tbuckley/cabot-search huggingface dataset:
Neutral endopeptidase modulates neurogenic inflammation
Authors: JA Nadel
Journal: European Respiratory Journal (1991)

A noncholinergic, nonadrenergic nervous system has been described, involving the sensory nerves in the airways. Chemicals, dusts and other irritants stimulate these sensory nerves to release substance P and related neuropeptides. These neuropeptides have the remarkable ability to affect multiple cells in the airways and to provoke many responses including cough, mucus secretion, smooth muscle contraction, plasma extravasation and neutrophil adhesion. This series of effects is termed "neurogenic inflammation." An enzyme exists on the surfaces of all lung cells that contain receptors for these neuropeptides. This enzyme, neutral endopeptidase (NEP), by cleaving and thus inactivating the neuropeptides, limits the concentration of the neuropeptide that reaches the receptor on the cell surface. Thus, neurogenic inflammatory responses are normally mild and presumably protective in nature. However, when NEP is inhibited pharmacologically (with NEP inhibitors) or by cigarette smoke, respiratory viral infection, or by inhalation of the industrial pollutant toluene diisocyanate, neurogenic inflammatory responses are exaggerated. Delivery of exogenous human recombinant NEP inhibits neurogenic inflammation. Finally, evidence is provided that corticosteroids suppress neurogenic plasma extravasation and that this drug can upregulate NEP in human airway tissue. Neutral endopeptidase cleaves multiple peptides. Thus, its selectivity resides, at least in part, on its fixed location on the surfaces of specific cells where it can modulate effects of peptides exposed to the cells' surfaces.
Human histocompatibility leukocyte antigen (HLA)-DM edits peptides presented by HLA-DR according to their ligand binding motifs.
Authors: S M van Ham, U Grüneberg, G Malcherek, I Bröker, A Melms, J Trowsdale
Journal: The Journal of Experimental Medicine (1996)

Human histocompatibility leukocyte antigen (HLA)-DM is a facilitator of antigen presentation via major histocompatibility complex (MHC) class II molecules. In the absence of HLA-DM, MHC class II molecules do not present natural peptides, but tend to remain associated with class II-associated invariant chain peptides (CLIP). Recently, DM was shown to catalyze the release of CLIP from HLA-DR. We have investigated which peptides bound to HLA-DR are vulnerable to release upon encountering DM. By directed substitution of allele-specific anchor residues between CLIP and DR3-cognate peptides and the application of recombinant DM we show that DM catalyzes the release of those peptides bound to HLA-DR3 that do not have appropriate anchor residues and, hence, no optimal ligand binding motif. Thus, HLA-DM acts as a peptide editor, facilitating selection of peptides that stably bind to class II molecules for eventual presentation to the immune system from the pool of available peptides.
Intensively timed induction therapy followed by autologous or allogeneic bone marrow transplantation for children with acute myeloid leukemia or myelodysplastic syndrome: a Childrens Cancer Group pilot study.
Authors: W G Woods, N Kobrinsky, J Buckley, S Neudorf, J Sanders, L Miller, D Barnard, D Benjamin, J DeSwarte, D Kalousek
Journal: Journal of Clinical Oncology (1993)

PURPOSE Childrens Cancer Group (CCG) protocol 2861 was designed to test the feasibility of aggressively timed induction therapy followed by autologous or allogeneic bone marrow transplantation (BMT) as the sole postremission therapy for newly diagnosed children with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). PATIENTS AND METHODS Between April 1988 and October 1989, 142 patients were eligible for study. All patients entered received a timing-intensive five-drug induction of dexamethasone, cytarabine (Ara-C), thioguanine, etoposide, and daunorubicin (DCTER) over 4 days with a second cycle administered after 6 days of rest, irrespective of hematologic status at that time. Most patients subsequently received a second two-cycle induction course. Those who achieved remission were eligible for bone marrow ablative therapy with busulfan and cyclophosphamide, followed by 4-hydroperoxy-cyclophosphamide (4-HC)-purged autologous or allogeneic BMT rescue. RESULTS One hundred eight (76%) patients achieved remission: 19 (13%) died of complications of the leukemia and/or chemotherapy, and 15 (11%) failed to achieve remission. Seventy-four patients subsequently underwent BMT with either autologous (n = 58) or allogeneic (n = 16) rescue. For patients who received autologous rescue with 4-HC-purged grafts, the actuarial disease-free survival (DFS) rate at 3 years from the day of transplant is 51%, compared with 55% for patients who received allogeneic grafts (P = .92). At 3 years, the overall actuarial survival rate for all 142 patients entered on this study is 45%, with an event-free survival (EFS) rate of 37%. Adverse prognostic factors for outcome included an elevated WBC count or the presence of CNS leukemia at the time of AML diagnosis. CONCLUSION Results suggest that aggressively timed induction therapy followed by marrow ablation and BMT rescue with either autologous or allogeneic grafts for children with newly diagnosed AML or MDS is both feasible and effective.
Hilar Cholangiocarcinoma: Photodynamic Therapy and Stenting
Authors: Marcus Wiedmann, Joachim Mössner, Helmut Witzigmann
Journal: Liver Cancer (2009)

Carcinomas of the biliary tree are rare tumors of the gastrointestinal tract with rising inci dence during the last years. Endoscopic therapy plays a central role in the preopera-tive and palliative treatment of extrahepatic cholangiocarcinoma (CC). In obstructive jaundice, biliary drainage may cause only few complications and relieves symptoms reliably. It can prevent further complica tions and is indispensable in the treatment of cholangitis. The principal drawbacks of biliary stents are stent occlusion and cholangitis. Prophylactic application of antibiotics and/or ursodeoxycholic acid has not been shown to be effective. Technical details concerning material, number and location of stents await further clarification. There are no prospective randomized tri als investigating the effect of preoperative biliary drainage on morbidity and mortality in jaundized patients before liver resection. Palliative surgical cholangio-jejunostomy with the bile duct of liver segment III for Klatskin-tumors is rarely performed due to the high success rate of stent therapy. Self-expandable metal stents (SEMS) are a safe, efficacious and less invasive treatment option for palliation of duodenal obstruc tion in biliary tract cancer. Technical com-plications can be managed endoscopically and the bile duct remains accessible for endoluminal treatment. Palliative photo-dynamic therapy (PDT) for non-resectable hilar CC is effective in prolonging survival, improving biliary drainage and quality of life, and represents a promising adjunct to palliative therapy. Early referral for PDT may provide maximum survival benefit. In contrast, neoadjuvant and adjuvant PDT for hilar CC is a new approach that needs further evaluation.
Abstract 18967: Analysis of Vitamin D Levels in Patients With and Without Statin-induced Myalgia - A Systematic Review and Meta-analysis of 7 Studies with 2416 Patients
Authors: Marta Michalska-Kasiczak, Amirhossein Sahebkar, Dimitri P Mikhailidis, Jacek Rysz, Paul Muntner, Peter P Toth, Steven R Jones, Manfredi Rizzo, G. Kees Hovingh, Michel Farnier, Gregory Y Lip, Maciej Banach
Journal: Circulation (2014)

Introduction: Vitamin D (vit D) deficiency may be associated with an increased risk of statin-related muscle complaints, and symptomatic myalgia in statin-treated patients. Hypothesis: The aim of this meta-analysis was to investigate whether subjects with statin-induced myalgia have lower serum vit D levels compared with those who are asymptomatic. Methods: We searched PubMed, Web of Science, Cochrane Library, Scopus and EMBASE (up to March 2014) to identify studies that investigated the impact of vit D levels in statin-treated subjects with and without myalgia. Two independent reviewers extracted data on study characteristics, methods and outcomes. Results: The electronic search yielded 437 articles, of those 20 were scrutinized in the full text, of which 13 studies were considered unsuitable. The final analysis included 7 studies with 2416 statin-treated patients divided to subgroups of patients with (n = 666 [27.6%]) or without (n = 1750) myalgia. The combination of data from individual observational studies revealed a significantly lower vit D plasma concentration in the statin-induced myalgia compared with the asymptomatic subgroup with weighted mean difference -9.41 ng/mL(95% confidence interval (Cl): -10.17 to -8.64; p &lt; 0.00001) (figure) . Conclusions: This meta-analysis provides evidence that low vit D levels are associated with myalgia in patients on statin therapy. Well-designed, randomized controlled trials are necessary to establish whether vitamin D supplementation reduces risk for statin myalgia in patients with vitamin D deficiency.
Demonstration of Antibody in Cat Sera to Feline Oncornavirus by Complement-Fixation Inhibition&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Richard G. Olsen, David S. Yohn
Journal: JNCI Journal of the National Cancer Institute (1972)

The complement-fixation inhibition test (CFI) was evaluated as a means to detect antibodies in cat sera to feline oncornavirus antigens. Antibody titers ranged from 1 :4 to >1 :256 in sera from neoplastic and normal cats. In contrast, antibodies were not detected in sera from germfree, clinically normal cats. The CFI antibody would not fix guinea pig or feline complement in direct CF tests and would not agglutinate tanned sheep red blood cells coated with feline leukemia virus (FeLV) antigen. Weak precipitin activity with FeLV antigen was detected in CFI positive sera. The specificity of the CFI test was confirmed by demonstration that serum titers were inversely proportional to FeLV antigen concentration. Means to define the specificities of the noncomplement-fixing feline antibodies for individual feline oncornavirus antigen were discussed.
What's in a name: Describing ductal carcinoma in situ (DCIS).
Authors: Lesley Fallowfield, Valerie A Jenkins, Lucy Matthews, Adele Francis, Daniel Rae
Journal: Journal of Clinical Oncology (2014)

e12020 Background: Despite aggressive management of DCIS invasive breast cancer incidence continues to rise. Data suggest that many women, especially those with screen detected low and intermediate grade DCIS, may be over treated. In the absence of definitive data about its natural history and consequently true risks of ever becoming invasive cancer, is it even appropriate to describe DCIS as cancer at all? A new trial in the UK, LORIS (Low Risk DCIS), compares surgery with active monitoring. Recruitment is likely to be challenging as the word carcinoma in DCIS may lead women to think that they have breast cancer, so clinicians must describe the condition in a balanced manner. We conducted a survey amongst the multidisciplinary British Breast Group (BBG), to determine which descriptions of low grade DCIS should be used when discussing the LORIS trial with patients. Methods: Attendees at the February 2013 BBG meeting participated in a questionnaire survey comprising 5 short descriptions adapted from UK cancer charities’ websites and one designed by the LORIS Trial Management Group (TMG). Respondents indicated if they would feel comfortable using each description with patients, then to state their most preferred and most disliked descriptions. Results: 54/73 (74%) attendees completed the survey: surgeons (41%), oncologists (24%), radiologists (13%), scientists (12.9%), pathologists (5.5%), other (3.6%). A majority (34/54; 63%) said they would be comfortable using the description which explained DCIS as abnormal cells in the milk ducts that had not spread into other breast tissue and which did not need urgent treatment as if it was breast cancer. This one, devised by the LORIS TMG was also the most preferred description (24/54; 44%). Portrayal of DCIS as the earliest possible form of breast cancer was the least preferred description (17/54; 31%). Conclusions: Little consensus exists regarding how best to explain low grade DCIS to patients. Cancer charity websites and clinicians use different terms. There is an urgent need when discussing DCIS trials, especially those with an active monitoring arm, to use consistent, accurate but non-alarming terminology avoiding the use of the words ‘early breast cancer’.
Enhanced Chondrogenesis of Induced Pluripotent Stem Cells From Patients With Neonatal‐Onset Multisystem Inflammatory Disease Occurs via the Caspase 1–Independent cAMP/Protein Kinase A/CREB Pathway
Authors: Koji Yokoyama, Makoto Ikeya, Katsutsugu Umeda, Hirotsugu Oda, Seishiro Nodomi, Akira Nasu, Yoshihisa Matsumoto, Kazushi Izawa, Kazuhiko Horigome, Toshimasa Kusaka, Takayuki Tanaka, Megumu K. Saito, Takahiro Yasumi, Ryuta Nishikomori, Osamu Ohara, Naoki Nakayama, Tatsutoshi Nakahata, Toshio Heike, Junya Toguchida
Journal: Arthritis & Rheumatology (2014)

Neonatal-onset multisystem inflammatory disease (NOMID) is a dominantly inherited autoinflammatory disease caused by NLRP3 mutations. NOMID pathophysiology is explained by the NLRP3 inflammasome, which produces interleukin-1β (IL-1β). However, epiphyseal overgrowth in NOMID is resistant to anti-IL-1 therapy and may therefore occur independently of the NLRP3 inflammasome. This study was undertaken to investigate the effect of mutated NLRP3 on chondrocytes using induced pluripotent stem cells (iPSCs) from patients with NOMID.We established isogenic iPSCs with wild-type or mutant NLRP3 from 2 NOMID patients with NLRP3 somatic mosaicism. The iPSCs were differentiated into chondrocytes in vitro and in vivo. The phenotypes of chondrocytes with wild-type and mutant NLRP3 were compared, particularly the size of the chondrocyte tissue produced.Mutant iPSCs produced larger chondrocyte masses than wild-type iPSCs owing to glycosaminoglycan overproduction, which correlated with increased expression of the chondrocyte master regulator SOX9. In addition, in vivo transplantation of mutant cartilaginous pellets into immunodeficient mice caused disorganized endochondral ossification. Enhanced chondrogenesis was independent of caspase 1 and IL-1, and thus the NLRP3 inflammasome. Investigation of the human SOX9 promoter in chondroprogenitor cells revealed that the CREB/ATF-binding site was critical for SOX9 overexpression caused by mutated NLRP3. This was supported by increased levels of cAMP and phosphorylated CREB in mutant chondroprogenitor cells.Our findings indicate that the intrinsic hyperplastic capacity of NOMID chondrocytes is dependent on the cAMP/PKA/CREB pathway, independent of the NLRP3 inflammasome.
Inhibition of p38 MAPK improves heart function in experimental pressure-overload induced right ventricular hypertrophy and failure
Authors: Baktybek Kojonazarov, Tatyana Novoyatleva, Xia Tian, Wiebke Janssen, Himal Luitel, Julia Newman, Philipp Kriechling, Zaneta Sabiska, Steven Evans, Friedrich Grimminger, Norbert Weissmann, Hossein Ardeschir Ghofrani, Werner Seeger, Ralph Schermuly
Journal: European Respiratory Journal (2014)

Introduction. The p38 mitogen-activated protein kinases (MAPK) considered as a key signaling pathway that responds to varied stresses, including those that contribute to heart failure. However, the role of p38 MAPK in pulmonary vascular and right ventricular remodeling is still to be elucidated. Therefore we thought to investigate the effects of p38alfa MAPK inhibition on pressure overload induced RV remodeling.  Methods. We have investigated the effects of p38 MAPK inhibitor PHA-00797804 (Pfizer, USA) in mice subjected either to hypoxia-induced PH or to pulmonary artery banding (PAB). After 21 days, mice exposed to hypoxia were randomized and treated by vehicle or 5 mg/kg bw PHA-00797804 for 14 days. PAB mice were treated by vehicle or PHA-00797804 in a dose 5 mg/kg bw from day 7 to 21. RV function and remodeling determined using echocardiography, invasive hemodynamic measurement and hitomorphometry.  Results. The 38 MAPK inhibition significantly decreased pulmonary vascular remodeling and markedly improved RV functions in hypoxic mice. Additionally, PHA-00797804 significantly increased cardiac output, tricuspid annular plane systolic excursion and improved myocardial performance index in PAB mice compared with placebo treated animals. Moreover, improvement in RV functions was associated with strong antifibrotic effect of PHA-00797804.  Conclusion. We have demonstrated that p38 MAPK plays a significant role in pulmonary vascular and RV remodeling. Inhibition of p38 MAPK by PHA-00797804 effectively improved RV remodeling and function in experimental models of PAH and RV hypertrophy.
Contrasting effects of acute insulin infusion on renal function in awake nondiabetic and diabetic rats.
Authors: B J Tucker, M M Mendonca, R C Blantz
Journal: Journal of the American Society of Nephrology (1993)

Glomerular hyperfiltration in established, moderately hyperglycemic, insulin-dependent diabetes has been hypothesized to be the result of mild volume expansion. Because glomerular hyperfiltration in diabetics is normalized by insulin treatment, then insulin treatment should also reduce extracellular fluid or plasma volume. Previous studies have demonstrated that acute insulin treatment in nondiabetic kidneys results in vasodilation and increased GFR. It is possible that stimuli to the diabetic kidney, as a result of insulin-induced fluid shifts that reduce extracellular fluid volume (ECF) via glucose transport, result in reduction in GFR, opposing the direct renal vasodilatory action of insulin. Awake, chronically cannulated Wistar rats were used in both nondiabetic and established, moderately hyperglycemic, streptozotocin diabetic conditions. After the initial measurements of GFR, RPF, and ECF were obtained, insulin R (5 U) was administered acutely, both groups of rats were glucose clamped at euglycemic levels, and the measurements were repeated. In nondiabetic rats, GFR increased from 0.90 +/- 0.04 to 1.12 +/- 0.06 mL/min.100 g body wt after insulin treatment (P < 0.05), whereas in diabetic rats, GFR, which was greater than in the nondiabetic rats (P < 0.05), decreased from 1.37 +/- 0.03 to 1.13 +/- 0.05 mL/min.100 g body wt (P < 0.05) after acute insulin treatment. The alterations in GFR paralleled the changes in RPF, and the GFR alterations are most likely mediated by the changes in RPF. ECF was not different between nondiabetic and diabetic rats (28 +/- 2 versus 26 +/- 2% of body wt, respectively) and was not significantly altered by acute insulin infusion. Therefore, the contrasting effects of insulin infusion on GFR and RPF in nondiabetic versus diabetic rats cannot be attributed to alterations in ECF. In addition, the data demonstrate that ECF expansion is not required to sustain glomerular hyperfiltration.
Impact of Plasma Lp-PLA2 Activity on the Progression of Aortic Stenosis
Authors: Romain Capoulade, Ablajan Mahmut, Lionel Tastet, Marie Arsenault, Élisabeth Bédard, Jean G. Dumesnil, Jean-Pierre Després, Éric Larose, Benoit J. Arsenault, Yohan Bossé, Patrick Mathieu, Philippe Pibarot
Journal: JACC. Cardiovascular imaging (2014)
Dose-Intensive Therapy for Limited-Stage Small-Cell Lung Cancer: Long-Term Outcome
Authors: Anthony Elias, Joseph Ibrahim, Arthur T. Skarin, Catherine Wheeler, Mary McCauley, Lois Ayash, Paul Richardson, Lowell Schnipper, Karen H. Antman, Emil Frei
Journal: Journal of Clinical Oncology (1999)

To determine progression-free survival (PFS) and overall long-term survival for limited-stage small-cell lung cancer (SCLC) patients aged 60 years or younger who respond to first-line chemotherapy followed by high-dose combination alkylating agents (cyclophosphamide 5,625 mg/m(2), cisplatin 165 mg/m(2), and carmustine 480 mg/m(2)) with hematologic stem-cell support and chest and prophylactic cranial radiotherapy.Patients were selected on the basis of their continued response to first-line therapy, their relative lack of significant comorbidity, and their ability to obtain financial clearance.Of 36 patients with stage III SCLC, nine patients (25%) had achieved a complete response (CR), 20 had achieved a near-CR, and seven had achieved a partial response before undergoing high-dose therapy. Toxicity included three deaths (8%). For all patients, the median PFS was 21 months. The 2- and 5-year survival rates after dose intensification were 53% (95% confidence interval [CI], 39% to 72%), and 41% (95% CI, 28% to 61%). Of the 29 patients who were in or near CR before undergoing high-dose therapy, 14 remain continuously progression-free a median of 61 months (range, 40 to 139 months) after high-dose therapy. Actuarial 2- and 5-year PFS rates were 57% (95% CI, 41% to 79%) and 53% (95% CI, 38% to 76%). By multivariate analysis, short intensive induction chemotherapy was associated with favorable outcome (P <.05).Use of high-dose systemic therapy with intensive local-regional radiotherapy was associated with manageable treatment-related morbidity and mortality. Patients who were in or near CR before intensification are enjoying an unmaintained 5-year PFS rate of 53%. Late complications were infrequent, and most patients returned to full-time work and activity. A randomized comparison of this approach and conventional-dose therapy should define the use of dose intensification with hematopoietic support in patients with responding limited-stage SCLC.
Abstract 11297: Chronic PPAR-γ Stimulation with Pioglitazone Increases Expression of Mitochondrial Antioxidants in Chronically Ischemic Pig Hearts
Authors: Eric K Long, Tammy A Butterick, Cayla M Duffy, Christopher T Holley, Jesús A Cabrera, Herbert B Ward, Rosemary F Kelly, Edward O McFalls
Journal: Circulation (2014)

Background: We hypothesized that chronic administration of the peroxisome proliferator-activated receptor (PPAR)γ agent pioglitazone (PIO) would increase the expression of mitochondrial anti-oxidant proteins within chronically ischemic heart tissue. Methods: Eighteen pigs underwent a thoracotomy with placement of a fixed constrictor around the LAD artery. At 8-weeks post-instrumentation, they were given daily doses of either PIO (3 mg/kg) or placebo in the chow for 4 weeks. Regional function by ECHO was measured at baseline and regional blood flows by μspheres were determined at baseline and during high-dose dobutamine (40 μg/kg/min). Post-sacrifice, mitochondria from the LAD region of both groups were isolated. Protein expression of PPARγ coactivator (PGC-1α) in nuclear fractions (Western blots) and antioxidant proteins (proteomic analysis with iTRAQ) were compared. Results: In all pigs, baseline regional wall thickening (%) was lower in the LAD versus Remote region (42±5% vs 58±5%; P<0.05). LAD blood fl...