tbuckley/cabot-search huggingface dataset:
The Glomerular Slit Diaphragm Is a Modified Adherens Junction
Authors: JOCHEN REISER, WILHELM KRIZ, MATTHIAS KRETZLER, PETER MUNDEL
Journal: Journal of the American Society of Nephrology (2000)

The glomerular slit diaphragm between podocyte foot processes shares typical morphologic features with an adherens junction. Differentiated cultured podocytes form cellular structures comparable to filtration slits in vivo. At those sites, zonula occludens-1 (ZO-1) was coexpressed with P-cadherin as well as with alpha-, beta-, and gamma-catenin. In situ, P-cadherin was detected at the slit diaphragm in association with ZO-1 as shown by confocal microscopy and immunogold double labeling electron microscopy. P-cadherin expression in vivo and in vitro was confirmed by reverse transcription-PCR. These findings led to the concept that the slit diaphragm represents an adherens junction composed of P-cadherin, alpha-, beta-, and gamma-catenin, and ZO-1. In contrast to an adherens junction of a similar composition recently described in cultured fibroblasts, the slit diaphragm complex does not contain vinculin, which was found in nearby focal contacts. A P-cadherin-based adherens junction is well-suited to explain the zipper-like structure of the slit diaphragm. The present study should allow new avenues leading to the identification of additional slit diaphragm-associated proteins conferring specificity to this unique cell junction.
Heat shock factor binding in Alu repeats expands its involvement in stress through an antisense mechanism
Authors: Rajesh Pandey, Amit K Mandal, Vineet Jha, Mitali Mukerji
Journal: Genome biology (2011)

Abstract Background Alu RNAs are present at elevated levels in stress conditions and, consequently, Alu repeats are increasingly being associated with the physiological stress response. Alu repeats are known to harbor transcription factor binding sites that modulate RNA pol II transcription and Alu RNAs act as transcriptional co-repressors through pol II binding in the promoter regions of heat shock responsive genes. An observation of a putative heat shock factor (HSF) binding site in Alu led us to explore whether, through HSF binding, these elements could further contribute to the heat shock response repertoire. Results Alu density was significantly enriched in transcripts that are down-regulated following heat shock recovery in HeLa cells. ChIP analysis confirmed HSF binding to a consensus motif exhibiting positional conservation across various Alu subfamilies, and reporter constructs demonstrated a sequence-specific two-fold induction of these sites in response to heat shock. These motifs were over-represented in the genic regions of down-regulated transcripts in antisense oriented Alus. Affymetrix Exon arrays detected antisense signals in a significant fraction of the down-regulated transcripts, 50% of which harbored HSF sites within 5 kb. siRNA knockdown of the selected antisense transcripts led to the over-expression, following heat shock, of their corresponding down-regulated transcripts. The antisense transcripts were significantly enriched in processes related to RNA pol III transcription and the TFIIIC complex. Conclusions We demonstrate a non-random presence of Alu repeats harboring HSF sites in heat shock responsive transcripts. This presence underlies an antisense-mediated mechanism that represents a novel component of Alu and HSF involvement in the heat shock response.
Adventure of Gene Therapy Into the Brain: A New Era for Cardiovascular Gene Therapy
Authors: Ryuichi Morishita
Journal: Circulation Research (2000)

ene therapy is emerging as a potential strategy for the treatment of cardiovascular diseases such as peripheral arterial disease, myocardial infarction, restenosis after angioplasty, and vascular bypass graft occlusion, for which current therapy is often inadequate.The first federally approved human gene therapy protocol started on September 14, 1990, in patients with adenosine deaminase deficiency.Ten years after the commencement of the first trial, more than 30 clinical studies of gene therapy for cardiovascular disease are under investigation.First, Isner and colleagues demonstrated the potential utility of gene therapy using an angiogenic growth factor (vascular endothelial growth factor [VEGF]) for the treatment of critical limb ischemia in human patients. 1,2More recently, his group revealed the usefulness of gene therapy using VEGF to treat ischemic heart disease. 3,4Although there are still many unresolved issues, human gene therapy for cardiovascular disease is now becoming a reality.
Substance P receptor expression in human skin keratinocytes and fibroblasts
Authors: J-Y. Liu, J-H. Hu, Q-G. Zhu, F-Q. Li, H-J. Sun
Journal: British Journal of Dermatology (2006)

Background There is increasing evidence that neuropeptides, especially substance P (SP), may be involved in the pathogenesis of cutaneous allergic inflammation (CAI). Objectives To investigate expression of the SP receptor (neurokinin-1 receptor, NK-1R) in human epidermal keratinocytes and dermal fibroblasts and its potential influence in CAI. Methods HaCaT cells (a human epidermal keratinocyte cell line) and dermal fibroblasts were cultured. The expression of NK-1R protein was examined by immunohistochemistry, and the mRNA level was detected by semiquantitative reverse transcriptase–polymerase chain reaction. The modulation of NK-1R expression in HaCaT cells and fibroblasts was detected by flow cytometry and Western blotting analysis. Results NK-1R expression was found in HaCaT cells and fibroblasts. The expression of NK-1R mRNA in fibroblasts was weaker than in HaCaT cells. SP and interferon (IFN)-γ significantly upregulated the expression of NK-1R. [d-Arg1, d-Trp7,9 Leu11]-SP (Spantide I), a panspecific NK-1R antagonist, reduced the expression of NK-1R stimulated by SP. Conclusions HaCaT cells and fibroblasts can express NK-1R at protein and transcription levels, and the expression was modulated by SP, IFN-γ and Spantide I. This indicates that keratinocytes and fibroblasts are involved in the regulation of skin immunity and that NK-1R may play an important role in the pathogenesis of CAI.
Transcytosis of <i>Listeria monocytogenes</i> across the intestinal barrier upon specific targeting of goblet cell accessible E-cadherin
Authors: Georgios Nikitas, Chantal Deschamps, Olivier Disson, Théodora Niault, Pascale Cossart, Marc Lecuit
Journal: The Journal of Experimental Medicine (2011)

Listeria monocytogenes (Lm) is a foodborne pathogen that crosses the intestinal barrier upon interaction between its surface protein InlA and its species-specific host receptor E-cadherin (Ecad). Ecad, the key constituent of adherens junctions, is typically situated below tight junctions and therefore considered inaccessible from the intestinal lumen. In this study, we investigated how Lm specifically targets its receptor on intestinal villi and crosses the intestinal epithelium to disseminate systemically. We demonstrate that Ecad is luminally accessible around mucus-expelling goblet cells (GCs), around extruding enterocytes at the tip and lateral sides of villi, and in villus epithelial folds. We show that upon preferential adherence to accessible Ecad on GCs, Lm is internalized, rapidly transcytosed across the intestinal epithelium, and released in the lamina propria by exocytosis from where it disseminates systemically. Together, these results show that Lm exploits intrinsic tissue heterogeneity to access its receptor and reveal transcytosis as a novel and unanticipated pathway that is hijacked by Lm to breach the intestinal epithelium and cause systemic infection.
Impact of different low-density lipoprotein (LDL) receptor mutations on the ability of LDL to support lymphocyte proliferation
Authors: Javier Martínez-Botas, Yajaira Suárez, Ayeleth Reshef, Pilar Carrero, Henar Ortega, Diego Gómez-Coronado, JoséLuis Teruel, Eran Leitersdorf, Miguel A. Lasunción
Journal: Metabolism (1999)
Pediatric Cancers Are Infiltrated Predominantly by Macrophages and Contain a Paucity of Dendritic Cells: a Major Nosologic Difference with Adult Tumors
Authors: Jukka Vakkila, Ronald Jaffe, Marilyn Michelow, Michael T. Lotze
Journal: Clinical Cancer Research (2006)

Adult cancer is frequently preceded by a period of prolonged chronic inflammation caused by infectious microbial agents or physical or chemical irritants. By contrast, an association between the classic pediatric neoplasias and inflammatory triggers is only rarely recognized. We hypothesized that the difference could be reflected in the inflammatory cell infiltrates of pediatric and adult cancer.Three investigators retrospectively studied 27 pediatric and 13 adult cancers at first diagnosis by immunohistochemistry. Inflammatory cells were identified and counted, and their location in relation to tumor tissue was analyzed.A majority of tumor-associated leukocytes (TAL) in adult tumors were located at the edges of tumor islands forming inflammatory foci between the supporting stroma and the malignant infiltrate. In contrast, TALs in pediatric tumors were scattered within the malignant tumor islands. In adult tumors, TALs were composed of diverse leukocyte types; but in pediatric tumors, the infiltrating cells were predominantly macrophages that accumulated in areas of necrosis within the tumors. The most striking feature in the pediatric tumors was the virtual absence of dendritic cells. The proportion of intratumoral dendritic cells in pediatric samples was 4.1%; whereas in adult tumors, they formed 36.9% of TALs within the tumor islands and 25.1% around the tumors.We conclude that TALs in pediatric cancers are composed mainly of macrophages and largely devoid of dendritic cell. The findings may provide a major nosologic difference reclassifying pediatric and adult tumors based on nominal inflammatory and noninflammatory etiologies.
Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts
Authors: Kiichi Nakahira, Hong Pyo Kim, Xue Hui Geng, Atsunori Nakao, Xue Wang, Noriko Murase, Peter F. Drain, Xiaomei Wang, Madhu Sasidhar, Elizabeth G. Nabel, Toru Takahashi, Nicholas W. Lukacs, Stefan W. Ryter, Kiyoshi Morita, Augustine M.K. Choi
Journal: The Journal of Experimental Medicine (2006)

Carbon monoxide (CO), a byproduct of heme catabolism by heme oxygenase (HO), confers potent antiinflammatory effects. Here we demonstrate that CO derived from HO-1 inhibited Toll-like receptor (TLR) 2, 4, 5, and 9 signaling, but not TLR3-dependent signaling, in macrophages. Ligand-mediated receptor trafficking to lipid rafts represents an early event in signal initiation of immune cells. Trafficking of TLR4 to lipid rafts in response to LPS was reactive oxygen species (ROS) dependent because it was inhibited by diphenylene iodonium, an inhibitor of NADPH oxidase, and in gp91phox-deficient macrophages. CO selectively inhibited ligand-induced recruitment of TLR4 to lipid rafts, which was also associated with the inhibition of ligand-induced ROS production in macrophages. TLR3 did not translocate to lipid rafts by polyinosine-polycytidylic acid (poly(I:C)). CO had no effect on poly(I:C)-induced ROS production and TLR3 signaling. The inhibitory effect of CO on TLR-induced cytokine production was abolished in gp91phox-deficient macrophages, also indicating a role for NADPH oxidase. CO attenuated LPS-induced NADPH oxidase activity in vitro, potentially by binding to gp91phox. Thus, CO negatively controlled TLR signaling pathways by inhibiting translocation of TLR to lipid rafts through suppression of NADPH oxidase–dependent ROS generation.
Antibodies to membrane structures that distinguish suppressor/cytotoxic and helper T lymphocyte subpopulations block the mixed leukocyte reaction in man.
Authors: E G Engleman, C J Benike, E Glickman, R L Evans
Journal: The Journal of Experimental Medicine (1981)

Two major subsets of human T lymphocytes that are functionally analogous to the mouse Lyt-2+ and Lyt-2- subsets have been defined by their expression of two thymus-dependent membrane antigens, Leu-2 and Leu-3. Leu-2+,3- cells have suppressor/cytotoxic functions and Leu-2-,3+ cells have helper functions. These studies were designed to determine the effects of adding IgG1 monoclonal anti-Leu-2 and anti-Leu-3 antibodies to the mixed leukocyte reaction (MLR). At high concentrations, each antibody partially inhibited the proliferative response of unseparated T cells and abolished the response of the isolated subset having the appropriate phenotype. An IgG1 monoclonal antibody to HLA-A2 and an IgG2a antibody to Leu-1, a pan-T antigen, failed to inhibited the MLR. These results suggest that the Leu-2 and Leu-3 antigens may have a direct role in the mechanism whereby T cells recognize and respond to alloantigen.
STUDIES ON THE MODE OF ACTION OF DIPHTHERIA TOXIN
Authors: Peter F. Bonventre, John G. Imhoff
Journal: The Journal of Experimental Medicine (1966)

The effect of crystalline diphtheria toxin on protein synthesis in vivo was evaluated in guinea pigs and mice. By two independent methods of analysis (microdensitometry of tissue radioautograms and radioactivity of tissue proteins), it was established that inhibition of protein synthesis was not a widespread metabolic effect of diphtheria toxin. In the sensitive guinea pig, only the heart and the pancreas showed any demonstrable reduction in the quantity of tritiated leucine incorporated into proteins following challenge of the animals with the crystalline toxin. No such inhibition was noted in mice which are resistant to the action of diphtheria toxin. The effect on the pancreas involved a decrease in the synthesis of pancreatic enzymes and their subsequent secretion. For reasons discussed, it was concluded that this lesion was not as significant as the inhibition of protein synthesis in the heart tissues. Although the rate of protein turnover in heart muscle is relatively low, an inhibition of 73% was noted when the exchange period with the tritiated leucine was 6 hr. It was suggested that the inhibition of protein synthesis in heart tissues could provide a biochemical rationale for the site and mode of action of diphtheria toxin in the sensitive mammalian host. An attempt was also made to correlate the biochemical heart lesion described here with past clinical evidence of cardiac failure and tissue pathology noted in many cases of fatal diphtheria infections of humans.
Anti-neutrophil elastase defense of the normal human respiratory epithelial surface provided by the secretory leukoprotease inhibitor.
Authors: C Vogelmeier, R C Hubbard, G A Fells, H P Schnebli, R C Thompson, H Fritz, R G Crystal
Journal: Journal of Clinical Investigation (1991)

Secretory leukoprotease inhibitor (SLPI), a 12-kD nonglycosylated serine antiprotease with a high capacity for inhibiting neutrophil elastase (NE), is produced by cells of mucosal surfaces including the human lung. The molar concentrations of SLPI in total respiratory tract epithelial lining fluid (ELF) were 56 +/- 10% that of alpha 1-antitrypsin, suggesting SLPI may be more important for the anti-NE protection of the pulmonary epithelial surface than previously thought. However, evaluation demonstrated that SLPI in respiratory ELF was only one-third functional. Studies aerosolizing recombinant SLPI (rSLPI) to sheep demonstrated that in the short term, neither aerosolization and alveolar deposition nor the lavage procedure inactivated the SLPI molecule. In vitro studies with rSLPI demonstrated that exposure to oxidants did not modify the form of the molecule, while exposure to oxidants and NE caused the molecule to be cleaved from 12 to 8 kD. Consistent with this, evaluation of SLPI in lavage fluid of individuals with cystic fibrosis (a condition with oxidants and NE on the respiratory epithelium) showed that the SLPI was degraded. However, evaluation of SLPI in normal ELF by molecular sieve analysis and Western analysis demonstrated an intact 12-kD molecule, suggesting that the partial inactivation of SLPI in normals in vivo is not because it is complexed to NE or exposed to oxidants + NE. Together, these observations demonstrate that SLPI is present in large amounts in respiratory ELF, but since the majority of the SLPI is inactive, it likely does not play a significant role in protecting the normal respiratory epithelium, except perhaps in the upper airways where the levels of SLPI are the highest.
Hygiene, atopy and wheeze–eczema–rhinitis symptoms in schoolchildren from urban and rural Ecuador
Authors: Philip J Cooper, Maritza Vaca, Alejandro Rodriguez, Martha E Chico, Darci N Santos, Laura C Rodrigues, Mauricio L Barreto
Journal: Thorax (2013)

<h3>Background</h3> Rural residence is protective against atopy and wheeze–rhinitis–eczema symptoms in developed countries, an effect attributed to farming and poor hygiene exposures. There are few data from developing countries addressing this question. We compared atopy and wheeze–rhinitis–eczema symptoms between urban and rural Ecuador, and explored the effects of farming and poor hygiene exposures. <h3>Methods</h3> We performed cross sectional studies of schoolchildren living in rural and urban Ecuador. Data on symptoms and farming/hygiene exposures were collected by parental questionnaire, atopy by allergen skin prick test reactivity and geohelminth infections by stool examinations. <h3>Results</h3> Among 2526 urban and 4295 rural schoolchildren, prevalence was: atopy (10.0% vs 12.5%, p=0.06), wheeze (9.4% vs 10.1%, p=0.05), rhinitis (8.1% vs 6.4%, p=0.02) and eczema (5.9% vs 4.7%, p=0.06). A small proportion of symptoms were attributable to atopy (range 3.9–10.7%) with greater attributable fractions for respiratory symptoms observed in urban schoolchildren. Respiratory symptoms were associated with poor hygiene/farming exposures: wheeze with lack of access to potable water; and rhinitis with household pets, no bathroom facilities and contact with large farm animals. Birth order was inversely associated with respiratory symptoms. Area of residence and atopy had few effects on these associations. <h3>Conclusions</h3> Urban schoolchildren living in Ecuador have a similar prevalence of atopy, eczema and wheeze but a higher prevalence of rhinitis compared with rural children. Some farming and poor hygiene exposures were associated with an increase in the prevalence of wheeze or rhinitis while birth order was inversely associated with these symptoms.
Acute myeloid leukemia-type chemotherapy for newly diagnosed patients without antecedent cytopenias having myelodysplastic syndrome as defined by French-American-British criteria: a Cancer and Leukemia Group B Study.
Authors: S H Bernstein, V L Brunetto, F R Davey, D Wurster-Hill, R J Mayer, R M Stone, C A Schiffer, C D Bloomfield
Journal: Journal of Clinical Oncology (1996)

PURPOSE To determine the treatment outcome of standard acute myeloid leukemia (AML)-type chemotherapy in a subset of patients with newly diagnosed myelodysplastic syndromes (MDS) compared with that of patients with de novo AML as defined using French-American-British (FAB) criteria. In addition, to determine the pretreatment variables having prognostic significance for treatment outcome in patients with MDS. PATIENTS AND METHODS Nine hundred seven newly diagnosed patients with no history of cytopenias having a local institutional de novo AML successfully karyotyped and treated on Cancer and Leukemia Group B (CALGB) protocols for AML from 1984 to 1992. Thirty-three of the 907 patients were reclassified as having MDS on central pathology review using FAB criteria and form the basis of this analysis. RESULTS The treatment outcomes for patients with MDS and AML were similar; the complete remission (CR) rate was 79% and 68%, respectively (P = .37); median CR duration was 11 and 15 months, respectively (P = .28); and median survival was 13 and 16 months, respectively (P = .72). For the MDS patients, there were no prognostic variables for CR rate identified. For CR duration, only the Sanz classification had prognostic value. The prognostic factors for survival in a univariate analysis included age, WBC count, Sanz classification, and percent blood blasts. In a proportional hazards analysis of survival, age greater than 60 years and WBC less than 2.6 x 10(9)/L were adverse prognostic factors. CONCLUSION In patients with no known history of cytopenias who are treated intensively at diagnosis, the FAB distinctions between MDS (refractory anemia with excess blasts and refractory anemia with excess blasts in transformation) and AML appear to have little therapeutic relevance.
Nonlinear pharmacokinetics of high-dose recombinant fusion protein CD4-IgG2 (PRO 542) observed in HIV-1–infected children
Authors: Courtney V. Fletcher, Jaime G. DeVille, Pearl M. Samson, John H. Moye, Joseph A. Church, Hans M.L. Spiegel, Paul Palumbo, Terence Fenton, M. Elizabeth Smith, Bobbie Graham, Joyce M. Kraimer, William T. Shearer
Journal: Journal of Allergy and Clinical Immunology (2007)
Lymphocyte-rich classical Hodgkin lymphoma (LRCHL): clinico-pathological characteristics and outcome of a rare entity
Authors: D. de Jong, J. Bosq, K.A. MacLennan, J. Diebold, J. Audouin, J. Chasle, A.-M. Mandard, J. Marnay, M. Henry-Amar
Journal: Annals of Oncology (2005)
Disposal of plasma heme in normal man and patients with intravascular hemolysis
Authors: David A. Sears
Journal: Journal of Clinical Investigation (1970)

The clearance of plasma protein-bound heme, its sites of removal, and the reutilization of hemeiron were studied by radioisotopic techniques in normal human subjects and in patients with intravascular hemolysis. In normal subjects, injected heme-(59)Fe was bound immediately by albumin and the beta(1)-globulin, hemopexin. Its clearance from the plasma was descr bed by a single exponential equation, and the half-life in plasma was 7-8 hr. Removal was largely by the liver. Iron reutilization began promptly, and half the injected heme-iron was incorporated into circulating red cells within one cell life-span. In patients with intravascular hemolysis, hemopexin was depleted, and injected heme was bound solely to albumin. Plasma clearance was described by a double exponential equation of the form: y = Ae(-k1t) + Be(-k2t). The half-lives of the two components averaged 3.9 and 22.2 hr, respectively. Removal was by the liver in at least some of the patients, and iron reutilization was variable, depending on the state of body iron stores. When hemopex'n was depleted in a normal subject by repeated heme injection, clearance mimicked that observed in the patients.
Acquired and natural immunity to gonococcal infection in chimpanzees.
Authors: S J Kraus, W J Brown, R J Arko
Journal: Journal of Clinical Investigation (1975)

Despite the fact that gonorrhea is our most common reportable infectious disease, little is known about natural and acquired resistance to Neisseria gonorrhoeae. With the chimpanzee model, which mimics human gonococcal infection in signs, symptoms, and host response, a natural resistance to gonococcal challenge was found. One aspect of this natural resistance became evident when the cervix and oral pharynx resisted more gonococci than the urethra. Natural resistance was also shown when environmental factors were found to influence resistance to gonococcal pharyngitis. In addition to natural resistance a postinfection-acquired immunity to the gonococcus was demonstrated. Following gonococcal pharyngitis, this anatomical location successfully resisted more gonococci than were initially resisted. Similarly, more gonococci were successfully resisted in rechallenging the urethra. These findings are related to the clinic situation and suggest possible new approaches to gonorrhea control.