tbuckley/cabot-search huggingface dataset:
Diaphragm Muscle Fiber Weakness in Pulmonary Hypertension
Authors: Frances S. de Man, Hieronymus W. H. van Hees, M. Louis Handoko, Hans W. Niessen, Ingrid Schalij, Marc Humbert, Peter Dorfmüller, Olaf Mercier, Harm-Jan Bogaard, Piet E. Postmus, Nico Westerhof, Ger J. M. Stienen, Willem J. van der Laarse, Anton Vonk-Noordegraaf, Coen A. C. Ottenheijm
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Recently it was suggested that patients with pulmonary hypertension (PH) suffer from inspiratory muscle dysfunction. However, the nature of inspiratory muscle weakness in PH remains unclear.Objectives: To assess whether alterations in contractile performance and in morphology of the diaphragm underlie inspiratory muscle weakness in PH.Methods: PH was induced in Wistar rats by a single injection of monocrotaline (60 mg/kg). Diaphragm (PH n = 8; controls n = 7) and extensor digitorum longus (PH n = 5; controls n = 7) muscles were excised for determination of in vitro contractile properties and cross-sectional area (CSA) of the muscle fibers. In addition, important determinants of protein synthesis and degradation were determined. Finally, muscle fiber CSA was determined in diaphragm and quadriceps of patients with PH, and the contractile performance of single fibers of the diaphragm.Measurements and Main Results: In rats with PH, twitch and maximal tetanic force generation of diaphragm strips were significantly lower, and the force-frequency relation was shifted to the right (i.e., impaired relative force generation) compared with control subjects. Diaphragm fiber CSA was significantly smaller in rats with PH compared with controls, and was associated with increased expression of E3-ligases MAFbx and MuRF-1. No significant differences in contractility and morphology of extensor digitorum longus muscle fibers were found between rats with PH and controls. In line with the rat data, studies on patients with PH revealed significantly reduced CSA and impaired contractility of diaphragm muscle fibers compared with control subjects, with no changes in quadriceps muscle.Conclusions: PH induces selective diaphragm muscle fiber weakness and atrophy.
Serum Markers in Patients with Resectable Pancreatic Adenocarcinoma: Macrophage Inhibitory Cytokine 1 versus CA19-9
Authors: Jens Koopmann, C. Nicole White Rosenzweig, Zhen Zhang, Marcia I. Canto, David A. Brown, Mark Hunter, Charles Yeo, Daniel W. Chan, Samuel N. Breit, Michael Goggins
Journal: Clinical Cancer Research (2006)

More accurate serum markers of pancreatic cancer could improve the early detection and prognosis of this deadly disease. We compared the diagnostic utility of a panel of candidate serum markers of pancreatic cancer.We collected preoperative serum from 50 patients with resectable pancreatic adenocarcinoma, as well as sera from 50 patients with chronic pancreatitis and 50 age/sex-matched healthy controls from our institution. Sera were analyzed for the following candidate markers of pancreatic cancer: CA19-9, macrophage inhibitory cytokine 1 (MIC-1), osteopontin, tissue inhibitor of metalloproteinase 1, and hepatocarcinoma-intestine-pancreas protein levels.By logistic regression analysis, MIC-1 and CA19-9 were significant independent predictors of diagnosis. Receiver operating characteristic curve analysis showed that MIC-1 was significantly better than CA19-9 in differentiating patients with pancreatic cancer from healthy controls (area under the curve is 0.99 and 0.78, respectively; P = 0.003), but not in distinguishing pancreatic cancer from chronic pancreatitis (area under the curve of 0.81 and 0.74, respectively; P = 0.63). Hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein, osteopontin, and tissue inhibitor of metalloproteinase 1 serum levels did not provide additional diagnostic power.In the differentiation of patients with resectable pancreatic cancer from controls, serum MIC-1 outperforms other markers including CA19-9.
Delivering optimal care to the person with asthma: what are the key components and what do we mean by patient education?
Authors: MR Partridge
Journal: European Respiratory Journal (1995)

The new understanding of the pathogenesis of asthma has led to an increasing perception of the disease as a chronic condition, rather than one consisting of acute exacerbations. Health professionals need to help patients to accept this new understanding, and this involves a consideration of how best to deliver care and how best to enhance compliance. Good communication is essential, and structured patient education has now been shown to be cost effective. All health professionals need to think how education may best be incorporated into their care. Such care will involve the development of a partnership between health professional and the patient and their loved ones, and the acquisition by patients of skills in self-management. Several unknowns remain regarding who benefits more from group education as opposed to individual education, and some details of guided self-management. However, in the face of clear evidence of the benefits of patient education, these areas for further study should not delay the adoption of a strong commitment to education by all of those who care for those with asthma.
Phase II study on mitoxantrone in adenoid cystic carcinomas of the head and neck
Authors: J. Verweij, P.H.M de Mulder, A. de Graeff, J.B. Vermorken, J. Wildier, J. Kerger, J. Schornagel, F. Cognetti, A. Kirkpatrick, T. Sahmoud, J.L. Lefebvre
Journal: Annals of Oncology (1996)
Medical, Nonmedical, or Antimedical Models for Mental Health Centers?
Authors: FRANK M. DU MAS
Journal: American Journal of Psychiatry (1974)

The trend toward community treatment of mental patients outside of institutions has resulted in changing concepts of mental health care. The author analyzes three models for mental health centers—medical, nonmedical, and antimedical—and suggests that a multistage transition through these models may occur, ending in a heterogeneous compromise. He predicts a returning emphasis on the medical model as the nonmedical mental health professions reach maturity.
Insights From LGI1 and CASPR2 Potassium Channel Complex Autoantibody Subtyping
Authors: Christopher J. Klein, Vanda A. Lennon, Paula A. Aston, Andrew McKeon, Orna O’Toole, Amy Quek, Sean J. Pittock
Journal: JAMA Neurology (2012)

To determine, in patients identified as seropositive for neuronal voltage-gated potassium channel (VGKC) complex autoantibodies, the spectrum of clinical presentations and frequency of leucine-rich glioma-inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) as defined antigenic neuronal targets in the VGKC macromolecular complex.Retrospective cohort study.Clinical practice, Mayo Clinic Neuroimmunology Laboratory and Department of Neurology.A total of 54 853 patients were evaluated, of whom 1992 were found to be VGKC complex IgG positive.From June 1, 2008, to June 30, 2010, comprehensive service serologic evaluation performed on 54853 patients with unexplained neurologic symptoms identified 1992 patients (4%) who were positive for VGKC complex IgG (values ≥ 0.03 nmol/L). Among 316 seropositive patients evaluated clinically at our institution, 82 (26%) were seropositive for LGI1 IgG and/or CASPR2 IgG. Of these 82 patients, 27% had low (0.03-0.09 nmol/L), 51% had medium (0.10-0.99 nmol/L), and 22% had high (≥ 1.00 nmol/L) VGKC complex IgG values. Leucine-rich glioma-inactivated protein 1 IgG positivity was associated with higher VGKC complex IgG values (P< .001) and cortical presentations (P< .001); CASPR2 IgG was associated with peripheral motor excitability (P= .009). However, neither autoantibody was pathognomonic for a specific neurologic presentation or correlated significantly with cancer. Neurologic phenotypes were diverse. Cerebrocortical manifestations (including cognitive impairment and seizures) were recorded in 76% of patients with LGI1 IgG alone (n=46) and 29% with CASPR2 IgG alone (n=28). Peripheral motor hyperexcitability was found in 21% of patients with CASPR2 IgG alone and 6.5% of patients with LGI1 IgG alone.The study emphasizes diverse and overlapping neurologic phenotypes across a range of VGKC complex IgG values and varying LGI1 IgG and CASPR2 IgG specificities. The frequent occurrence of LGI1 IgG and CASPR2 IgG in serum samples with low and medium VGKC complex IgG values supports the clinical significance of low values in clinical evaluation. Additional antigenic components of VGKC macromolecular complexes remain to be defined.
PLASMA PROTEIN METABOLISM—ELECTROPHORETIC STUDIES
Authors: L. J. Zeldis, E. L. Alling
Journal: The Journal of Experimental Medicine (1945)

Electrophoretic patterns of normal dog plasma in veronal buffer at pH 8.5 are shown to be essentially similar to patterns of human plasma. Dog albumin has a higher mobility than human albumin and in a mixture of dog and human plasmas migrates as a partially separated peak. Normal dog plasma frequently shows four alpha globulin peaks. Rates of restoration of plasma protein components in dogs subjected to acute plasmapheresis have been studied by electrophoresis. During the first 24 hours following such acute depletion, appreciable quantities of all electrophoretic components of the plasma proteins enter the circulating blood stream even when food is not given and has not been given for 12 hours before plasmapheresis. In such fasting periods albumin and total globulin appear in approximately the proportions present in normal plasma. Alpha and beta globulins continue relatively elevated during subsequent days in which caloric and protein intakes are adequate for weight and nitrogen gains. Initial albumin levels, however, are regained more slowly than those of total globulin. The relative proportions of the electrophoretic components of plasma proteins may be disturbed from normal following a single acute depletion for as long as 2 to 3 weeks after the total protein level has returned to normal. Abnormally high beta globulin and fibrinogen, but a low albumin, were found in a dog with an acute and chronic cholangitis and hepatitis. Similar elevation of gamma globulin was noted in a dog in which a hemolytic reaction occurred.
Increased serum levels of LL37, HMGB1 and S100A9 during exacerbation in COPD patients
Authors: Simon D. Pouwels, Martijn C. Nawijn, Erik Bathoorn, Annelies Riezebos-Brilman, Antoon J.M. van Oosterhout, Huib A.M. Kerstjens, Irene H. Heijink
Journal: European Respiratory Journal (2015)

Chronic obstructive pulmonary disease (COPD) is a severe and progressive lung disease characterised by destruction of lung parenchyma and chronic airway inflammation [1]. A major cause of COPD is chronic exposure to noxious gases and particles, including cigarette smoke. During exacerbation, COPD patients experience a worsening of symptoms that coincides with increased inflammation and accelerated decline in lung function, resulting in a decrease in quality of life and increased healthcare costs. Approximately half of the COPD exacerbations causing hospitalisation are associated with respiratory viral and/or bacterial infections [2]. However, the underlying mechanisms causing COPD exacerbations are unknown [3]. Molecules derived from viruses and bacteria during airway infection can trigger the activation of pattern recognition receptors (PRRs) on lung structural and innate immune cells, and may thus contribute to the aggravation of inflammation during COPD exacerbations [1]. Interestingly, damage-associated molecular patterns (DAMPs) released from damaged or necrotic cells are also known to activate PRRs, including Toll-like receptors (TLRs) and the receptor for advanced glycation end-products (RAGE) [4]. A role for DAMPs has been proposed in the pathogenesis of COPD, as various DAMPs have been found to be increased in lung fluids and serum of COPD patients [5, 6]. Furthermore, Ager , the gene encoding RAGE, has been identified by genome-wide association studies as a susceptibility gene for COPD [7, 8]. Moreover, the serum levels of soluble RAGE (sRAGE), a decoy receptor for RAGE, were shown to be significantly lower in COPD patients, while the RAGE ligand EN-RAGE (also known as S100 calcium-binding protein (S100)A12) was significantly higher in COPD patients compared with smoking and nonsmoking controls [9]. It is currently unknown, however, whether DAMPs play a role in COPD exacerbations. Here, we hypothesised that the release of DAMPs is increased during exacerbations of COPD. Serum levels of the RAGE-activating DAMPs LL37, HMGB1 and S100A9 are increased during exacerbation in COPD patients http://ow.ly/Idh3r
Lung function decline in patients with severe alpha1-antitrypsin deficiency
Authors: Karl P. Sylvester, Jess Matthews, Matthew A. Rutter, Tom Dymond, Ravi Mahadeva
Journal: European Respiratory Journal (2014)

Severe alpha 1 -antittrypsin deficiency (AATD) is the only known genetic cause of emphysema. There appears to be variability in the clinical course of AATD associated COPD.  We present preliminary characterisation of the change in FEV 1  in a cohort of patients with severe AATD.  Forced expiratory flow-volume loops measured to ATS/ERS guidelines were retrospectively reviewed from 38 consecutive patients. Values were expressed as mls.  There were 38 individuals (18 males), 1 smoker/28 ex-smokers/9 never smokers. Median age (yrs); 64 (16-81) with at least 3 years follow-up. 52.6% had a median decline in FEV 1  of 66mls/year (35-218), greater than the mean rate of decline in COPD (Vestbo J et al, NEJM 2011), including 5 never smokers. 47.4% of the cohort had a decline in FEV 1   1;  median 23 (-27 -133), 4 never smokers. 50% of these had an improvement in FEV 1  with a median (range) 52 (21 to 133) mls/yr. 71% of never smokers and smokers declined ≥33mls per year.  The rate of decline was lower in those with FEV 1    There is considerable variability in change in FEV 1  in patients with severe AATD even in never smokers. A substantial proportion of patients had a faster rate of decline than COPD patients. Interestingly there was also an improvement in lung function in some individuals following attendance at a specialist centre. Further analysis of other lung function parameters and environmental factors e.g. occupation is required which should aid counselling patients and targeting therapies.
Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a phase II trial
Authors: Benedikte Hasselbalch, Ulrik Lassen, Steinbjørn Hansen, Mats Holmberg, Morten Sørensen, Michael Kosteljanetz, Helle Broholm, Marie-Thérése Stockhausen, Hans Skovgaard Poulsen
Journal: Neuro-Oncology (2010)

The aim of this clinical trial was to investigate safety and efficacy when combining cetuximab with bevacizumab and irinotecan in patients with recurrent primary glioblastoma multiforme (GBM). Patients were included with recurrent primary GBM and progression within 6 months of ending standard treatment (radiotherapy and temozolomide). Bevacizumab and irinotecan were administered IV every 2 weeks. The first 10 patients received bevacizumab 5 mg/kg, but this was increased to 10 mg/kg after interim safety analysis. Irinotecan dose was based on whether patients were taking enzyme-inducing antiepileptic drugs or not: 340 and 125 mg/m2, respectively. Cetuximab 400 mg/m2 as loading dose followed by 250 mg/m2 weekly was administered IV. Forty-three patients were enrolled in the trial, of which 32 were available for response. Radiographic responses were noted in 34%, of which 2 patients had complete responses and 9 patients had partial responses. The 6-month progression-free survival probability was 30% and median overall survival was 29 weeks (95% CI: 23–37 weeks). One patient had lacunar infarction, 1 patient had multiple pulmonary embolisms, and 3 patients had grade 3 skin toxicity, for which 1 patient needed plastic surgery. One patient was excluded due to suspicion of interstitial lung disease. Three patients had deep-vein thrombosis; all continued on study after adequate treatment. Cetuximab in combination with bevacizumab and irinotecan in recurrent GBM is well tolerated except for skin toxicity, with an encouraging response rate. However, the efficacy data do not seem to be superior compared with results with bevacizumab and irinotecan alone.
Application of an Algorithm for the Diagnosis of Asthma in Chinese Families
Authors: JUAN C. CELEDON, EDWIN K. SILVERMAN, SCOTT T. WEISS, BINYAN WANG, ZHIAN FANG, XIPING XU
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Phenotype assessment is a crucial issue in gene mapping studies of asthma. Recently, Panhuysen and coworkers proposed an algorithm to define the asthma phenotype in gene mapping family-based studies. We classified members of 2,756 Chinese families ascertained on the basis of the presence of two or more siblings and no more than one parent with asthma using a slightly modified version of the aforementioned algorithm. Among 4,097 Chinese parents, 404 (9.9%) were classified as having “definite asthma,” 284 (6.9%) as “probable asthma,” 1,193 (29.1%) as “unclassifiable obstructive airway disease,” 626 (15.3%) as “COPD,” and 1,590 (38.8%) as “unaffected” (no obstructive airway disease). Among 6,424 Chinese offspring, 1,065 (16.6%) were classified as having “definite asthma,” 820 (12.8%) as “probable asthma,” 1,996 (31.1%) as “unclassifiable obstructive airway disease,” 228 (3.5%) as “COPD,” and 2,315 (36%) as “unaffected.” The use of the algorithm proposed by Panhuysen and coworkers in a Chinese population with a high prevalence of smoking would result in the exclusion of subjects with asthma who smoke or who have severe airflow obstruction from linkage analysis, as well as in an inability to explore any potential interactions between genetic factors and cigarette smoking in the pathogenesis of asthma. In the absence of a “gold standard,” definitions of asthma that incorporate a combination of respiratory symptoms, increased airway responsiveness or bronchodilator response, and a physician's diagnosis of asthma are reasonable. The choice of a particular diagnostic algorithm for family-based genetic studies of asthma should be made according to factors such as the prevalence of smoking in the study population. Genetic studies of intermediate phenotypes related to asthma, which are objectively defined and may be influenced by a smaller number of genes, continue to be of great importance.
Metronomic Dosing of BH3 Mimetic Small Molecule Yields Robust Antiangiogenic and Antitumor Effects
Authors: Atsushi Imai, Benjamin D. Zeitlin, Fernanda Visioli, Zhihong Dong, Zhaocheng Zhang, Sudha Krishnamurthy, Emily Light, Frank Worden, Shaomeng Wang, Jacques E. Nör
Journal: Cancer Research (2011)

Bcl-2 is an antiapoptotic protein that has also been found to function as a proangiogenic signaling molecule. Improvements in antiangiogenic therapy can be engendered by metronomic dosing. Thus, we hypothesized that BH3-mimetic drugs that antagonize Bcl-2 family proteins may exert a greater efficacy when dosed metronomically. To examine this hypothesis, we employed AT101, an orally available and well-tolerated BH3-mimetic drug that has been established as effective. In a mouse xenograft model of human squamous cell carcinomas (SCC) that includes a humanized vasculature, we explored the effects of docetaxel in combination with either daily (metronomic) or weekly (bolus) doses of AT101. In addition, we explored the effect of single or combination therapy on angiogenesis and survival of endothelial or SCC cells in vitro. Metronomic AT101 therapy increased mouse survival, decreased tumor mitotic index, and decreased tumor microvessel density, compared with bolus therapy. Therapeutic potentiation was achieved by similar overall drug exposure and without altering systemic toxicities. Combinations of AT101 and docetaxel produced additive toxicity in both endothelial and SCC tumor cells. Notably, subapoptotic concentrations of AT101 potently inhibited the angiogenic potential of endothelial cells. Taken together, our findings unveil the efficacious benefits that can be achieved by metronomic delivery of BH3-mimetic drugs, in particular suggesting that SCC patients with might benefit from low-dose continuous administration of these drugs.
The primacy of scaffolding within groups for the evolution of group-level traits
Authors: Linnda R. Caporael, Colin K. Garvey
Journal: Behavioral and Brain Sciences (2014)

Abstract Although both a “simple dyad or a population of thousands” are groups, these are, respectively, face-to-face embodied groups and collective symbolic groups. We applaud Smaldino for recognizing and describing the concept of the group-level trait. As an expansion, we propose an evolutionary-developmental model of face-to-face groups that scaffolds theorizing the evolution of cultural group-level traits.
Specific codon 13 K-ras mutations are predictive of clinical outcome in colorectal cancer patients, whereas codon 12 K-ras mutations are associated with mucinous histotype
Authors: V. Bazan, M. Migliavacca, I. Zanna, C. Tubiolo, N. Grassi, M.A. Latteri, M. La Farina, I. Albanese, G. Dardanoni, S. Salerno, R.M. Tomasino, R. Labianca, N. Gebbia, A. Russo
Journal: Annals of Oncology (2002)
Genetic Predictors of MEK Dependence in Non–Small Cell Lung Cancer
Authors: Christine A. Pratilas, Aphrothiti J. Hanrahan, Ensar Halilovic, Yogindra Persaud, Junichi Soh, Dhananjay Chitale, Hisayuki Shigematsu, Hiromasa Yamamoto, Ayana Sawai, Manickam Janakiraman, Barry S. Taylor, William Pao, Shinichi Toyooka, Marc Ladanyi, Adi Gazdar, Neal Rosen, David B. Solit
Journal: Cancer Research (2008)

Abstract Hyperactivated extracellular signal-regulated kinase (ERK) signaling is common in human cancer and is often the result of activating mutations in BRAF, RAS, and upstream receptor tyrosine kinases. To characterize the mitogen-activated protein kinase/ERK kinase (MEK)/ERK dependence of lung cancers harboring BRAF kinase domain mutations, we screened a large panel of human lung cancer cell lines (n = 87) and tumors (n = 916) for BRAF mutations. We found that non–small cell lung cancers (NSCLC) cells with both V600E and non-V600E BRAF mutations were selectively sensitive to MEK inhibition compared with those harboring mutations in epidermal growth factor receptor (EGFR), KRAS, or ALK and ROS kinase fusions. Supporting its classification as a “driver” mutation in the cells in which it is expressed, MEK inhibition in V600EBRAF NSCLC cells led to substantial induction of apoptosis, comparable with that seen with EGFR kinase inhibition in EGFR mutant NSCLC models. Despite high basal ERK phosphorylation, EGFR mutant cells were uniformly resistant to MEK inhibition. Conversely, BRAF mutant cell lines were resistant to EGFR inhibition. These data, together with the nonoverlapping pattern of EGFR and BRAF mutations in human lung cancer, suggest that these lesions define distinct clinical entities whose treatment should be guided by prospective real-time genotyping. To facilitate such an effort, we developed a mass spectrometry-based genotyping method for the detection of hotspot mutations in BRAF, KRAS, and EGFR. Using this assay, we confirmed that BRAF mutations can be identified in a minority of NSCLC tumors and that patients whose tumors harbor BRAF mutations have a distinct clinical profile compared with those whose tumors harbor kinase domain mutations in EGFR. [Cancer Res 2008;68(22):9375–83]