tbuckley/cabot-search huggingface dataset:
Evaluation of exhaled nitric oxide and nitric oxide metabolites in exhaled breath condensate during asthma*1
Authors: D. Jourd'heuil, F.L. Jourd'heuil, K.S. Patil, A. Harish, P.J. Feustel, H. Jafri, M.A. Pasha
Journal: Journal of Allergy and Clinical Immunology (2004)
Bruch's Membrane Opening Minimum Rim Width and Retinal Nerve Fiber Layer Thickness in a Normal White Population
Authors: Balwantray C. Chauhan, Vishva M. Danthurebandara, Glen P. Sharpe, Shaban Demirel, Christopher A. Girkin, Christian Y. Mardin, Alexander F. Scheuerle, Claude F. Burgoyne
Journal: Ophthalmology (2015)
Use of Biomarkers and Surrogate Endpoints in Drug Development and Regulatory Decision Making: Criteria, Validation, Strategies
Authors: LJ Lesko, AJ Atkinson
Journal: The Annual Review of Pharmacology and Toxicology (2001)

In the future, biomarkers will play an increasingly important role in all phases of drug development, including regulatory review. However, only a few of these biomarkers will become established well enough to serve in regulatory decision making as surrogate endpoints, thereby substituting for traditional clinical endpoints. Even generally accepted surrogate endpoints are unlikely to capture all the therapeutic benefits and potential adverse effects a drug will have in a diverse patient population. Accordingly, combinations of biomarkers probably will be needed to provide a more complete characterization of the spectrum of pharmacologic response. In the future, pharmacogenomic approaches, including those based on differential expression of gene arrays, will provide panels of relevant biomarkers that can be expected to transform the drug development process.
The effects of oestrogens on linear bone growth
Authors: A. Juul
Journal: Human Reproduction Update (2001)

Regulation of linear bone growth in children and adolescents comprises a complex interaction of hormones and growth factors. Growth hormone (GH) is considered to be the key hormone regulator of linear growth in childhood. The pubertal increase in growth velocity associated with GH has traditionally been attributed to testicular androgen secretion in boys, and to oestrogens or adrenal androgen secretion in girls. Research data indicating that oestrogen may be the principal hormone stimulating the pubertal growth spurt in boys as well as girls is reviewed. Such an action is mediated by oestrogen receptors (ER-α and ER-β) in the human growth plate, and polymorphisms in the ER gene may influence adult height in healthy subjects. Prepubertal oestradiol concentrations are significantly higher in girls than in boys, explaining sex-related differences in pubertal onset. Men with a disruptive mutation in the ER gene (oestrogen resistance) or in the CYP19 gene (aromatase deficiency) who have no pubertal growth spurt and continue to grow into adulthood due to lack of epiphyseal fusion supports this notion. Furthermore, phenotypic females with complete androgen insensitivity syndrome have a normal female growth spurt despite lack of androgen action. Oestrogens may also influence linear bone growth indirectly via modulation of the GH-insulin-like growth factor-I (IGF-I) axis. Thus, ER blockade diminishes endogenous GH secretion, androgen receptor (AR) blockade increases GH secretion in peripubertal boys, and non-aromatizable androgens [oxandrolone or dihydrotestosterone (DHT)] have no effect on GH secretion. Treatment with aromatase inhibitors reduces circulating IGF-I concentrations in healthy males, and reduces growth in boys with testotoxicosis. Taken together, these findings suggest that oestrogens may, in addition to their direct effects, stimulate GH secretion and thereby increase circulating IGF-I, which in turn may stimulate growth. Thus, oestrogens have important biphasic actions on longitudinal growth in boys as well as in girls. Very low levels of oestrogens may stimulate bone growth without affecting sexual maturation directly at the growth plate as well as through stimulation of the GH-IGF axis, which in turn may stimulate growth. Conversely, higher levels of oestrogens stimulate secondary sexual characteristics and epiphyseal fusion.
Bronchial carcinoma in patients with pre-existing unilateral lung disease.
Authors: T Yoneyama, T Naruke, K Suemasu, S Ishikawa
Journal: Thorax (1976)

Forty-six cases of primary bronchogenic carcinoma occurring in patients with other unilateral pleuropulmonary diseases were studied. In 37 cases (80-4%) carcinoma developed in the previously healthy lung. All but one squamous-cell carcinoma and all of five undifferentiated small-cell carcinomas developed in the previously healthy lung while 7 of 15 adenocarcinomas were in the lung with impaired ventilation. It is suggested that the bronchial epithelium of the healthy lung is more exposed to exogenous carcinogens than that of the diseased, underventilated lung, resulting in a higher risk of development of squamous-cell and undifferentiated small-cell carcinoma.
Potential Impact of Intermittent Preventive Treatment (IPT) on Spread of Drug-Resistant Malaria
Authors: Wendy Prudhomme O'Meara, David L Smith, F. Ellis McKenzie
Journal: PLoS Medicine (2006)

Treatment of asymptomatic individuals, regardless of their malaria infection status, with regularly spaced therapeutic doses of antimalarial drugs has been proposed as a method for reducing malaria morbidity and mortality. This strategy, called intermittent preventive treatment (IPT), is currently employed for pregnant women and is being studied for infants (IPTi) as well. As with any drug-based intervention strategy, it is important to understand how implementation may affect the spread of drug-resistant parasites. This is a difficult issue to address experimentally because of the limited size and duration of IPTi trials as well as the intractability of distinguishing the spread of resistance due to conventional treatment of malaria episodes versus that due to IPTi when the same drug is used in both contexts.Using a mathematical model, we evaluated the possible impact of treating individuals with antimalarial drugs at regular intervals regardless of their infection status. We translated individual treatment strategies and drug pharmacokinetics into parasite population dynamic effects and show that immunity, treatment rate, drug decay kinetics, and presumptive treatment rate are important factors in the spread of drug-resistant parasites. Our model predicts that partially resistant parasites are more likely to spread in low-transmission areas, but fully resistant parasites are more likely to spread under conditions of high transmission, which is consistent with some epidemiological observations. We were also able to distinguish between spread of resistance due to treatment of symptomatic infections and that due to IPTi. We showed that IPTi could accelerate the spread of resistant parasites, but this effect was only likely to be significant in areas of low or unstable transmission.The results presented here demonstrate the importance of considering both the half-life of a drug and the existing level of resistance when choosing a drug for IPTi. Drugs to which little or no resistance exists are not advisable for IPT in high-transmission areas, but IPTi is not likely to significantly impact the spread of highly resistant parasites in areas where partial resistance is already established. IPTi is more likely to accelerate the spread of resistance in high-transmission areas than is IPT in adults (i.e., pregnant women).
Hepatic Resection After Rescue Cetuximab Treatment for Colorectal Liver Metastases Previously Refractory to Conventional Systemic Therapy
Authors: René Adam, Thomas Aloia, Francis Lévi, Dennis A. Wicherts, Robbert J. de Haas, Bernard Paule, Marie-Pierre Bralet, Mohamed Bouchahda, David Machover, Michel Ducreux, Vincent Castagne, Daniel Azoulay, Denis Castaing
Journal: Journal of Clinical Oncology (2007)

In patients with unresectable colorectal liver metastases (CLM) resistant to first-line chemotherapy, the impact of cetuximab therapy on resectability is unknown. This study was performed to determine the post-cetuximab resectability rate and to examine postoperative outcomes for these heavily pretreated patients.From February 2004 to April 2006, we evaluated 151 patients with unresectable CLM resistant to initial chemotherapy and subsequently treated with systemic cetuximab. Resectability rates, patient outcomes, and tumoral and nontumoral liver pathology were assessed.A total of 27 patients underwent surgery after a median of six cycles of cetuximab + irinotecan (20 of 27), oxaliplatin (four of 27), or both (one of 27). Eighteen patients (67%) had experienced treatment failure after at least two lines of chemotherapy before cetuximab. Twenty-five of the 27 patients who had surgery underwent hepatectomy: nine of 133 patients who were treated completely at our institution (resectability rate, 7%) and 16 of 18 patients who were referred from other institutions after systemic cetuximab therapy. Postoperative mortality was 3.7% (one of 27), with a complication rate of 50%. Histopathologic liver abnormalities were found in nine patients (36%), without specific lesions attributable to cetuximab. After median follow-up of 16 months, 23 of 25 patients who underwent resection (92%) were alive, and 10 patients (40%) were disease free. Median overall (OS) and progression-free survival (PFS) from initiation of cetuximab therapy were 20 and 13 months, respectively.For CLM refractory to conventional chemotherapy, combination therapy with cetuximab increases resectability rates without increasing operative mortality or liver injury. The median OS and PFS of 20 and 13 months, respectively, suggest that this novel oncosurgical strategy benefits patients with previously refractory disease who respond subsequently to cetuximab.
Interactions between human eosinophils and schistosomula of schistosoma mansoni. II. The mechanism of irreversible eosinophil adherence
Authors: AE Butterworth, MA Vadas, DL Wassom, A Dessein, M Hogan, B Sherry, GJ Gleich, David JR
Journal: The Journal of Experimental Medicine (1979)

Previous work (1)(1) has shown that normal human eosinophils show a preferential capacity, in comparison with neutrophils, to bind to antibody- coated schistosomula of Schistosoma mansoni. This effect is attributable to a temperature-dependent function of the eosinophil which renders its binding stable and irreversible by aggregated gamma globulin or Staphylococcus aureus protein A. In contrast, the binding of neutrophils is readily reversible by these agents. It has now been shown that the differences observed between eosinophils and neutrophils is a property of their interaction with living schistosomula. When dead or artificially damaged schistosomula were tested, neutrophils showed a markedly enhanced capacity to adhere, in both the presence and absence of anti-chistosomular serum. Subsequent experiments were designed to test the hypothesis that the strong, stable binding of eosinophils was attributable to degranulation, with release of granule contents which would then serve as ligands to bind the cell to the organism. First, an enhanced adherence both of eosinophils and of neutrophils could be demonstrated in the presence of eosinophil major basic protein (MBP) or of protamine, a high molecular weight cation. Second, the binding of eosinophils induced by concanavalin A (Con A) was found to differ markedly from that induced by antischistosomular serum. Con A-mediated binding of eosinophils was fully reversible by alpha-methyl-mannoside, was not associated with damage to the organism, and did not lead to degranulation of the cell, as estimated by measuring the release of MBP into the culture supernate. However, induction of degranulation of concanavalin A-bound eosinophils, but not of neutrophils, with the calcium ionophore A23187 converted the reaction into one which was no longer reversible by alpha- methylmannoside and in which damage to the organism now did occur. These findings support the hypothesis that the stable binding of eosinophils is associated with degranulation, a process which may contribute to the preferential capacity of this cell to mediate antibody-dependent damage to schistosomula.
Therapeutic Approach for Diabetic Nephropathy Using Gene Delivery of Translocase of Inner Mitochondrial Membrane 44 by Reducing Mitochondrial Superoxide Production
Authors: Yanling Zhang, Jun Wada, Izumi Hashimoto, Jun Eguchi, Akihiro Yasuhara, Yashpal S. Kanwar, Kenichi Shikata, Hirofumi Makino
Journal: Journal of the American Society of Nephrology (2006)

Hyperglycemia-induced overproduction of mitochondrial reactive oxygen species has emerged as a major player in diabetic vascular complications. Mammalian translocase of inner mitochondrial membrane 44 (TIM44) was identified by upregulation in diabetic mouse kidneys. TIM44 functions as a membrane anchor of mitochondrial heat-shock protein 70 (mtHsp70) to TIM23 complex and is involved in the import of mitochondria-targeted preproteins into mitochondrial matrix. The process is dependent on inner membrane potential and ATP hydrolysis on ATPase domain of mitochondrial heat-shock protein 70. Hemagglutination virus of Japan–envelope vector that carries pcDNA3.1 plasmid that contains the full-length cDNA of TIM44 and control plasmid were injected weekly into the tail vein of uninephrectomized streptozotocin-induced diabetic CD-1 mice. The gene delivery alleviated proteinuria and renal hypertrophy at 8 wk after the injection, inhibited renal cell proliferation and apoptosis, and suppressed superoxide production. <i>In vitro</i> experiments, using human proximal tubular (HK2) cells, revealed that the gene delivery of TIM44 reversed high glucose–induced metabolic and cellular abnormalities such as enhanced reactive oxygen species production, increased ATP contents, alterations in inner membrane potential, increased cell proliferation, and apoptosis. Transfection with siRNA and expressing vector of TIM44 revealed that TIM44 facilitates import of antioxidative enzymes such as superoxide dismutase and glutathione peroxidase into mitochondria. The gene delivery of TIM44 therefore seems to be beneficial for the maintenance of mitochondrial function and is a novel therapeutic approach for diabetic nephropathy.
Circulating Exosomes Induced by Cardiac Pressure Overload Contain Functional Angiotensin II Type 1 Receptors
Authors: Gianluigi Pironti, Ryan T. Strachan, Dennis Abraham, Samuel Mon-Wei Yu, Minyong Chen, Wei Chen, Kenji Hanada, Lan Mao, Lewis J. Watson, Howard A. Rockman
Journal: Circulation (2015)

Whether biomechanical force on the heart can induce exosome secretion to modulate cardiovascular function is not known. We investigated the secretion and activity of exosomes containing a key receptor in cardiovascular function, the angiotensin II type I receptor (AT1R).Exosomes containing AT1Rs were isolated from the media overlying AT1R-overexpressing cells exposed to osmotic stretch and from sera of mice undergoing cardiac pressure overload. The presence of AT1Rs in exosomes was confirmed by both electron microscopy and radioligand receptor binding assays and shown to require β-arrestin2, a multifunctional adaptor protein essential for receptor trafficking. We show that functional AT1Rs are transferred via exosomes in an in vitro model of cellular stretch. Using mice with global and cardiomyocyte conditional deletion of β-arrestin2, we show that under conditions of in vivo pressure overload the cellular source of the exocytosis of exosomes containing AT1R is the cardiomyocyte. Exogenously administered AT1R-enriched exosomes target cardiomyocytes, skeletal myocytes, and mesenteric resistance vessels and are sufficient to confer blood pressure responsiveness to angiotensin II infusion in AT1R knockout mice.AT1R-enriched exosomes are released from the heart under conditions of in vivo cellular stress to likely modulate vascular responses to neurohormonal stimulation. In the context of the whole organism, the concept of G protein-coupled receptor trafficking should consider circulating exosomes as part of the reservoir of functional AT1Rs.
Prognostic impact of intratumoral vascular invasion in non-small cell lung cancer patients
Authors: R. Maeda, J. Yoshida, G. Ishii, T. Hishida, M. Nishimura, K. Nagai
Journal: Thorax (2010)

<h3>Objective</h3> Intratumoral vascular invasion (IVI) in patients with non-small cell lung cancer (NSCLC) has been reported to be a strong independent predictor of recurrence, but it has not been incorporated in the TNM classifications including the latest 7th edition. The purpose of this study was to evaluate its significance as a risk factor for recurrence. <h3>Methods</h3> Between July 1992 and December 2006, 2295 consecutive patients with pathological T1–4N0–2 NSCLC underwent complete resection with systematic lymph node dissection at the National Cancer Center Hospital East. The recurrence-free proportion was estimated using the Kaplan–Meier method and differences were determined by the log rank test. Cox proportional hazard ratios were used to identify independent risk factors for recurrence. <h3>Results</h3> The proportion of recurrence-free patients at 5 years was 85.0% for patients without IVI and 51.5% for patients with IVI (p&lt;0.001). On multivariate analyses, IVI proved to be an independently statistically significant risk factor for recurrence (HR 1.866, p&lt;0.001). The recurrence-free proportion of patients with IVI was significantly lower than for patients without IVI in T1a (93.1% vs 69.3%, p&lt;0.001), T1b (89.7% vs 62.7%, p&lt;0.001), T2a (78.4% vs 53.0%, p&lt;0.001), T2b (70.5% vs 46.4%, p=0.021) and T3 (53.1% vs 37.4%, p=0.031) subgroups. <h3>Conclusions</h3> In resected patients with T1–4N0–2 NSCLC, IVI was an independently significant risk factor for recurrence. IVI should be examined and its data collected to be considered for the next revision of the TNM staging system.
Effects of sports activity in athletes with bicuspid aortic valve and mild aortic regurgitation
Authors: G Galanti, L Stefani, L Toncelli, M C R Vono, R Mercuri, N Maffulli
Journal: British Journal of Sports Medicine (2008)

In this study, the impact of regular training on left ventricle morphology in a group of athletes with bicuspid aortic valve (BAV) was evaluated.Longitudinal cohort study. A group of competitive athletes with BAV was followed up with a yearly standard echocardiographic examination for 5 years.Sport Medicine Centre, University of Florence, Pre-Participation Protocol Study.A group of 88 consecutive athletes diagnosed with BAV was identified in the period January to December 1999, and 30 of these completed a 5-year follow-up. They were compared with a group of 56 athletes with a normal tricuspid valve (TAV).BAV athletes showed significant progressive increase in left ventricular dimensions and aortic diameters at four levels. The values were within the range of the general and non-athletic BAV populations. In TAV athletes, the aortic and left ventricle dimensions did not increase significantly and remained within physiological range.Left ventricular dimensions in competitive BAV athletes remain within the normal range. There is, however, a significant progressive increase in the BAV group compared with the TAV group. These results are in agreement with data obtained in previous studies on the non-athletic BAV population. Sports activity does not have an additional effect on cardiac morphology in athletes with asymptomatic BAV associated with mild regurgitation, for at least 5 years.
Novel Deer-Associated Parapoxvirus Infection in Deer Hunters
Authors: Amira A. Roess, Anjela Galan, Edward Kitces, Yu Li, Hui Zhao, Christopher D. Paddock, Patricia Adem, Cynthia S. Goldsmith, Debra Miller, Mary G. Reynolds, Sherif R. Zaki, Inger K. Damon
Journal: New England Journal of Medicine (2010)

Parapoxviruses are a genus of the double-stranded DNA family of poxviruses that infect ruminants, and zoonotic transmission to humans often results from occupational exposures. Parapoxvirus infection in humans begins with an incubation period of 3 to 7 days, followed by the development of one or more erythematous maculopapular lesions that evolve over the course of several weeks into nodules. In 2009, parapoxvirus infection was diagnosed in two deer hunters in the eastern United States after the hunters had field-dressed white-tailed deer. We describe the clinical and pathological features of these infections and the phylogenetic relationship of a unique strain of parapoxvirus to other parapoxviruses. Deer populations continue to increase, leading to the possibility that there will be more deer-associated parapoxvirus infections.
Mutations in the gene encoding gap junction protein β-3 associated with autosomal dominant hearing impairment
Authors: Jia-hui Xia., Chun-yu Liu, Bei-sha Tang, Qian Pan, Lei Huang, He-ping Dai, Bao-rong Zhang, Wei Xie, Dong-xu Hu, Duo Zheng, Xiao-liu Shi, De-an Wang, Kun Xia, Kuan-ping Yu, Xiao-dong Liao, Yong Feng, Yi-feng Yang, Jian-yun Xiao, Ding-hua Xie, Jian-zheng Huang
Journal: Nature Genetics (1998)
Human leukocyte antigen genes may outweigh racial background when generating a specific immune response in sarcoidosis
Authors: J. Grunewald, A. Eklund
Journal: European Respiratory Journal (2001)

Presented is a sarcoidosis patient of African origin, who was adopted at an early age and grew up in Sweden. This patient displayed an immune response identical to that previously reported in human leukocyte antigen (HLA)-DR17 positive Caucasian sarcoidosis patients in Scandinavia, with T-cell receptor AV2S3+ T-cells accumulating in the lungs. HLA typing also established that she was DR17 positive, which is a rare HLA type for individuals of African origin. To the authors' knowledge, this specific immune response has not previously been reported in patients of African origin. Moreover, the clinical manifestations of sarcoidosis were similar to those known to be strongly linked to HLA-DR17 in Scandinavians, i.e. with Löfgren's syndrome. The case presented here suggests certain human leukocyte antigen genes to be strongly linked to specific immune responses that are identical irrespective of the racial background. If such an immune response were important for the subsequent clinical manifestations, this case would argue for the importance of human leukocyte antigen genes in the genetic predisposition to sarcoidosis.