tbuckley/cabot-search huggingface dataset:
Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils
Authors: Shijun Wang, Mathieu-Benoit Voisin, Karen Y. Larbi, John Dangerfield, Christoph Scheiermann, Maxine Tran, Patrick H. Maxwell, Lydia Sorokin, Sussan Nourshargh
Journal: The Journal of Experimental Medicine (2006)

The mechanism of leukocyte migration through venular walls in vivo is largely unknown. By using immunofluorescence staining and confocal microscopy, the present study demonstrates the existence of regions within the walls of unstimulated murine cremasteric venules where expression of key vascular basement membrane (BM) constituents, laminin 10, collagen IV, and nidogen-2 (but not perlecan) are considerably lower (&amp;lt;60%) than the average expression detected in the same vessel. These sites were closely associated with gaps between pericytes and were preferentially used by migrating neutrophils during their passage through cytokine-stimulated venules. Although neutrophil transmigration did not alter the number/unit area of extracellular matrix protein low expression sites, the size of these regions was enlarged and their protein content was reduced in interleukin-1β–stimulated venules. These effects were entirely dependent on the presence of neutrophils and appeared to involve neutrophil-derived serine proteases. Furthermore, evidence was obtained indicating that transmigrating neutrophils carry laminins on their cell surface in vivo. Collectively, through identification of regions of low extracellular matrix protein localization that define the preferred route for transmigrating neutrophils, we have identified a plausible mechanism by which neutrophils penetrate the vascular BM without causing a gross disruption to its intricate structure.
CYSTIC FIBROSIS OF THE PANCREAS
Authors: B. Shannon Danes, Alexander G. Bearn
Journal: The Journal of Experimental Medicine (1969)

103 individuals from 16 families with cystic fibrosis and 87 individuals without family history of cystic fibrosis have been studied using the methods of cell culture. Skin fibroblast cultures derived from 19 affected children, and fibroblast cultures from 11 different organs obtained at autopsy from two affected children, showed cellular metachromasia. The morphological appearance and the intracellular mucopolysaccharide content enabled these cultures to be divided into two distinct classes. Class I had discrete cytoplasmic metachromatic vesicles and a mucopolysaccharide content similar to that observed in normal fibroblasts. In class II the metachromasia was present in both vesicles and granules and was evenly distributed throughout the cytoplasm. The mucopolysaccharide content of these cells was markedly increased. The cultures derived from the parents, presumed heterozygotes, and other members of each family showed cells with the same type of metachromasia as that demonstrated by the propositus. These data strongly suggest that cystic fibrosis is not a homogeneous entity and, moreover, can be caused by homozygosity of genes at two distinct loci. The recognition of cytoplasmic abnormalities in skin fibroblasts derived from affected individuals and heterozygous carriers for cystic fibrosis should facilitate genetic and biochemical studies on the heterogeneity of this inborn error of metabolism.
MAP Kinase Kinase 6–p38 MAP Kinase Signaling Cascade Regulates Cyclooxygenase-2 Expression in Cardiac Myocytes In Vitro and In Vivo
Authors: Norbert Degousee, Joshua Martindale, Eva Stefanski, Martin Cieslak, Thomas F. Lindsay, Jason E. Fish, Philip A. Marsden, Donna J. Thuerauf, Christopher C. Glembotski, Barry B. Rubin
Journal: Circulation Research (2003)

Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in delayed prostaglandin biosynthesis. The purpose of this study was to evaluate the role of the MAP kinase kinase 6 (MKK6)-p38 MAPK signaling cascade in the regulation of myocardial COX-2 gene expression, in vitro and in vivo. RT-PCR analysis identified p38alpha and p38beta2 MAPK mRNA in rat cardiac myocytes. Interleukin-1beta induced the phosphorylation of p38alpha and p38beta2 MAPK in cardiomyocytes and stimulated RNA polymerase II binding to the COX-2 promoter, COX-2 transcription, COX-2 protein synthesis, and prostaglandin E2 (PGE2) release. Infecting cardiomyocytes with adenoviruses that encode mutant, phosphorylation-resistant MKK6 or p38beta2 MAPK inhibited interleukin-1beta-induced p38 MAPK activation, COX-2 gene expression, and PGE2 release. Treatment with the p38alpha and p38beta2 MAPK inhibitor, SB202190, attenuated interleukin-1beta-induced COX-2 transcription and accelerated the degradation of COX-2 mRNA. Cells infected with adenoviruses encoding wild-type or constitutively activated MKK6 or p38beta2 MAPK, in the absence of interleukin-1beta, exhibited increased cellular p38 MAPK activity, COX-2 mRNA expression, and COX-2 protein synthesis, which was blocked by SB202190. In addition, elevated levels of COX-2 protein were identified in the hearts of transgenic mice with cardiac-restricted expression of wild-type or constitutively activated MKK6, in comparison with nontransgenic littermates. These results provide direct evidence that MKK6 mediated p38 MAPK activation is necessary for interleukin-1beta-induced cardiac myocyte COX-2 gene expression and PGE2 biosynthesis in vitro and is sufficient for COX-2 gene expression by cardiac myocytes in vitro and in vivo.
Differential Methylation Hybridization Array of Endometrial Cancers Reveals Two Novel Cancer-Specific Methylation Markers
Authors: Israel Zighelboim, Paul J. Goodfellow, Amy P. Schmidt, Ken C. Walls, Mary Ann Mallon, David G. Mutch, Pearlly S. Yan, Tim Hui-Ming Huang, Matthew A. Powell
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To identify novel endometrial cancer-specific methylation markers and to determine their association with clinicopathologic variables and survival outcomes. Experimental Design: Differential methylation hybridization analysis (DMH) was done for 20 endometrioid endometrial cancers using normal endometrial DNA as a reference control. Combined bisulfite restriction analysis (COBRA) was used to verify methylation of sequences identified by DMH. Bisulfite sequencing was undertaken to further define CpG island methylation and to confirm the reliability of the COBRA. The methylation status of newly identified markers and the MLH1 promoter was evaluated by COBRA in a large series of endometrioid (n = 361) and non-endometrioid uterine cancers (n = 23). Results: DMH and COBRA identified two CpG islands methylated in tumors but not in normal DNAs: SESN3 (PY2B4) and TITF1 (SC77F6/154). Bisulfite sequencing showed dense methylation of the CpG islands and confirmed the COBRA assays. SESN3 and TITF1 were methylated in 20% and 70% of endometrioid tumors, respectively. MLH1 methylation was seen in 28% of the tumors. TITF1 and SESN3 methylation was highly associated with MLH1 methylation (P &amp;lt; 0.0001). SESN3 and TITF1 were methylated in endometrioid and non-endometrioid tumors, whereas MLH1 methylation was restricted to endometrioid tumors. Methylation at these markers was not associated with survival outcomes. Conclusions: The 5′ CpG islands for SESN3 and TITF1 are novel cancer-specific methylation markers. Methylation at these loci is strongly associated with aberrant MLH1 methylation in endometrial cancers. SESN3, TITF1 and MLH1 methylation did not predict overall survival or disease-free survival in this large cohort of patients with endometrioid endometrial cancer.
Novel Germline Mutation in the Transmembrane Domain of HER2 in Familial Lung Adenocarcinomas
Authors: Hiromasa Yamamoto, Koichiro Higasa, Masakiyo Sakaguchi, Kazuhiko Shien, Junichi Soh, Koichi Ichimura, Masashi Furukawa, Shinsuke Hashida, Kazunori Tsukuda, Nagio Takigawa, Keitaro Matsuo, Katsuyuki Kiura, Shinichiro Miyoshi, Fumihiko Matsuda, Shinichi Toyooka
Journal: JNCI Journal of the National Cancer Institute (2013)

We encountered a family of Japanese descent in which multiple members developed lung cancer. Using whole-exome sequencing, we identified a novel germline mutation in the transmembrane domain of the human epidermal growth factor receptor 2 ( HER2 ) gene (G660D). A novel somatic mutation (V659E) was also detected in the transmembrane domain of HER2 in one of 253 sporadic lung adenocarcinomas. Because the transmembrane domain of HER2 is considered to be responsible for the dimerization and subsequent activation of the HER family and downstream signaling pathways, we performed functional analyses of these HER2 mutants. Mutant HER2 G660D and V659E proteins were more stable than wild-type protein. Both the G660D and V659E mutants activated Akt. In addition, they activated p38, which is thought to promote cell proliferation in lung adenocarcinoma. Our findings strongly suggest that mutations in the transmembrane domain of HER2 may be oncogenic, causing hereditary and sporadic lung adenocarcinomas.
Role of serum IgA. Hepatobiliary transport of circulating antigen.
Authors: M W Russell, T A Brown, J Mestecky
Journal: The Journal of Experimental Medicine (1981)

The IgA mediated hepatobiliary excretion of antigen from the circulation was studied using a radiolabeled haptenated protein (dinitrophenyl-human serum albumin) injected intravenously in mice together with monoclonal anti-dinitrophenyl antibodies of different immunoglobulin classes. Antibodies were obtained from ascitic fluids of mice bearing the MOPC315 myeloma (IgA), or immune spleen cell hybridomas (IgG and IgM). IgA antibody brought about the transport of large amounts of antigen from the circulation to the bile during 1-3h. Analysis of bile by gel filtration showed that a large part of the transported antigen remained intact and complexed with IgA. Neither IgA of different specificity nor anti-dinitrophenyl IgM medicated biliary transport of antigen. With anti-dinitrophenyl IgG, only small amounts of low molecular weight fragments of labeled antigen were found in he bile. Preformed immune complex of radiolabeled antigen and IgA antibody were rapidly transported from the circulation to the bile, resulting in threefold-higher levels of radioactivity in bile than in serum. It is proposed that an important function of serum IgA is to mediate the hepatobiliary excretion of corresponding circulating antigens.
Reflex changes in hindlimb and renal vascular resistance in response to distention of the isolated pulmonary arteries of the dog.
Authors: J R Ledsome, W O Kan
Journal: Circulation Research (1977)

We describe a preparation that uses a constant flow, right heart bypass for perfusion of an isolated pouch of the main pulmonary arteries at controlled pressures, and show that increments in pressure in the pulmonary arterial pouch are accompanied by increases in systemic vascular resistance and in hindlimb vascular resistance. These changes are demonstrated over the whole range of 5-120 cm H2O pressure in the pulmonary arterial pouch. In contrast there are no significant changes in renal vascular resistance or heart rate. We find that changing the temperature of the perfusate in the pulmonary arterial pouch from 37 degrees C to 30 degress C is associated with a decrease in systemic vascular resistance. Furthermore, the effects of raising the pulmonary arterial pouch pressure and of cooling are abolished by cervical vagotomy. These findings suggest that there is a tonic reflex vasoconstrictor tone generated by the activity of receptors lying in or close to the walls of the pulmonary artery. These findings also suggest that the differential effects on systemic vascular resistance and renal resistance may provide one mechanism by which changes in blood volume may lead to appropriate changes in renal solute excretion.
Evaluation of Parathyroid Gland Lesions
Authors: D. Robert Dufour
Journal: JAMA (1982)

To the Editor.—  The recent article by Carnevale et al (1981;246:1332) emphasizes the difficulty in histopathological diagnosis of parathyroid gland lesions, since their illustrations are clearly not what they are claimed to be. Neither Fig 1 nor 3 is compatible with parathyroid adenoma; instead, they represent nodular (Fig 1) and diffuse (Fig 3) chief-cell hyperplasia. Although it may be difficult in some cases to differentiate hyperplasia from adenoma, the glands in the illustrations have an intimate admixture of chief cells and fat cells and lack a dominant, encapsulated nodule. These features are present in cases of hyperplasia but are not seen in cases of adenoma. In addition, the gland in Fig 2 shows a distinct nodular pattern in the upper half and near the lower border, a finding seen in hyperplastic glands.  As the article clearly emphasizes, visualization of all four glands at surgery is of critical importance in determining
Pulmonary cannonballs and more like never before
Authors: Mohammed H AlShati
Journal: Thorax (2013)

A 44-year-old man presented to hospital with haemoptysis and progressive dyspnoea. Examination revealed room air oxygen saturation of 91% with diffuse chest crackles, gynaecomastia and hepatosplenomegaly. Scrotal examination was unremarkable. Radiological investigations revealed numerous bilateral pulmonary nodules of variable size (cannonball appearance) (figure 1), gynaecomastia (figure 2A), hepatosplenomegaly and a large retroperitoneal mass (figure 2B). Scrotal ultrasound showed no abnormalities.



Figure 1 
Plain posteroanterior chest radiograph (A) and axial CT scan in the lung window (B) showing numerous bilateral …
Care of Diabetic Pregnant Women by Primary-Care Physicians: Reported Strategies for Managing Pregestational and Gestational Diabetes
Authors: David G Marrero, Patricia Moore, Carl D Langefeld, Alan Golichowski, Charles M Clark
Journal: Diabetes Care (1992)

Objective —To ascertain the strategies used by primary-care physicians for treating pregestational and gestational diabetes mellitus (GDM) during pregnancy, because many women with pregnancies complicated by these types of diabetes are treated by physicians who have no special training in intensive diabetes management. Research Design and Methods —Two hundred twenty-four family-practice (FP) physicians and 184 obstetrics/gynecology (OB/GYN) physicians were surveyed by mail. Results —When compared with OB/GYNs, FPs were less likely to screen all pregnant women for GDM (P = 0.03), use multiple-injection insulin regimens (P = 0.004) or self-monitoring of blood glucose (SMBG) (P = 0.01) for Pre-GDM patients, and refer these patients to a specialist for medical (P = 0.01) or ophthalmologic (P &amp;lt; 0.001) care. FPs were more likely to implement insulin therapy (P = 0.003), SMBG (P = 0.02), and examine eyes for retinopathy (P &amp;lt; 0.001) when treating gestational patients. Conclusions —These data show that there are considerable discrepancies between the strategies used by FPs and OB/GYNs and also suggest that physicians in both groups are under-utilizing recommended treatment strategies described in publications targeted specifically to primary-care physicians. Increased exposure to and dissemination of guidelines for diabetes management and additional medical school and postgraduate education programs are recommended as methods to improve utilization of these strategies.
Mathematical Modeling and Optimization of Drug Delivery from Intratumorally Injected Microspheres
Authors: Abraham Rami Tzafriri, Elyakum Itzhak Lerner, Moshe Flashner-Barak, Michael Hinchcliffe, Eli Ratner, Hanna Parnas
Journal: Clinical Cancer Research (2005)

Paclitaxel is a highly promising phase-sensitive antitumor drug that could conceivably be improved by extended lower dosing as opposed to intermittent higher dosing. Although intratumoral delivery of paclitaxel to the whole tumor at different loads and rates has already been achieved, determining an optimal release mode of paclitaxel for tumor eradication remains difficult. This study set out to rationally design such an optimal microsphere release mode based on mathematical modeling.A computational reaction-diffusion framework was used to model drug release from intratumorally injected microspheres, drug transport and binding in tumor interstitum, and drug clearance by microvasculature and intracellular uptake and binding.Numerical simulations suggest that interstitial drug concentration is characterized by a fast spatially inhomogeneous rise phase, during which interstitial and intracellular binding sites are saturated, followed by a slow spatially homogeneous phase that is governed by the rate of drug release from microspheres. For zero-order drug release, the slow phase corresponds to a plateau drug concentration that is proportional to the ratio of the rate of blood clearance of drug to the rate of drug release from microspheres. Consequently, increasing the duration of intratumoral drug release extends the duration of cell exposure to the drug but lowers the plateau drug concentration. This tradeoff implies that intratumoral drug release can be designed to optimize tumor cell kill. Synthesizing our modeling predictions with published dose-response data, we propose an optimal protocol for the delivery of paclitaxel-loaded microspheres to small solid tumors.
Phase I Study of Aerosolized SLIT Cisplatin in the Treatment of Patients with Carcinoma of the Lung
Authors: Bart P.H. Wittgen, Peter W.A. Kunst, Kasper van der Born, Atie W. van Wijk, Walter Perkins, Frank G. Pilkiewicz, Roman Perez-Soler, Susan Nicholson, Godefridus J. Peters, Pieter E. Postmus
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To investigate the safety and pharmacokinetics of aerosolized Sustained Release Lipid Inhalation Targeting (SLIT) Cisplatin in patients with lung carcinoma. Experimental Design: Phase I, dose-escalating study of SLIT Cisplatin given in two sessions daily. Safety data, including laboratory variables, adverse events, pulmonary function tests, and radiographic imaging, were collected and analyzed for all patients to determine toxicity. Pharmacokinetic monitoring was done during the first course. Results: Seventeen patients and one tracheostomy patient on compassionate use received treatment. Aerosolized cisplatin was well tolerated. No dose-limiting toxicity was observed at the maximum delivered dose. Safety data showed no hematologic toxicity, nephrotoxicity, ototoxicity, or neurotoxicity. Most common adverse events were nausea (64.7%), vomiting (47.1%), dyspnea (64.7%), fatigue (64.7%), and hoarseness (47.1%). Pharmacokinetic data showed very low plasma platinum levels only with the longest repeated inhalations. Common Toxicity Criteria grade 2 decrease in forced expiratory volume in one second and diffusing lung capacity for carbon monoxide after one course occurred both in two patients and grade one decrease in forced expiratory volume in one second and diffusing lung capacity for carbon monoxide in six and five patients, respectively. Direct airway deposition via the tracheostomy resulted in clinical deterioration after two cycles best described as bronchitis, completely reversible within days. Overall response: stable disease in 12 patients and progressive disease in 4 patients (one patient received one cycle). Conclusions: Aerosolized liposomal cisplatin was found to be feasible and safe.
Lymphocyte-Rich Classical Hodgkin's Lymphoma: Clinical Presentation and Treatment Outcome in 100 Patients Treated Within German Hodgkin's Study Group Trials
Authors: Alexander Shimabukuro-Vornhagen, Heinz Haverkamp, Andreas Engert, Leopold Balleisen, Peter Majunke, Günther Heil, Hans Theodor Eich, Harald Stein, Volker Diehl, Andreas Josting
Journal: Journal of Clinical Oncology (2005)

To investigate the clinical characteristics and treatment outcome of patients with lymphocyte-rich classical Hodgkin's lymphoma (LRCHL) compared with other histologic subtypes of Hodgkin's lymphoma (HL).From a total of 2,715 patients with biopsy-proven HL treated within the trials HD7 to HD12 of the German Hodgkin's Study Group, 100 patients (4%) with LRCHL, 145 patients (5%) with lymphocyte-predominant HL (LPHL), 1,688 patients (62%) with nodular sclerosis, 731 patients (27%) with mixed cellularity, and 23 patients (1%) with lymphocyte depletion were identified. Patients with LRCHL had a median age of 38 years (range, 16 to 74 years).Compared with other histologic subtypes, patients with LRCHL are, on average, older and usually present with early stages of disease (stage I, 34%; stage II, 46%). The median time of follow-up was 32.2 months (95% CI, 28.2 to 37.0 months). Complete and partial remission was achieved in 96 patients (96%) and four patients (4%), respectively, with LRCHL. The event-free and overall survival rates were 97% (95% CI, 93% [corrected] to 100% [corrected]) and 97% (95% CI, 93% [corrected] to 100% [corrected]), respectively, at 30 months. Only three patients died; all of the deaths were caused by treatment-related toxicities.LRCHL is a distinct subtype of CHL, with features of CHL and LPHL, and is a rare entity accounting for only 4% of HLs. LRCHL has a different pattern of clinical presentation and age and sex distribution than other CHLs. It is associated with an excellent prognosis if treated with current treatment regimens. When treating patients with LRCHL, great attention should be paid to avoid acute toxicities.
Credibility of claims of subgroup effects in randomised controlled trials: systematic review
Authors: X. Sun, M. Briel, J. W. Busse, J. J. You, E. A. Akl, F. Mejza, M. M. Bala, D. Bassler, D. Mertz, N. Diaz-Granados, P. O. Vandvik, G. Malaga, S. K. Srinathan, P. Dahm, B. C. Johnston, P. Alonso-Coello, B. Hassouneh, S. D. Walter, D. Heels-Ansdell, N. Bhatnagar, D. G. Altman, G. H. Guyatt
Journal: BMJ (2012)

<b>Objective</b> To investigate the credibility of authors' claims of subgroup effects using a representative sample of recently published randomised controlled trials. <b>Design</b> Systematic review. <b>Data source</b> Core clinical journals, as defined by the National Library of Medicine, in Medline. <b>Study selection</b> Randomised controlled trials published in 2007. Using prespecified criteria, teams of trained reviewers independently judged whether authors claimed subgroup effects and the strength of their claims. Reviewers assessed each of these claims against 10 predefined criteria, developed through a search of existing criteria and a consensus process. <b>Results</b> Of 207 randomised controlled trials reporting subgroup analyses, 64 (31%) made claims for the primary outcome. Of those, 20 were strong claims and 28 claims of a likely effect. Authors included subgroup variables measured at baseline in 60 (94%) trials, used subgroup variable as a stratification factor at randomisation in 13 (20%), clearly prespecified their hypotheses in 26 (41%), correctly prespecified direction in 4 (6%), tested a small number of hypotheses in 28 (44%), carried out a test of interaction that proved statistically significant in 6 (9%), documented replication of a subgroup effect with previous related studies in 21 (33%), identified consistency of a subgroup effect across related outcomes in 19 (30%), and provided a compelling indirect evidence for the effect in 14 (22%). In the 19 trials making more than one claim, only one (5%) checked the independence of the interaction. Of the 64 claims, 54 (84%) met four or fewer of the 10 criteria. For strong claims, more than 50% failed each of the individual criteria, and only three (15%) met more than five criteria. <b>Conclusion</b> Authors often claim subgroup effects in their trial report. However, the credibility of subgroup effects, even when claims are strong, is usually low. Users of the information should treat claims that fail to meet most criteria with scepticism. Trial researchers should report the conduct of subgroup analyses and provide sufficient evidence when claiming a subgroup effect or suggesting a possible effect.