial for protein misfolding diseases such as DRM. We addressed this question by blocking the activity of xanthine oxidase (XO), a superoxide-generating enzyme that is upregulated in our model of DRM. The XO inhibitor oxypurinol was administered to CryAB(R120G) mice for a period of 1 or 3 months. Mitochondrial function was dramatically improved in treated animals in terms of complex I activity and conservation of mitochondrial membrane potential. Oxypurinol also largely restored normal mitochondrial morphology. Surprisingly, however, cardiac contractile function and cardiac compliance were unimproved, indicating that the contractile deficit might be independent of mitochondrial dysfunction and the initiation of apoptosis. Using magnetic bead microrheology at the single cardiomyocyte level, we demonstrated that sarcomeric disarray and accumulation of the physical aggregates resulted in significant changes in the cytoskeletal mechanical properties in the CryAB(R120G) cardiomyocytes. Our findings indicate that oxypurinol treatment largely prevented mitochondrial deficiency in DRM but that contractility was not improved because of mechanical deficits in passive cytoskeletal stiffness.
Successful Transplantation of a Human Leukemia Cell Line Into Nude Mice: Conditions Optimizing Graft Acceptance&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN4"&gt;4&lt;/xref&gt;
Authors: H W Ziegler, G Frizzera, F H Bach
Journal: JNCI Journal of the National Cancer Institute (1982)

Conditions were determined for successful subcutaneous tumor development of MOLT-4 human T-cell leukemia cells in BALB/c nude (nu/nu) female mice. MOLT-4 cells injected alone at one site resulted in tumors in none of 21 mice, whereas MOLT-4 cells injected with X-irradiated human fibrosarcoma cells (HT-1080) at another site resulted in tumors in 5 of 21 mice. When X-irradiated three times with 200 rad over a 3-week period and then inoculated with MOLT-4 cells and X-irradiated HT-1080 cells, 19 of 25 mice developed tumors, which indicated that a combination of X-irradiation of the recipients and inoculation of an admixture of the leukemia cells with X-irradiated fibrosarcoma cells markedly increases tumor incidence. The cells growing in the tumors had the characteristics of MOLT-4, as assessed by marker studies and histology.
Usefulness of the Chronic Obstructive Pulmonary Disease Assessment Test to Evaluate Severity of COPD Exacerbations
Authors: Alex J. Mackay, Gavin C. Donaldson, Anant R. C. Patel, Paul W. Jones, John R. Hurst, Jadwiga A. Wedzicha
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

The Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) is an eight-item questionnaire designed to assess and quantify the impact of COPD symptoms on health status. COPD exacerbations impair quality of life and are characterized by worsening respiratory symptoms from the stable state. We hypothesized that CAT scores at exacerbation relate to exacerbation severity as measured by exacerbation duration, lung function impairment, and systemic inflammation.To evaluate the usefulness of the CAT to assess exacerbation severity.One hundred sixty-one patients enrolled in the London COPD cohort completed the CAT at baseline (stable state), exacerbation, and during recovery between April 2010 and June 2011.Frequent exacerbators had significantly higher baseline CAT scores than infrequent exacerbators (19.5 ± 6.6 vs. 16.8 ± 8.0, P = 0.025). In 152 exacerbations, CAT scores rose from an average baseline value of 19.4 ± 6.8 to 24.1 ± 7.3 (P < 0.001) at exacerbation. Change in CAT score from baseline to exacerbation onset was significantly but weakly related to change in C-reactive protein (rho = 0.26, P = 0.008) but not to change in fibrinogen (rho = 0.09, P = 0.351) from baseline to exacerbation. At exacerbation, rises in CAT score were significantly associated with falls in FEV(1) (rho = -0.20, P = 0.032). Median recovery time as judged by symptom diary cards was significantly related to the time taken for the CAT score to return to baseline (rho = 0.42, P = 0.012).The CAT provides a reliable score of exacerbation severity. Baseline CAT scores are elevated in frequent exacerbators. CAT scores increase at exacerbation and reflect severity as determined by lung function and exacerbation duration.
Febuxostat Compared with Allopurinol in Patients with Hyperuricemia and Gout
Authors: Michael A. Becker, H. Ralph Schumacher, Robert L. Wortmann, Patricia A. MacDonald, Denise Eustace, William A. Palo, Janet Streit, Nancy Joseph-Ridge
Journal: New England Journal of Medicine (2005)

Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol for patients with hyperuricemia and gout.We randomly assigned 762 patients with gout and with serum urate concentrations of at least 8.0 mg per deciliter (480 micromol per liter) to receive either febuxostat (80 mg or 120 mg) or allopurinol (300 mg) once daily for 52 weeks; 760 received the study drug. Prophylaxis against gout flares with naproxen or colchicine was provided during weeks 1 through 8. The primary end point was a serum urate concentration of less than 6.0 mg per deciliter (360 micromol per liter) at the last three monthly measurements. The secondary end points included reduction in the incidence of gout flares and in tophus area.The primary end point was reached in 53 percent of patients receiving 80 mg of febuxostat, 62 percent of those receiving 120 mg of febuxostat, and 21 percent of those receiving allopurinol (P<0.001 for the comparison of each febuxostat group with the allopurinol group). Although the incidence of gout flares diminished with continued treatment, the overall incidence during weeks 9 through 52 was similar in all groups: 64 percent of patients receiving 80 mg of febuxostat, 70 percent of those receiving 120 mg of febuxostat, and 64 percent of those receiving allopurinol (P=0.99 for 80 mg of febuxostat vs. allopurinol; P=0.23 for 120 mg of febuxostat vs. allopurinol). The median reduction in tophus area was 83 percent in patients receiving 80 mg of febuxostat and 66 percent in those receiving 120 mg of febuxostat, as compared with 50 percent in those receiving allopurinol (P=0.08 for 80 mg of febuxostat vs. allopurinol; P=0.16 for 120 mg of febuxostat vs. allopurinol). More patients in the high-dose febuxostat group than in the allopurinol group (P=0.003) or the low-dose febuxostat group discontinued the study. Four of the 507 patients in the two febuxostat groups (0.8 percent) and none of the 253 patients in the allopurinol group died; all deaths were from causes that the investigators (while still blinded to treatment) judged to be unrelated to the study drugs (P=0.31 for the comparison between the combined febuxostat groups and the allopurinol group).Febuxostat, at a daily dose of 80 mg or 120 mg, was more effective than allopurinol at the commonly used fixed daily dose of 300 mg in lowering serum urate. Similar reductions in gout flares and tophus area occurred in all treatment groups.
Stable hematopoietic cell engraftment after low-intensity nonmyeloablative conditioning in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome
Authors: Lauri M. Burroughs, Troy R. Torgerson, Rainer Storb, Paul A. Carpenter, David J. Rawlings, Jean Sanders, Andrew M. Scharenberg, Suzanne Skoda-Smith, Janet Englund, Hans D. Ochs, Ann E. Woolfrey
Journal: Journal of Allergy and Clinical Immunology (2010)
Clinical spectrum of pulmonary and pleural tuberculosis: a report of 5,480 cases
Authors: S Aktogu, A Yorgancioglu, K Cirak, T Kose, SM Dereli
Journal: European Respiratory Journal (1996)

The aim of the present study was to investigate the epidemiological, clinical, laboratory and radiological features of patients with active pulmonary tuberculosis (TB) (with or without pleural involvement) or with pleural TB (in the absence of radiological parenchymal disease). A systematic predetermined form, including 60 items regarding the above-mentioned features, was completed for 5,480 patients. Sputum smear and culture data, radiological findings, and additional extrapulmonary involvement were evaluated in the patients with pulmonary TB (n = 5,094). Epidemiological features, and other clinical and laboratory characteristics were investigated in all patients (n = 5,480). TB was more common among persons aged 20-39 yrs, males, and those living in large urban centres in our region. There were 4,268 newly detected patients (78%), and 1,212 active ex-patients (22%) who had history of previous antituberculosis treatment. Additional extrapulmonary involvement was found in 455 patients (9%). Sputum samples were smear-positive in 3,916 (79%), and culture-positive in 3,748 cases (76%). Most common radiological patterns were parenchymal infiltrate in 5,017 (99%), and cavitation in 3,363 (66%). Unusual radiological patterns were also noted, i.e., lower lung field TB (LLFTB) in 317 cases (6.2%), pneumothorax in 78 cases (1.5%), and miliary pattern in 66 cases (1.3%). In conclusion, because of the more frequent occurrence in the younger age group, it is considered that the prevalence of disease is still high and that the transmission of tubercle bacilli is not decreasing in our region. The highest risk group consisted of male subjects and those living in urban centres. The high percentage of active ex-patients suggests that new control programmes for tuberculosis are required in Turkey.
Clinical outcomes of transjugular intrahepatic portosystemic shunt for portal hypertension: Korean multicenter real-practice data
Authors: Hyung Ki Kim, Yoon Jun Kim, Woo Jin Chung, Soon Sun Kim, Jae Jun Shim, Moon Seok Choi, Do Young Kim, Dae Won Jun, Soon Ho Um, Sung Jae Park, Hyun Young Woo, Young Kul Jung, Soon Koo Baik, Moon Young Kim, Soo Young Park, Jae Myeong Lee, Young Seok Kim
Journal: Clinical and Molecular Hepatology (2014)

See the commentary-article "Do cirrhotic patients with a high MELD score benefit from TIPS?" on page 15.
Regenerative Medicine for the Respiratory System
Authors: Katrien M. Brouwer, Henk R. Hoogenkamp, Willeke F. Daamen, Toin H. van Kuppevelt
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Regenerative medicine (RM) is a new field of biomedical science that focuses on the regeneration of tissues and organs and the restoration of organ function. Although regeneration of organ systems such as bone, cartilage, and heart has attracted intense scientific research over recent decades, RM research regarding the respiratory system, including the trachea, the lung proper, and the diaphragm, has lagged behind. However, the last 5 years have witnessed novel approaches and initial clinical applications of tissue-engineered constructs to restore organ structure and function. In this regard, this article briefly addresses the basics of RM and introduces the key elements necessary for tissue regeneration, including (stem) cells, biomaterials, and extracellular matrices. In addition, the current status of the (clinical) application of RM to the respiratory system is discussed, and bottlenecks and recent approaches are identified. For the trachea, several initial clinical studies have been reported and have used various combinations of cells and scaffolds. Although promising, the methods used in these studies require optimization and standardization. For the lung proper, only (stem) cell-based approaches have been probed clinically, but it is becoming apparent that combinations of cells and scaffolds are required to successfully restore the lung's architecture and function. In the case of the diaphragm, clinical applications have focused on the use of decellularized scaffolds, but novel scaffolds, with or without cells, are clearly needed for true regeneration of diaphragmatic tissue. We conclude that respiratory treatment with RM will not be realized tomorrow, but its future looks promising.