tbuckley/cabot-search huggingface dataset:
Indigenous enteric eosinophils control DCs to initiate a primary Th2 immune response in vivo
Authors: Derek K. Chu, Rodrigo Jimenez-Saiz, Christopher P. Verschoor, Tina D. Walker, Susanna Goncharova, Alba Llop-Guevara, Pamela Shen, Melissa E. Gordon, Nicole G. Barra, Jennifer D. Bassett, Joshua Kong, Ramzi Fattouh, Kathy D. McCoy, Dawn M. Bowdish, Jonas S. Erjefält, Oliver Pabst, Alison A. Humbles, Roland Kolbeck, Susan Waserman, Manel Jordana
Journal: The Journal of Experimental Medicine (2014)

Eosinophils natively inhabit the small intestine, but a functional role for them there has remained elusive. Here, we show that eosinophil-deficient mice were protected from induction of Th2-mediated peanut food allergy and anaphylaxis, and Th2 priming was restored by reconstitution with il4+/+ or il4−/− eosinophils. Eosinophils controlled CD103+ dendritic cell (DC) activation and migration from the intestine to draining lymph nodes, events necessary for Th2 priming. Eosinophil activation in vitro and in vivo led to degranulation of eosinophil peroxidase, a granule protein whose enzymatic activity promoted DC activation in mice and humans in vitro, and intestinal and extraintestinal mouse DC activation and mobilization to lymph nodes in vivo. Further, eosinophil peroxidase enhanced responses to ovalbumin seen after immunization. Thus, eosinophils can be critical contributors to the intestinal immune system, and granule-mediated shaping of DC responses can promote both intestinal and extraintestinal adaptive immunity.
Ionic Determinants of Atrial Fibrillation and Ca <sup>2+</sup> Channel Abnormalities
Authors: Stanley Nattel
Journal: Circulation Research (1999)

ver the past several years, there has been increasing interest in understanding the basic mechanisms underlying atrial fibrillation (AF).The rise in interest is partly related to the prevalence of AF, which is presently the most common arrhythmia in clinical practice, and partly to the fact that the treatment of AF remains inadequate, making new insights into basic mechanisms essential for improving therapy. 1 Of great importance, as well, has been the development of new, clinically relevant animal models of the arrhythmia 2,3 and advances in scientific methodology, including high-density mapping, patch-clamp recording, and molecular cloning of ion channels, that have permitted much more sophisticated approaches to defining AF mechanisms at very basic levels.The studies by Van Wagoner et al 4 reported in this issue of Circulation Research provide important information about the potential role of Ca 2ϩ channel abnormalities in clinical AF and at the same time, raise some intriguing questions.To appreciate the results of these findings presented by Van Wagoner et al, it is important to place them in the context of preceding work on the ionic determinants of AF.
The cryopreservation of ovarian tissue as a strategy for preserving the fertility of cancer patients
Authors: H Newton
Journal: Human Reproduction Update (1998)

The cryopreservation of ovarian tissue is a promising new method for conserving the fecundity of young cancer patients from the sterilizing effects of chemotherapy and/or radiotherapy. In murine and ovine studies the orthotopic insertion of frozen-thawed ovarian grafts into sterilized hosts has resulted in the birth of healthy offspring. Examination of human ovarian tissue after cryopreservation has shown that substantial numbers of morphologically normal and viable primordial follicles survive freeze-thawing. To date however, there is no efficient procedure for using the frozen-banked tissue to restore fertility to patients with ovarian failure. Autografting at an orthotopic or heterotopic site has the greatest potential for success but there is concern that the technique may reintroduce malignant cells to patients in remission from disease. Follicle isolation from the thawed tissue and growth to maturity in vitro is a preferable option but at present the technique is in its infancy. This review presents past and present research in the field of ovarian tissue cryopreservation and explores the possible strategies by which frozen-banked tissue from cancer patients could be used to restore fertility.
Role of Angiotensin II–Regulated Apoptosis Through Distinct AT <sub>1</sub> and AT <sub>2</sub> Receptors in Neointimal Formation
Authors: Jun Suzuki, Masaru Iwai, Hironori Nakagami, Lan Wu, Rui Chen, Takashi Sugaya, Mareomi Hamada, Kunio Hiwada, Masatsugu Horiuchi
Journal: Circulation (2002)

Background— In vitro studies suggest that angiotensin II type 1 and type 2 (AT 1 and AT 2 ) receptors exert opposite effects in terms of vasoconstriction, natriuresis, and cell growth, but the role of these receptors in cardiovascular remodeling in vivo is still an enigma. In this study, we tested the hypothesis that AT 2 exerts an antiproliferative effect by inducing apoptosis, thereby antagonizing AT 1a in vascular remodeling. Methods and Results— Vascular injury was induced by polyethylene cuff placement around the left femoral artery of AT 1a -null (AT 1a KO), AT 2 -null (AT 2 KO), and wild-type mice. Neointimal formation as well as DNA synthesis in vascular smooth muscle cells (VSMC) after vascular injury was exaggerated in AT 2 KO mice, but they were both suppressed in AT 1a KO mice compared with those in wild-type mice. In contrast, the number of apoptotic cells in the injured artery in VSMC was significantly increased in AT 1a KO mice but decreased in AT 2 KO mice. Reverse transcriptase–polymerase chain reaction analysis revealed that the expression of bax mRNA was attenuated in AT 2 KO mice. On the other hand, the expression of bcl-2 and bcl-x L mRNA was enhanced in AT 2 KO mice but attenuated in AT 1a KO mice. Immunohistochemical staining with antibody to the bcl-2 protein family supported these results. Conclusions— Our results suggest that AT 2 exerts antiproliferative effects and proapoptotic changes in VSMC by counteracting AT 1a in the process of neointimal formation after vascular injury.
Treatment for Myeloma Bone Disease
Authors: Howard S. Yeh, James R. Berenson
Journal: Clinical Cancer Research (2006)

Abstract Multiple myeloma (MM) is a B cell malignancy characterized by enhanced bone loss commonly associated with diffuse osteopenia, focal lytic lesions, pathologic fractures, hypercalcemia, and bony pain. Bone destruction in MM results from asynchronous bone turnover wherein increased osteoclastic bone resorption is not accompanied by a comparable increase in bone formation. Consequently, patients with MM frequently require radiation therapy, surgery, and analgesic medications. The recent development of minimally invasive surgical procedures such as kyphoplasty allows patients with myeloma with vertebral compression fractures to have immediate improvement in their quality of life with shorter hospital stays. Bisphosphonates are specific inhibitors of osteoclastic activity, and these agents have been evaluated in patients with MM with bone disease during the past 15 years. Monthly i.v. infusions of either pamidronate or zoledronic acid have reduced the skeletal complications among patients with MM and are now a mainstay of myeloma therapy. Orally administered bisphosphonates, in contrast, have shown little ability to slow the development of skeletal complications in these patients. Although preclinical studies suggest that nitrogen-containing bisphosphonates have potent antitumor effects, clinical trials will be necessary, probably at higher doses given more slowly, to establish their possible antitumor effects clinically. Moreover, recent advances in the use of bone-seeking radiopharmaceuticals make these attractive therapeutic candidates to combine with bisphosphonates or radiosensitizing drugs (e.g., bortezomib) to achieve a synergistic effect. As our understanding of the pathophysiology of myeloma bone disease continues to grow, new target therapies will continue to emerge, offering new and more advanced options for the management of myeloma bone disease.
Case-based discussion from North Tyneside General Hospital: somatostatin analogues in yellow nail syndrome associated with recurrent pleural effusions
Authors: Kristian G Brooks, Carlos Echevarria, David Cooper, Stephen C Bourke
Journal: Thorax (2014)

Kristian Brooks (KB): A 77-year-old man presented to accident and emergency with a 1-month history of progressive breathlessness and reduced exercise tolerance. He had no chest pain, cough or wheeze, but had bilateral leg swelling and 4 kg weight loss. He had long-standing nail dystrophy and, following presentation with recurrent lower respiratory tract infections several years previously, bronchiectasis had been confirmed on high-resolution CT. He was a lifelong non-smoker, but had significant occupational asbestos exposure. There was no relevant family history. Chest radiograph showed large bilateral pleural effusions. Blood tests, including markers of infection and inflammation, were unremarkable. An ultrasound-guided pleural tap showed a lymphocytic exudate.

Stephen C Bourke (SCB): The combination of nail dystrophy, lymphocytic pleural effusions, bronchiectasis and lymphoedema is consistent with yellow nail syndrome (YNS), but coexistent malignancy or other pathology should be excluded, particularly in view of the history of weight loss and asbestos exposure. Pleural fluid should be sent for cholesterol and triglycerides, cytology and culture, including mycobacterium TB. Thoracic CT and echocardiography should be performed. Overall, the most common causes for lymphocytic effusions are malignancy or TB. In a case series of 41 patients with YNS, around half had pleural effusions, which were predominantly lymphocyte-rich and more often bilateral than unilateral.1 Chylothorax may also occur in YNS, classically appearing milky white due to high levels of triglycerides, but may be yellow or blood stained.

KB: No malignant cells were seen in the pleural fluid, and TB stain and culture were negative. Thoracic CT showed bilateral effusions, segmental consolidation in the left lower lobe and bilateral pleural plaques, but no pulmonary masses or lymphadenopathy. Echocardiography showed normal biventricular function and no evidence of a pericardial effusion. Previous medical …
Clinical Cancer Advances 2012 and Neoadjuvant Chemoradiotherapy in Operable Gastroesophageal Cancers
Authors: Peter A. Beatty, George Laking
Journal: Journal of Clinical Oncology (2013)

from that of patients in CR, as well as patients whose disease progresses slowly at a pace similar to that of patients in PR, despite a lack of response to therapy.In most patients, immunoglobulin light chain amyloidosis is a rapidly progressing disease, and treatment succeeds in altering its course only if it can improve or at least prevent progression of vital organ damage, and inparticular,cardiacdysfunction. 4 Manyearlydeathsoccurinthefirstfew months after diagnosis in patients with advanced heart involvement who do not survive long enough to be evaluable for response.However, a significant proportion of deaths occur between 3 and 12 months after treatment initiation, as emphasized by the current analysis.Thus, it is imperative that patients are observed quite closely to detect early treatment failure and unsatisfactory responses.Patients with inadequate treatment outcomes should be promptly offered second-line therapies.The analyses of our cohort and of the Boston University patient population suggest that evaluation of response at 1 year does not allow this fine discrimination and timely intervention.We recommend that hematologic response be assessed earlier, possibly no later than 3 months after treatment initiation.Clearly, PR is not a satisfactory treatment end point, but can slow the pace of the disease, widening the therapeutic window.As for patients in VGPR, the majority will have excellent outcomes, but some will still progress in the first few months after evaluation of response.These latter patients, who require further treatment, could be identified by the absence of organ improvement, coupling measurement of biomarkers of organ function with assessment of hematologic response.
Neurokinin<sub>1</sub> Receptor Antagonists as Potential Antidepressants
Authors: Steven C. Stout, Michael J. Owens, Charles B. Nemeroff
Journal: The Annual Review of Pharmacology and Toxicology (2001)

Selective, nonpeptide antagonists for tachykinin receptors first became available ten years ago. Of the three known tachykinin receptors, drug development has focused most intensively on the substance P-preferring receptor, neurokinin(1) (NK(1)). Although originally studied as potential analgesic compounds, recent evidence suggests that NK(1) receptor antagonists may possess antidepressant and anxiolytic properties. If confirmed by further controlled clinical studies, this will represent a mechanism of action distinct from all existing antidepressant agents. As reviewed in this chapter, the existing preclinical and clinical literature is suggestive of, but not conclusive, concerning a role of substance P and NK(1) receptors in the pathophysiology of depression and/or anxiety disorders. The ongoing clinical trials with NK(1) receptor antagonists have served as an impetus for much needed, basic research in this field.
Hypoxic Sensitizers — Implications for Radiation Therapy
Authors: J. Donald Chapman
Journal: New England Journal of Medicine (1979)

THE proliferative capacity of human cells can be destroyed by ionizing radiation, and the rate of killing by radiation is 2.5 to three times higher in the presence of oxygen than under hypoxic conditions. Since solid tumors often have zones of necrosis and consequently are likely to contain hypoxic yet viable cells, this radiobiologic effect may have implications for cancer therapy. Radioresistant tumor cells that survive treatment can become reoxygenated and lead to a recurrence of the disease.A recent analysis of 2803 patients with carcinoma of the cervix treated with radiation therapy indicated that those with hemoglobin levels of . . .
Abstract 5523: Adoptive cellular immunotherapy contributes to better survival for NSCLC patients: Case-control study of 395 Japanese patients with advanced NSCLC
Authors: Kenzo Soejima, Kazuro Iwai, Yoshimasa Umesato, Shigenori Goto, Shoji Kudo
Journal: Cancer Research (2011)

Abstract Adoptive cellular immunotherapy (ITx) targeting various types of carcinoma including the lung is widely used, yet the clinical effectiveness has not been evaluated in large cases of lung carcinoma. So we carried out a case-control study to investigate the effect of ITx for the treatment of advanced non-small cell lung cancer (NSCLC) patients in Japanese population. Between 2001 and 2006, 163 patients were identified as having advanced NSCLC with ECOG performance status (PS) 0/1 who underwent ITx with or without standard chemotherapy (CTx). The controls were 232 advanced NSCLC patients with PS 0/1 who had standard CTx or BSC alone. Overall survival (OS) and 1- and 2-year survival were obtained with Kaplan-Meyer survival curves and compared using log-rank and generalized Wilcoxon analysis. Multivariate analysis with Cox proportional hazard models was also performed to analyze survival. The mean age of total population was 64.8 + 10.6 years. There were 251 males and 144 females and 295 adenocarcinoma (Ad) and 74 squamous cell carcinoma (Sq) patients. The mean period and frequency of ITx was 10.2 months and 8.7 times, respectively. Median OS for CTx and ITx + CTx was 15.7 and 20.8 months, respectively. Multivariate analysis with Cox proportional hazard model showed that sex (male vs female) (HR=0.33, p&amp;lt;0.001) and histology (Ad vs Sq) (HR=0.14, p=0.045) were independent predictors of OS. It is revealed that ITx when administered as monotherapy was effective compared to BSC in male with Sq (HR=0.47, p=0.038) and female with Ad (HR=0.53, p=0.016). Additional effect of ITx on CTx was obtained in Ad histology, especially in female (p=0.039). The present findings suggest that ITx may contribute to better survival for advanced or metastatic NSCLC patients under certain circumstances. These results should be confirmed in large prospective clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5523. doi:10.1158/1538-7445.AM2011-5523
Caspase-3 Regulation of Diaphragm Myonuclear Domain during Mechanical Ventilation–induced Atrophy
Authors: Joseph M. McClung, Andreas N. Kavazis, Keith C. DeRuisseau, Darin J. Falk, Melissa A. Deering, Youngil Lee, Takao Sugiura, Scott K. Powers
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Unloading the diaphragm via mechanical ventilation (MV) results in rapid diaphragmatic fiber atrophy. It is unknown whether the myonuclear domain (cytoplasmic myofiber volume/myonucleus) of diaphragm myofibers is altered during MV.We tested the hypothesis that MV-induced diaphragmatic atrophy is associated with a loss of myonuclei via a caspase-3-mediated, apoptotic-like mechanism resulting in a constant myonuclear domain.To test this postulate, Sprague-Dawley rats were randomly assigned to a control group or to experimental groups exposed to 6 or 12 h of MV with or without administration of a caspase-3 inhibitor.After 12 h of MV, type I and type IIa diaphragm myofiber areas were decreased by 17 and 23%, respectively, and caspase-3 inhibition attenuated this decrease. Diaphragmatic myonuclear content decreased after 12 h of MV and resulted in the maintenance of a constant myonuclear domain in all fiber types. Both 6 and 12 h of MV resulted in caspase-3-dependent increases in apoptotic markers in the diaphragm (e.g., number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive nuclei and DNA fragmentation). Caspase-3-dependent increases in apoptotic markers occurred after 6 h of MV, before the onset of myofiber atrophy.Collectively, these data support the hypothesis that the myonuclear domain of diaphragm myofibers is maintained during prolonged MV and that caspase-3-mediated myonuclear apoptosis contributes to this process.
Progress and Potential for Regenerative Medicine
Authors: Geoffrey C. Gurtner, Matthew J. Callaghan, Michael T. Longaker
Journal: Annual Review of Medicine (2006)

Regenerative medicine focuses on new therapies to replace or restore lost, damaged, or aging cells in the human body to restore function. This goal is being realized by collaborative efforts in nonmammalian and human development, stem cell biology, genetics, materials science, bioengineering, and tissue engineering. At present, understanding existing reparative processes in humans and exploring the latent ability to regenerate tissue remains the focus in this field. This review covers recent work in limb regeneration, fetal wound healing, stem cell biology, somatic nuclear transfer, and tissue engineering as a foundation for developing new clinical therapies to augment and stimulate human regeneration.
Early Aldosterone-Induced Gene Product Regulates the Epithelial Sodium Channel by Deubiquitylation
Authors: Panagiotis Fakitsas, Gabriele Adam, Dorothe[Combining Acute Accent]e Daidie[Combining Acute Accent], Miguel X. van Bemmelen, Fatemeh Fouladkou, Andrea Patrignani, Ulrich Wagner, Richard Warth, Simone M.R. Camargo, Olivier Staub, Franc[COMBINING CEDILLA]ois Verrey
Journal: Journal of the American Society of Nephrology (2007)

The mineralocorticoid hormone aldosterone controls sodium reabsorption and BP largely by regulating the cell-surface expression and function of the epithelial sodium channel (ENaC) in target kidney tubules. Part of the stimulatory effect of aldosterone on ENaC is mediated by the induction of serum- and glucocorticoid-regulated kinase 1 (Sgk1), a kinase that interferes with the ubiquitylation of ENaC by ubiquitin-protein ligase Nedd4-2. In vivo early aldosterone-regulated mRNA now has been identified in microselected mouse distal nephron by microarray. From 22 mRNA that displayed a two-fold or more change, 13 were downregulated and nine were upregulated. Besides Sgk1, the induced mRNA include Grem2 (protein related to DAN and cerebrus [PRDC]), activating transcription factor 3, cAMP responsive element modulator, and the ubiquitin-specific protease Usp2-45. The induction of this last enzyme isoform was verified in mouse distal nephron tubule at the protein level. With the use of Hek293 cells, Xenopus oocytes, and mpkCCD(c14) cells as expression systems, it was shown that Usp2-45 deubiquitylates ENaC and stimulates ENaC-mediated sodium transport, an effect that is not additive to that of Sgk1. A deubiquitylating enzyme that targets ENaC in vitro and thus may play a role in sodium transport regulation was identified within a series of new in vivo early aldosterone-regulated gene products.
Pulmonary embolism shock. Physiologic basis of a bedside screening test
Authors: L. R. Del Guercio
Journal: JAMA (1966)

Cardiovascular variables were measured in 43 shock patients in whom pulmonary embolism was at first thought to be the cause. It was found that those patients who were to die of pulmonary embolism could be identified by markedly elevated mean right ventricular pressures and low total blood flows, even though systemic blood pressures and oxygen tensions were maintained near normal levels with vasopressors and oxygen therapy. This finding led to the development of a rapid, safe, bedside screening test for pulmonary embolism shock using flow-guided, intracardiac electrocardiographically monitored, right ventricular manometry. Selective pulmonary angiography can be performed with the same catheter to confirm the diagnosis and to indicate the most expedient operative approach.
MIF magnifies malarial anemia
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2006)

A study on page 1185 shows that the immune system's attempt to fight off malaria-causing parasites triggers severe anemia, a lethal complication of the disease. Parasite-induced synthesis of the cytokine MIF (migration inhibitory factor), say McDevitt and colleagues, decreases the production of red blood cells (RBCs) from the bone marrow.






Figure 1

The cytokine MIF, produced by macrophages in response to malarial hemozoin (black), triggers anemia in the infected host.




Parasites of the Plasmodium genus use host RBCs as multiplication factories, rupturing the cells as progeny parasites exit. Plasmodium infection also hampers the production of new RBCs from the bone marrow, an effect this group recently attributed to MIF, which is produced by macrophages that ingest infected RBCs. MIF helps activate T cells and is required to combat other infectious microbes including Salmonella and Leishmania.

But in malaria, MIF works against the host (although it probably also has benefits). In their new study, McDevitt et al. confirm MIF as the culprit of malarial anemia by showing that parasite-infected mice that lack MIF were less anemic and survived longer than wild-type mice. In vitro, the cytokine both suppressed the differentiation of RBCs from progenitor cells and decreased their hemoglobin content, possibly as a result of disrupted ERK–MAPK signaling in these cells.

Monocytes from humans carrying known “high producer” MIF gene polymorphisms secreted more MIF in response to the malarial pigment hemozoin than did those from individuals without this allele. And this group recently found a high prevalence of the low producer genotype among malaria-infected people in endemic regions of Africa, perhaps the result of an evolutionary survival advantage of keeping MIF levels low.

Population studies are now underway to determine whether MIF levels influence susceptibility to or severity of malaria in humans. In the meantime, synthetic inhibitors of MIF–currently in clinical development–might provide an effective alternative to the costly (and risky) blood transfusions currently used to treat malarial anemia.