tbuckley/cabot-search huggingface dataset:
Optimization of the Ultrasound-Induced Blood-Brain Barrier Opening
Authors: Elisa E. Konofagou
Journal: Theranostics (2012)

Current treatments of neurological and neurodegenerative diseases are limited due to the lack of a truly non-invasive, transient, and regionally selective brain drug delivery method.The brain is particularly difficult to deliver drugs to because of the blood-brain barrier (BBB).The impermeability of the BBB is due to the tight junctions connecting adjacent endothelial cells and highly regulatory transport systems of the endothelial cell membranes.The main function of the BBB is ion and volume regulation to ensure conditions necessary for proper synaptic and axonal signaling.However, the same permeability properties that keep the brain healthy also constitute the cause of the tremendous obstacles posed in its pharmacological treatment.The BBB prevents most neurologically active drugs from entering the brain and, as a result, has been isolated as the rate-limiting factor in brain drug delivery.Until a solution to the trans-BBB delivery problem is found, treatments of neurological diseases will remain impeded.Over the past decade, methods that combine Focused Ultrasound (FUS) and microbubbles have been shown to offer the unique capability of noninvasively, locally and transiently open the BBB so as to treat central nervous system (CNS) diseases.Four of the main challenges that have been taken on by our group and discussed in this paper are: 1) assess its safety profile, 2) unveil the mechanism by which the BBB opens and closes, 3) control and predict the opened BBB properties and duration of the opening and 4) assess its premise in brain drug delivery.All these challenges will be discussed, findings in both small (mice) and large (non-human primates) animals are shown and finally the clinical potential for this technique is shown.
Eccrine poromas in a patient with mycosis fungoides treated with electron beam therapy.
Authors: M. Kurokawa, M. Amano, H. Miyaguni, S. Tateyama, K. Ogata, M. Idemori, M. Setoyama
Journal: British Journal of Dermatology (2001)

We describe a 72-year-old man with mycosis fungoides (MF) followed up at our hospital for more than 20 years, who has developed 14 eccrine poromas (EPs) in the past 12 years. Twelve of these tumours were ascertained as EP histopathologically without any findings of malignancy and the other two were clinically diagnosed and are not yet resected. To our knowledge, this is the first case report of MF complicated with multiple EPs. In our patient, all EPs arose in skin areas previously irradiated with an electron beam for the treatment of MF, suggesting that electron beam irradiation might have an effect on the development of EPs.
Effect of Hypokalemia and Hypomagnesemia Produced by Hemodialysis on Vascular Resistance in Canine Skeletal Muscle
Authors: D. K. Anderson, S. A. Roth, R. A. Brace, D. Radawski, F. J. Hoddy, J. B. Scott
Journal: Circulation Research (1972)

Hemodialysis was used to study the effect of an acute local decrease in plasma [K + ] or [Mg 2+ ] or in both on vascular resistance in skeletal muscle. A dialyzer was placed in the arterial supply of the collateral-free gracilis muscle of the dog and blood flow was held constant while measuring perfusion pressure. Pressure increased linearly with decreased [K + ] down to 0.2 mEq/liter. A 50% decrease in [K + ] produced a 12% increase in resistance. Prolonged hypokalemia produced a sustained increase in perfusion pressure and a decreased responsiveness to close arterial injection of norepinephrine. Removal of up to 84% of the plasma Mg 2+ produced no effect, either alone or in conjunction with hypokalemia. When the potassium level of the perfusing blood was changed from normal to hypokalemic during the dilation brought on by simulated exercise, the resistance did not change. In addition, the magnitude of the resistance changes seen during exercise were much greater than could be induced by local changes in plasma [K + ] alone. It is concluded that hypokalemia produces active constriction of vascular smooth muscle. However, this study fails to lend support to the idea that potassium alone is responsible for exercise dilation.
STUDIES ON THE MECHANISM OF RECOVERY IN PNEUMOCOCCAL PNEUMONIA
Authors: W. Barry Wood, Mary Ruth Smith, Barbara Watson
Journal: The Journal of Experimental Medicine (1946)

1. Evidence has been presented in previous publications that the phagocytosis of pneumococci in the pneumonic lung during chemotherapy is due neither to specific opsonins nor to capsular injury (1, 2). The present studies have shown that the phagocytosis taking place in the lung is independent of any sort of intermediary factor and results from a direct action of the phagocytic cells upon the pneumococci. 2. Phagocytosis in the absence of antibody has been demonstrated not only in the lungs of living rats but in formalin-fixed lungs, on the surfaces of a variety of tissues (both freshly removed from the animal and previously "killed" with heat), and on the surfaces of such inert materials as moistened filter paper, cloth, and fiber glass. On the other hand, smooth materials such as glass, cellophane, albumin, and paraffin have failed to support the phagocytic reaction. This latter observation indicates that the physical character of the surface to which the leucocytes have access constitutes a determining factor in the non-antibody mechanism of phagocytosis. 3. Further experiments have defined the relationship of "surface phagocytosis" to that induced by specific opsonins. The non-antibody mechanism was found to operate only upon surfaces of suitable physical properties, whereas opsonins enabled phagocytes floating freely in a fluid medium to engulf the fully encapsulated organisms. 4. Direct visualization of the surface phenomenon in the lung revealed that leucocytes phagocyte the virulent organisms in the absence of antibody only after having trapped them against the alveolar walls. Once the encapsulated pneumococci have been ingested, they can be seen to undergo digestion within a few hours. The discovery of the phenomenon of surface phagocytosis affords clarification of previously unanswered problems concerning the mechanism of recovery in pneumococcal pneumonia.
PPARγ deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage
Authors: Faezeh Vasheghani, Yue Zhang, Ying-Hua Li, Meryem Blati, Hassan Fahmi, Bertrand Lussier, Peter Roughley, David Lagares, Helal Endisha, Bahareh Saffar, Daniel Lajeunesse, Wayne K Marshall, Y Raja Rampersaud, Nizar N Mahomed, Rajiv Gandhi, Jean-Pierre Pelletier, Johanne Martel-Pelletier, Mohit Kapoor
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Objectives</h3> We have previously shown that peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor, is essential for the normal growth and development of cartilage. In the present study, we created inducible cartilage-specific PPARγ knockout (KO) mice and subjected these mice to the destabilisation of medial meniscus (DMM) model of osteoarthritis (OA) to elucidate the specific in vivo role of PPARγ in OA pathophysiology. We further investigated the downstream PPARγ signalling pathway responsible for maintaining cartilage homeostasis. <h3>Methods</h3> Inducible cartilage-specific PPARγ KO mice were generated and subjected to DMM model of OA. We also created inducible cartilage-specific PPARγ/mammalian target for rapamycin (mTOR) double KO mice to dissect the PPARγ signalling pathway in OA. <h3>Results</h3> Compared with control mice, PPARγ KO mice exhibit accelerated OA phenotype with increased cartilage degradation, chondrocyte apoptosis, and the overproduction of OA inflammatory/catabolic factors associated with the increased expression of mTOR and the suppression of key autophagy markers. In vitro rescue experiments using PPARγ expression vector reduced mTOR expression, increased expression of autophagy markers and reduced the expression of OA inflammatory/catabolic factors, thus reversing the phenotype of PPARγ KO mice chondrocytes. To dissect the in vivo role of mTOR pathway in PPARγ signalling, we created and subjected PPARγ-mTOR double KO mice to the OA model to see if the genetic deletion of mTOR in PPARγ KO mice (double KO) can rescue the accelerated OA phenotype observed in PPARγ KO mice. Indeed, PPARγ-mTOR double KO mice exhibit significant protection/reversal from OA phenotype. <h3>Significance</h3> PPARγ maintains articular cartilage homeostasis, in part, by regulating mTOR pathway.
Abstract P6-13-01: Impact of the Number of Prior Chemotherapy Regimens on Overall Survival (OS) among Subjects with Locally Recurrent or Metastatic Breast Cancer Treated with Eribulin Mesylate: Results from the Phase III EMBRACE Study
Authors: JL Blum, CJ Twelves, C Akerele, S Seegobin, J Wanders, J. Cortes
Journal: Cancer Research (2010)

Abstract Background: The randomized, controlled, open-label, phase III EMBRACE study compared the efficacy and safety of eribulin mesylate (E7389) vs. treatment of the physician's choice (TPC) in heavily pretreated subjects with late-stage breast cancer. The study met its primary endpoint by showing that eribulin significantly prolonged OS vs. TPC (HR: 0.809; 95% CI: 0.660-0.991; p=0.041). This exploratory subgroup analysis aimed to determine the influence of the number of prior regimens on OS among eribulin-treated subjects. Methods: Eligible subjects had locally recurrent or metastatic breast cancer and had received 2-5 prior chemotherapy regimens, including an anthracycline and a taxane, with ≥2 of the regimens given for locally recurrent or metastatic disease. Subjects had to show progression on or within 6 months of the last chemotherapy regimen. Subjects were stratified by geographic region, HER2/neu status, and prior capecitabine treatment and then randomized 2:1 to receive eribulin 1.4 mg/m2 intravenously over 2-5 minutes on Days 1 and 8 every 21 days or an approved TPC. Results: A total of 762 subjects in 135 centers worldwide were randomized to receive either eribulin (n=508) or TPC (n=254). Subjects had a median age of 55 years, 92% were white, 76% were postmenopausal, and 81 % had taxane-refractory disease. Overall, 47% and 53% of subjects had received ≥3 and &amp;gt;3 prior chemotherapy regimens in total, respectively. Seventy-five percent and 25% of subjects received ≥3 and &amp;gt;3 prior chemotherapy regimens in total for locally recurrent or metastatic disease, respectively. Subgroup analysis identified consistently longer median OS with eribulin vs. TPC in subjects who received ≥3 prior chemotherapy regimens, both in total and specifically for locally recurrent or metastatic disease (Table). Lesser improvements in OS with eribulin vs. TPC were observed in subjects who received &amp;gt;3 prior chemotherapy regimens. The study was not powered to show statistical significance for this subgroup analysis. Conclusion: In this retrospective subgroup analysis, the OS benefit with eribulin appears greater for subjects with locally recurrent or metastatic breast cancer who received fewer previous therapies. Additional studies are underway to confirm these findings in less heavily pretreated patients. Table. Overall survival by treatment history vs. TPC Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-13-01.
A Prospective Analysis of Airborne Metal Exposures and Risk of Parkinson Disease in the Nurses’ Health Study Cohort
Authors: Natalia Palacios, Kathryn Fitzgerald, Andrea L. Roberts, Jaime E. Hart, Marc G. Weisskopf, Michael A. Schwarzschild, Alberto Ascherio, Francine Laden
Journal: Environmental Health Perspectives (2014)

Background: Exposure to metals has been implicated in the pathogenesis of Parkinson disease (PD).Objectives: We sought to examine in a large prospective study of female nurses whether exposure to airborne metals was associated with risk of PD.Methods: We linked the U.S. Environmental Protection Agency (EPA)'s Air Toxics tract-level data with the Nurses' Health Study, a prospective cohort of female nurses. Over the course of 18 years of follow-up from 1990 through 2008, we identified 425 incident cases of PD. We examined the association of risk of PD with the following metals that were part of the first U.S. EPA collections in 1990, 1996, and 1999: arsenic, antimony, cadmium, chromium, lead, manganese, mercury, and nickel. To estimate hazard ratios (HRs) and 95% CIs, we used the Cox proportional hazards model, adjusting for age, smoking, and population density.Results: In adjusted models, the HR for the highest compared with the lowest quartile of each metal ranged from 0.78 (95% CI: 0.59, 1.04) for chromium to 1.33 (95% CI: 0.98, 1.79) for mercury.Conclusions: Overall, we found limited evidence for the association between adulthood ambient exposure to metals and risk of PD. The results for mercury need to be confirmed in future studies.Citation: Palacios N, Fitzgerald K, Roberts AL, Hart JE, Weisskopf MG, Schwarzschild MA, Ascherio A, Laden F. 2014. A prospective analysis of airborne metal exposures and risk of Parkinson disease in the Nurses' Health Study Cohort. Environ Health Perspect 122:933–938; http://dx.doi.org/10.1289/ehp.1307218
Improving the TB case management: the International Standards for Tuberculosis care
Authors: G. B. Migliori, P. C. Hopewell, F. Blasi, A. Spanevello, M. C. Raviglione
Journal: European Respiratory Journal (2006)

Tuberculosis (TB) is currently the leading cause of death from a curable infectious disease 1. The World Health Organization (WHO) estimates that 8.9 million new TB cases occurred in 2004 (of which 3.9 million were sputum smear positive), although only about half of the estimated number were reported by public health systems 1, 2.

Whilst the highest TB incidence rate is in sub-Saharan Africa (estimated to be 356 new cases per 100,000 population per yr), in most countries of the former Soviet Union the estimated incidence rate exceeds 100 new cases per 100,000 population per yr 1, 2.

Although the rate of increase in the TB incidence rate is decreasing, the global TB notification grew by 1% between 2003 and 2004, the last year for which data are available. This continued increase is largely the result of the striking increase in cases in sub-Saharan Africa and, to a lesser extent, in the former USSR. Whilst the worsening of the TB incidence in Africa is due to the HIV epidemic compounded by an insufficient health infrastructure, it is due to different causes in Eastern Europe, including economic decline, increased poverty, social disruption and sub-standard health services. In addition, as a result of these factors, >10% of new TB cases in the Baltic states and in some parts of Russia are multidrug-resistant (MDR-TB), i.e. resistant to at least isoniazid and rifampicin 3.

In the European region, 445,000 new TB cases and nearly 70,000 deaths …
Cell-Specific Regulatory Modules Control Expression of Genes in Vascular and Visceral Smooth Muscle Tissues
Authors: April M. Hoggatt, Gina M. Simon, B. Paul Herring
Journal: Circulation Research (2002)

A novel approach with chimeric SM22α/telokin promoters was used to identify gene regulatory modules that are required for regulating the expression of genes in distinct smooth muscle tissues. Conventional deletion or mutation analysis of promoters does not readily distinguish regulatory elements that are required for basal gene expression from those required for expression in specific smooth muscle tissues. In the present study, the mouse telokin gene was isolated, and a 370-bp (−190 to 180) minimal promoter was identified that directs visceral smooth muscle–specific expression in vivo in transgenic mice. The visceral smooth muscle–specific expression of the telokin promoter transgene is in marked contrast to the reported arterial smooth muscle–specific expression of a 536-bp minimal SM22α (−475 to 61) promoter transgene. To begin to identify regulatory elements that are responsible for the distinct tissue-specific expression of these promoters, a chimeric promoter in which a 172-bp SM22α gene fragment (−288 to −116) was fused to the minimal telokin promoter was generated and characterized. The −288 to −116 SM22α gene fragment significantly increased telokin promoter activity in vascular smooth muscle cells in vitro and in vivo. Conversely, a fragment of the telokin promoter (−94 to −49) increased the activity of the SM22α promoter in visceral smooth muscle cells of the bladder. Together, these data demonstrate that both vascular- and visceral smooth muscle–specific regulatory modules direct gene expression in subsets of smooth muscle tissues.
Keratinocyte growth factor-induced proliferation of rat airway epithelium is restricted to Clara cells in vivo
Authors: H. Fehrenbach, A. Fehrenbach, T. Pan, M. Kasper, R.J. Mason
Journal: European Respiratory Journal (2002)

Keratinocyte growth factor (KGF) is a potent mitogen of pulmonary bronchial and alveolar epithelial cells. However, it is unclear which type(s) of airway epithelial cells (AEC) proliferate(s) in response to KGF. AEC proliferation was induced in rats by either endobronchial instillation of 5 mg recombinant human (rHu) KGF per kg body weight or by adenoviral transfer of the human KGF gene (Ad5-HuKGF). Alterations in terminal airway AEC were followed for up to 7 days after rHuKGF, and for up to 28 days after Ad5-HuKGF. Cell proliferation, as assessed by immunohistochemistry (IHC) for incorporated 5-bromo-2′-deoxyuridine (BrdU) and quantified by stereology, peaked at days 1–2 and was resolved by day 7 after rHuKGF and by day 21 after Ad5-HuKGF. Double immunofluorescence labelling for BrdU or Ki-67 on the one hand, and for Clara cell specific protein 10 (CC10) and calcitonin-gene related peptide on the other hand, demonstrated that Clara cells, not pulmonary neuroendocrine cells, proliferated in response to human KGF. TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling) method in conjunction with IHC for MNF116 failed to detect significant numbers of apoptotic AEC. IHC in conjunction with stereology revealed transient phenotypic alterations with a decrease in CC10, an increase in surfactant protein D and an increase in CD44v6 in AEC. The authors conclude that Clara cells responded to human keratinocyte growth factor in vivo by proliferation as well as by changes in protein expression, whereas no significant response was observed in pulmonary neuroendocrine cells. As Clara cells are intimately involved in airway epithelial repair, ion and fluid transport, and modulate lung inflammation, the potential of human keratinocyte growth factor to protect the lung may in part rely on the response of Clara cells.
AA Amyloidosis: Pathogenesis and Targeted Therapy
Authors: Gunilla T. Westermark, Marcus Fändrich, Per Westermark
Journal: Annual Review of Pathology Mechanisms of Disease (2014)

The understanding of why and how proteins misfold and aggregate into amyloid fibrils has increased considerably during recent years. Central to amyloid formation is an increase in the frequency of the β-sheet structure, leading to hydrogen bonding between misfolded monomers and creating a fibril that is comparably resistant to degradation. Generation of amyloid fibrils is nucleation dependent, and once formed, fibrils recruit and catalyze the conversion of native molecules. In AA amyloidosis, the expression of cytokines, particularly interleukin 6, leads to overproduction of serum amyloid A (SAA) by the liver. A chronically high plasma concentration of SAA results in the aggregation of amyloid into cross-β-sheet fibrillar deposits by mechanisms not fully understood. Therefore, AA amyloidosis can be thought of as a consequence of long-standing inflammatory disease. This review summarizes current knowledge about AA amyloidosis. The systemic amyloidoses have been regarded as intractable conditions, but improvements in the understanding of fibril composition and pathogenesis over the past decade have led to the development of a number of different therapeutic approaches with promising results.
Degeneracy of Antigen Recognition as the Molecular Basis for the High Frequency of Naive A2/Melan-A Peptide Multimer+ CD8+ T Cells in Humans
Authors: Valérie Dutoit, Verena Rubio-Godoy, Mikäel J. Pittet, Alfred Zippelius, Pierre-Yves Dietrich, Frédérique Anne Legal, Philippe Guillaume, Pedro Romero, Jean-Charles Cerottini, Richard A. Houghten, Clemencia Pinilla, Danila Valmori
Journal: The Journal of Experimental Medicine (2002)

In contrast with the low frequency of most single epitope reactive T cells in the preimmune repertoire, up to 1 of 1,000 naive CD8+ T cells from A2+ individuals specifically bind fluorescent A2/peptide multimers incorporating the A27L analogue of the immunodominant 26–35 peptide from the melanocyte differentiation and melanoma associated antigen Melan-A. This represents the only naive antigen-specific T cell repertoire accessible to direct analysis in humans up to date. To get insight into the molecular basis for the selection and maintenance of such an abundant repertoire, we analyzed the functional diversity of T cells composing this repertoire ex vivo at the clonal level. Surprisingly, we found a significant proportion of multimer+ clonotypes that failed to recognize both Melan-A analogue and parental peptides in a functional assay but efficiently recognized peptides from proteins of self- or pathogen origin selected for their potential functional cross-reactivity with Melan-A. Consistent with these data, multimers incorporating some of the most frequently recognized peptides specifically stained a proportion of naive CD8+ T cells similar to that observed with Melan-A multimers. Altogether these results indicate that the high frequency of Melan-A multimer+ T cells can be explained by the existence of largely cross-reactive subsets of naive CD8+ T cells displaying multiple specificities.
Overexpression of the 5-Hydroxytryptamine Transporter Gene
Authors: Margaret R. MacLean, Graeme A. Deuchar, Martin N. Hicks, Ian Morecroft, Sanbing Shen, John Sheward, Janet Colston, Lynn Loughlin, Margaret Nilsen, Yvonne Dempsie, Anthony Harmar
Journal: Circulation (2004)

Background— Increased serotonin (5-hydroxytryptamine, 5-HT) transporter activity has been observed in human familial pulmonary hypertension. Methods and Results— We investigated pulmonary hemodynamics and the development of hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling in mice overexpressing the gene for the 5-HT transporter (5-HTT+ mice). Right ventricular pressure was elevated 3-fold in normoxic 5-HTT+ mice compared with their wild-type controls. Hypoxia-induced increases in right ventricular hypertrophy and pulmonary vascular remodeling were also potentiated in the 5-HTT+ mice. 5-HTT–like immunoreactivity, protein, and binding sites were markedly increased in the lungs from the 5-HTT+ mice. Hypoxia, however, decreased 5-HT transporter immunoreactivity, mRNA transcription, protein, and binding sites in both wild-type and 5-HTT+ mice. Conclusions— Increased 5-HT transporter expression causes elevated right ventricular pressures, and this occurs before the onset of right ventricular hypertrophy or pulmonary arterial remodeling. Hypoxia-induced remodeling is, however, increased in 5-HTT+ mice, whereas hypoxia inhibits 5-HTT expression. This provides a unique model that demonstrates differential mechanisms for familial pulmonary arterial hypertension and pulmonary arterial hypertension with hypoxemia.