tbuckley/cabot-search huggingface dataset:
Age-Specific Incidence of Breast Cancer Subtypes: Understanding the Black–White Crossover
Authors: Christina A Clarke, Theresa H M Keegan, Juan Yang, David J Press, Allison W Kurian, Anish H Patel, James V Lacey
Journal: JNCI Journal of the National Cancer Institute (2012)

Background Breast cancer incidence is higher among black women than white women before age 40 years, but higher among white women than black women after age 40 years (black–white crossover). We used newly available population-based data to examine whether the age-specific incidences of breast cancer subtypes vary by race and ethnicity.
Crystalglobulin-Induced Nephropathy
Authors: Vinay Gupta, Mireille El Ters, Kianoush Kashani, Nelson Leung, Samih H. Nasr
Journal: Journal of the American Society of Nephrology (2014)

Crystalline nephropathy refers to renal parenchymal deposition of crystals leading to kidney damage. The most common forms of crystalline nephropathy encountered in renal pathology are nephrocalcinosis and oxalate nephropathy. Less frequent types include urate nephropathy, cystinosis, dihydroxyadeninuria, and drug-induced crystalline nephropathy (e.g., caused by indinavir or triamterene). Monoclonal proteins can also deposit in the kidney as crystals and cause tissue damage. This occurs in conditions such as light chain proximal tubulopathy, crystal-storing histiocytosis, and crystalglobulinemia. The latter is a rare complication of multiple myeloma that results from crystallization of monoclonal proteins in the systemic vasculature, leading to vascular injury, thrombosis, and occlusion. In this report, we describe a case of crystalglobulin-induced nephropathy and discuss its pathophysiology and the differential diagnosis of paraprotein-induced crystalline nephropathy.
Connexin 43 Inhibition Sensitizes Chemoresistant Glioblastoma Cells to Temozolomide
Authors: Susan F. Murphy, Robin T. Varghese, Samy Lamouille, Sujuan Guo, Kevin J. Pridham, Pratik Kanabur, Alyssa M. Osimani, Shaan Sharma, Jane Jourdan, Cara M. Rodgers, Gary R. Simonds, Robert G. Gourdie, Zhi Sheng
Journal: Cancer Research (2015)

Resistance of glioblastoma (GBM) to the front-line chemotherapeutic agent temozolomide (TMZ) continues to challenge GBM treatment efforts. The repair of TMZ-induced DNA damage by O-6-methylguanine-DNA methyltransferase (MGMT) confers one mechanism of TMZ resistance. Paradoxically, MGMT-deficient GBM patients survive longer despite still developing resistance to TMZ. Recent studies indicate that the gap junction protein connexin 43 (Cx43) renders GBM cells resistant to TMZ through its carboxyl terminus (CT). In this study, we report insights into how Cx43 promotes TMZ resistance. Cx43 levels were inversely correlated with TMZ sensitivity of GBM cells, including GBM stem cells. Moreover, Cx43 levels inversely correlated with patient survival, including as observed in MGMT-deficient GBM patients. Addition of the C-terminal peptide mimetic αCT1, a selective inhibitor of Cx43 channels, sensitized human MGMT-deficient and TMZ-resistant GBM cells to TMZ treatment. Moreover, combining αCT1 with TMZ-blocked AKT/mTOR signaling, induced autophagy and apoptosis in TMZ-resistant GBM cells. Our findings suggest that Cx43 may offer a biomarker to predict the survival of patients with MGMT-independent TMZ resistance and that combining a Cx43 inhibitor with TMZ could enhance therapeutic responses in GBM, and perhaps other TMZ-resistant cancers.
Avian Influenza A (H5N1) in 10 Patients in Vietnam
Authors: Tran Tinh Hien, Nguyen Thanh Liem, Nguyen Thi Dung, Luong Thi San, Pham Phuong Mai, Nguyen van Vinh Chau, Pham Thi Suu, Vo Cong Dong, Le Thi Quynh Mai, Ngo Thi Thi, Dao Bach Khoa, Le Phuc Phat, Nguyen Thanh Truong, Hoang Thuy Long, Cao Viet Tung, Le Truong Giang, Nguyen Dac Tho, Le Hong Nga, Nguyen Thi Kim Tien, Le Hoang San, Le Van Tuan, Christiane Dolecek, Tran Tan Thanh, Menno de Jong, Constance Schultsz, Peter Cheng, Wilina Lim, Peter Horby, Jeremy Farrar
Journal: New England Journal of Medicine (2004)

Recent outbreaks of avian influenza A (H5N1) in poultry throughout Asia have had major economic and health repercussions. Human infections with this virus were identified in Vietnam in January 2004.
Effector T lymphocytes in lymphocytic choriomeningitis virus-infected mice. Cytolytic activity of Lyt-23 spleen cells in vitro does not correlate with elimination of infectious virus from spleens.
Authors: M Varho, F Lehmann Grube, M M Simon
Journal: The Journal of Experimental Medicine (1981)

The T lymphocytes from mice recovering from infection with lymphocytic choriomeningitis virus were selected for subclasses by treatment with anti-Lyt antisera and complement. Lyt-23 cells and mixtures of lyt-1 and Lyt-23 cells caused up to one-half the destruction of cultivated target cells as compared with untreated T lymphocytes; Lyt-1 cells alone were not cytotoxic. Selected and unselected spleen T cells were also inoculated intravenously into previously infected mice. Whereas unselected cells reduced infectious virus in the spleens of the recipients approximately 100-fold, only marginal effects, which were not preferentially associated with one particular subclass, were seen with selected LYT-23 or Lyt-1 lymphocytes or a mixture of both. Apparently the Lyt-23 cells, shown to by cytolytic for infected cells in vitro, did not cause elimination of a measurable quantity of the virus from mice.
SC-39026, a serine elastase inhibitor, prevents muscularization of peripheral arteries, suggesting a mechanism of monocrotaline-induced pulmonary hypertension in rats.
Authors: R Ilkiw, L Todorovich-Hunter, K Maruyama, J Shin, M Rabinovitch
Journal: Circulation Research (1989)

In rats injected with the toxin monocrotaline, altered synthesis and distribution of pulmonary artery elastin suggest that increased elastase activity may be important in the development of vascular changes and progressive pulmonary hypertension. To test this hypothesis, male Sprague-Dawley rats (250-300 g) were given 40 mg/kg of the elastase inhibitor SC-39026 in a carboxymethylcellulose vehicle or vehicle only by gavage, 12 hours before and twice daily for 8 days after a single subcutaneous injection of either monocrotaline (60 mg/kg) or saline. Thirteen days after injection, indwelling cardiovascular catheters were inserted under pentobarbital anesthesia, and at 15 days after injection, pulmonary and systemic hemodynamic measurements were recorded with the animals awake. At post-mortem examination, the lungs were perfused and morphometric techniques applied for light and electron microscopic evaluation. Saline-injected rats given either SC-39026 or vehicle were similar in all features assessed. In contrast, monocrotaline-injected rats given SC-39026 had significantly lower mean pulmonary artery pressure than those given vehicle (21.0 +/- 1.6 vs. 27.5 +/- 0.8 mm Hg, p less than 0.05), and this correlated with a significant reduction in the number of abnormally muscularized arteries at alveolar wall level (r2 = 0.89, p less than 0.001). SC-39026 did not significantly reduce monocrotaline-induced medial hypertrophy of muscular arteries, endothelial injury, and associated subendothelial edema; nor was there a significant increase in the proportion of the medial elastin, although a trend was apparent. Additional groups of monocrotaline injected rats were followed 3 weeks after injection, but both SC-39026 and vehicle-treated rats were similar at this point. Our data suggest that increased serine elastase activity associated with endothelial injury may mediate early abnormal pulmonary vascular smooth muscle differentiation resulting in muscularization of normally nonmuscular peripheral arteries and pulmonary hypertension induced in rats by injection of the toxin monocrotaline. Lack of persistence of this protective effect suggests that there may be continued elastase activity in this model. Failure to inhibit medial hypertrophy with SC-39026 suggests that a different mechanism or a different elastase may be involved in this structural change.
Skin lesions in human yersiniosis.
Authors: KIRSTI-MARIA NIEMI, MATTI HANNUKSELA, OSMO P. SALO
Journal: British Journal of Dermatology (1976)

Various types of skin manifestations of human yersiniosis were examined with routine histological and immunohistological methods. The biopsy material consisted of sixteen cases of erythema nodosum, eight cases of erythema multiforme, and one case of erythema figuratum. The principal histopathological changes in erythema nodosum were septal or diffuse, mild panniculitis and in seven cases also necrotizing vasculitis in small, medium-sized or large arteries. Perivascular lymphocytic infiltration without vasculitis was the most prominent feature in erythema figuratum. By using a polyvalent conjugate, immunoglobulins in vessel walls in the dermis were found in two cases of EM. The rapid course of the skin eruptions and the frequency of necrotizing vasculitis in arteries fit the changes seen in an experimental Arthus reaction, in which necrotizing vasculitis is followed by lymphocytic inflammation consistent with a delayed type of reaction.
Taking a stand
Authors: J H C Morgan
Journal: BMJ (1982)

Following an experimental design replicating typical winery conditions, a Riesling wine was bottled with different headspace oxygen levels and sealed with either a co-extruded closure or a screw cap, in order to investigate the impact of headspace oxygen and closure oxygen transfer rate on wine evolution. Using luminescence technology, dissolved oxygen and headspace oxygen, as well as oxygen ingress through the closure, were monitored during 24 months of bottle storage. Under typical winery conditions, headspace oxygen introduced at bottling was found to be a major component of oxygen in bottled wine. Headspace oxygen at bottling affected loss of sulfur dioxide during bottle storage, being the main cause of sulfur dioxide decline during the first four months after bottling, in 375 mL bottles. The loss of sulfur dioxide was found to be not correlated with the evolution of dissolved oxygen, but with the total amount of oxygen consumed by the wine. After 24 months in the bottle, color differences due to different headspace oxygen and closure oxygen transfer rate were generally minor. Conversely, differences in closure oxygen transfer rate were responsible for significant differences in the final concentration of the off-odor compound hydrogen sulfide, with screw cap generally associated with higher levels of this compound. Even if less significantly, the amount of oxygen present in the headspace at bottling also had an effect on final hydrogen sulfide, with higher concentration of this compound observed in wines bottled with lower headspace oxygen.
Multiple Repair Pathways Mediate Tolerance to Chemotherapeutic Cross-linking Agents in Vertebrate Cells
Authors: Kuniharu Nojima, Helfrid Hochegger, Alihossein Saberi, Toru Fukushima, Koji Kikuchi, Michio Yoshimura, Brian J. Orelli, Douglas K. Bishop, Seiki Hirano, Mioko Ohzeki, Masamichi Ishiai, Kazuhiko Yamamoto, Minoru Takata, Hiroshi Arakawa, Jean-Marie Buerstedde, Mitsuyoshi Yamazoe, Takuo Kawamoto, Kasumi Araki, Jun A. Takahashi, Nobuo Hashimoto, Shunichi Takeda, Eiichiro Sonoda
Journal: Cancer Research (2005)

Abstract Cross-linking agents that induce DNA interstrand cross-links (ICL) are widely used in anticancer chemotherapy. Yeast genetic studies show that nucleotide excision repair (NER), Rad6/Rad18-dependent postreplication repair, homologous recombination, and cell cycle checkpoint pathway are involved in ICL repair. To study the contribution of DNA damage response pathways in tolerance to cross-linking agents in vertebrates, we made a panel of gene-disrupted clones from chicken DT40 cells, each defective in a particular DNA repair or checkpoint pathway, and measured the sensitivities to cross-linking agents, including cis-diamminedichloroplatinum (II) (cisplatin), mitomycin C, and melphalan. We found that cells harboring defects in translesion DNA synthesis (TLS), Fanconi anemia complementation groups (FANC), or homologous recombination displayed marked hypersensitivity to all the cross-linking agents, whereas NER seemed to play only a minor role. This effect of replication-dependent repair pathways is distinctively different from the situation in yeast, where NER seems to play a major role in dealing with ICL. Cells deficient in Rev3, the catalytic subunit of TLS polymerase Polζ, showed the highest sensitivity to cisplatin followed by fanc-c. Furthermore, epistasis analysis revealed that these two mutants work in the same pathway. Our genetic comprehensive study reveals a critical role for DNA repair pathways that release DNA replication block at ICLs in cellular tolerance to cross-linking agents and could be directly exploited in designing an effective chemotherapy. (Cancer Res 2005; 65(24): 11704-11)
Emerging Themes and Therapeutic Prospects for Anti-Infective Peptides
Authors: Nannette Y. Yount, Michael R. Yeaman
Journal: The Annual Review of Pharmacology and Toxicology (2011)

Pathogens resistant to most conventional anti-infectives are a harbinger of the need to discover and develop novel anti-infective agents and strategies. Endogenous host defense peptides (HDPs) have retained evolution-tested efficacy against pathogens that have become refractory to traditional antibiotics. Evidence indicates that HDPs target membrane integrity, bioenergetics, and other essential features of microbes that may be less mutable than conventional antibiotic targets. For these reasons, HDPs have received increasing attention as templates for development of potential anti-infective therapeutics. Unfortunately, advances toward this goal have proven disappointing, in part owing to limited understanding of relevant structure-activity and selective toxicity relationships in vivo, a limited number of reports and overall understanding of HDP pharmacology, and the difficulty of cost-effective production of such peptides on a commodity scale. However, recent molecular insights and technology innovations have led to novel HDP-based and mimetic anti-infective peptide candidates designed to overcome these limitations. Although initial setbacks have presented challenges to therapeutic development, emerging themes continue to highlight the potential of HDP-based anti-infectives as a platform for next-generation therapeutics that will help address the growing threat of multidrug-resistant infections.
The effects of rheumatoid factor and anticitrullinated peptide antibodies on bone erosions in rheumatoid arthritis
Authors: H W van Steenbergen, S Ajeganova, K Forslind, B Svensson, A H M van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2014)

With interest we read the article by Hecht et al 1 who studied the associations of anticitrullinated peptide antibodies (ACPA) and rheumatoid factor (RF) with bone erosions in rheumatoid arthritis (RA). The background of this study was that ACPAs directed against citrullinated vimentin induce differentiation of osteoclasts, indicating that ACPA has a direct effect on bone resorption.2 No biological data are available on whether RF also affects bone cells and, given the overlap between ACPA-positivity and RF-positivity, the authors wanted to distinguish the association between RF and bone erosions from the association between ACPA and bone erosions. In a cross-sectional study, high-resolution peripheral quantitative CT (HR-pQCT) images of metacarpophalangeal (MCP) 2–4 joints of 238 patients with RA were made and groups of patients with different combinations of autoantibodies were compared. The authors observed mainly differences in erosive burden in patients with both antibodies compared with those without antibodies. In a subgroup analysis, they also reported a higher erosive burden in ACPA+/RF+ patients compared with ACPA+/RF− patients. Based on their findings the authors suggested that RF may act as an enhancer of bone loss in ACPA-positive patients.

HR-pQCT is an interesting tool that admits …
Phase I trial of liposomal encapsulated doxorubicin (Myocet™; D-99) and weekly docetaxel in advanced breast cancer patients
Authors: E. Mrózek, C.A. Rhoades, J. Allen, E.M. Hade, C.L. Shapiro
Journal: Annals of Oncology (2005)

We conducted a phase I trial to determine the safety and maximum tolerated dose (MTD) of non-pegylated liposome-encapsulated doxorubicin (Myocet; D-99) administered with weekly docetaxel in metastatic breast cancer (MBC) patients.Twenty-one patients with no prior chemotherapy for MBC received D-99 (60 or 50 mg/m2) intravenously (i.v.) on day 1 and escalating doses of docetaxel (25, 30 and 35 mg/m2 i.v. on days 1 and 8 in cohorts of three to six patients. Treatment cycles were repeated every 21 days for a maximum of six cycles.The maximum tolerated dose (MTD) was 50 mg/m2 of D-99 in combination with 25 mg/m2 of weekly docetaxel. The most common grade 4 toxicity was neutropenia that occurred in 42 (41%) of treatment cycles, with 10 hospitalizations for febrile neutropenia. Serious protocol-defined cardiac events occurred in three (14%) patients, with two (10%; 95% confidence interval [CI] 1% to 30%) developing congestive heart failure (CHF) after a total cumulative anthracycline dose (adjuvant doxorubicin + D-99) of 540 mg/m2.D-99 in combination with weekly docetaxel, at the doses and schedule as administered in this trial, is not recommended for phase II testing. Additional trials, using different doses and schedules, are required to evaluate the potential side-effects and efficacy of D-99 and docetaxel.
Activated protein phosphatase PP2A by formoterol enhances nuclear translocation of glucocorticoid receptor induced by budesonide
Authors: Yoshiki Kobayashi, Nicolas Mercado, Anna Miller-Larsson, Peter Barnes, Kazuhiro Ito
Journal: European Respiratory Journal (2011)

Introduction: We have reported that formoterol (FM), a long-acting β2- adrenoceptor agonist, restores corticosteroid (CS) sensitivity by activation of a serine/threonine protein phosphatase PP2A (ERJ 2009;34:583s). However, the molecular mechanisms how FM activates PP2A and restores CS sensitivity have not been elucidated.

Aims: To investigate the mechanism of PP2A activation by FM and the involvement of PP2A in glucocorticoid receptor (GR) nuclear translocation induced by CS budesonide (BUD).

Methods: Phosphatase activity of immunopurified PP2A from U937 monocytic cells was measured by fluorescence-based assay. A549 lung epithelial cells, without functional β2-adrenoceptor, were used as control cells. Direct effect of FM was evaluated using PP2A immunopurified from cell membrane and recombinant PP2A. Nuclear/cytoplasmic GR ratios under PP2A inhibition by okadaic acid (OA) or overexpression were determined by western-blot.

Results: FM enhanced PP2A activity in both U937 and A549 cells and the effects were not blocked by a β2-adrenoceptor inhibitor (ICI-118551). FM directly activated PP2A-immunoprecipitates in the membrane and recombinant PP2A. PP2A was detected in GR-immunoprecipitates. PP2A inactivation by OA reduced GR nuclear translocation by BUD and abrogated FM-mediated increase of GR translocation while PP2A overexpression enhanced BUD-induced GR translocation and further increased enhancement of GR translocation by FM.

Conclusions: FM directly activates PP2A in a β2-adrenoceptor-independent manner. PP2A associated with GR enhances GR nuclear translocation by BUD. This mechanism may contribute to the clinical benefits of BUD+FM combination therapy.
Glycemic Control and Hypoglycemia
Authors: Lawrence C. Perlmuter, Brian P. Flanagan, Parinda H. Shah, Sant P. Singh
Journal: Diabetes Care (2008)

Glycemic control remains a delicate balancing act. The diabetic patient is tasked with maintaining euglycemic blood glucose levels, a goal requiring education, decision strategies, volitional control, and the wisdom to avoid hyper- and hypoglycemia, with the latter defined as plasma glucose less than ∼60 mg/dl. Glucose levels must be controlled continuously and without holidays. Failure to maintain euglycemia results from biological factors and psychosocial factors including overmedication and/or inappropriate choices regarding food, drink, and, in certain cases, exercise.

Diabetic patients, especially those treated with insulin, are at risk for developing hypoglycemia. Treatment, even with oral agents such as sulfonylureas, increases this risk. Asymptomatic episodes of hypoglycemia may constitute up to 10% of a 24-h period in diabetic patients (1,2). Individuals with type 1 diabetes average 43 symptomatic episodes annually; insulin-treated individuals with type 2 diabetes average 16 episodes (3). As for severe hypoglycemic episodes, patients with type 1 diabetes experience up to two episodes annually, whereas patients with type 2 diabetes experience about one episode over 5 years. The risk increases with a history of hypoglycemia and an increased number of years of insulin treatment (3,4).

Hypoglycemia deprives the brain of the constant supply of glucose needed for energy. Such low levels of blood glucose are sensed by the ventromedial hypothalamus (5). In turn, a counterregulatory hormonal cascade is activated to rapidly restore euglycemia that begins with inhibition of insulin secretion. Thereafter, the release of glucagon and epinephrine elevates endogenous glucose production through increased hepatic glycogenolysis and gluconeogenesis, as well as renal gluconeogenesis. Growth hormone and cortisol are slow-acting adjustments to prolonged hypoglycemia (6). Hypoglycemia may promote oxidative stress and neuronal cell death, primarily as a consequence of neuronal NADPH oxidase activation and extracellular zinc release during glucose reperfusion. Thus, heightened glucose concentrations during reperfusion …
IMMUNOCHEMICAL STUDIES ON BLOOD GROUPS
Authors: Harold Baer, Elvin A. Kabat, Vesta Knaub
Journal: The Journal of Experimental Medicine (1950)

Blood group substances have been isolated from the saliva of human beings of blood group B and from the linings of individual horse stomachs. The properties of the human B substances are similar to those of hog and human blood group substances previously isolated. The horse substances showed lower hexosamine and reducing sugar and higher total and non-hexosamine nitrogen than do the materials from the other species. Materials isolated from individual horse stomachs possess either A or B activity or both. Certain stomachs yielded products of identical analytical composition but with neither blood group A, B, or O activity as measured by their ability to inhibit isoagglutination. Fucose has been identified as a constituent of the horse blood group substances.
Ocular Amyloid Angiopathy Associated with Familial Amyloidotic Polyneuropathy Caused by Amyloidogenic Transthyretin Y114C
Authors: Takahiro Kawaji, Yukio Ando, Masaaki Nakamura, Taro Yamashita, Miki Wakita, Eiko Ando, Akira Hirata, Hidenobu Tanihara
Journal: Ophthalmology (2005)