tbuckley/cabot-search huggingface dataset:
HOXB13 Induces Growth Suppression of Prostate Cancer Cells as a Repressor of Hormone-Activated Androgen Receptor Signaling
Authors: Chaeyong Jung, Ran-Sook Kim, Hong-Ji Zhang, Sang-Jin Lee, Meei-Huey Jeng
Journal: Cancer Research (2004)

Abstract Androgen receptor (AR) signals play a decisive role in regulating the growth and differentiation of both normal and cancerous prostate cells by triggering the regulation of target genes, in a process in which AR cofactors have critical functions. Because of the highly prostate-specific expression pattern of HOXB13, we studied the role of this homeodomain protein in prostate cells. Expression of HOXB13 was limited to AR-expressing prostate cells. Reporter transcription assay demonstrated that HOXB13 significantly suppressed hormone-mediated AR activity in a dose-responsive manner, and suppression was specific to AR with which HOXB13 physically interacts. Overexpression of HOXB13 further down-regulated the androgen-stimulated expression of prostate-specific antigen, and suppression of endogenous HOXB13 stimulated transactivation of AR. Functionally, HOXB13 suppressed growth of LNCaP prostate cancer cells, which could be counteracted by additional hormone-activated AR. On the other hand, the growth-suppressive function of HOXB13 in AR-negative CV-1 cells was not affected by AR. These results suggest that HOXB13 functions as an AR repressor to modulate the complex AR signaling and subsequent growth regulation of prostate cancer cells. In addition to the loss of HOXB13 expression, maintaining AR may be an important step for prostate cancer cells to tolerate the suppressor function of HOXB13. Altogether, our data present a novel mechanism for the HOXB13-mediated repression of AR signaling, which can be interpreted to a growth-suppressive event.
Effector Memory T Cells, Early Metastasis, and Survival in Colorectal Cancer
Authors: Franck Pagès, Anne Berger, Matthieu Camus, Fatima Sanchez-Cabo, Anne Costes, Robert Molidor, Bernhard Mlecnik, Amos Kirilovsky, Malin Nilsson, Diane Damotte, Tchao Meatchi, Patrick Bruneval, Paul-Henri Cugnenc, Zlatko Trajanoski, Wolf-Herman Fridman, Jérôme Galon
Journal: New England Journal of Medicine (2005)

The role of tumor-infiltrating immune cells in the early metastatic invasion of colorectal cancer is unknown.
Murine epidermal Langerhans cells mature into potent immunostimulatory dendritic cells in vitro.
Authors: G Schuler, R M Steinman
Journal: The Journal of Experimental Medicine (1985)

Murine epidermal Langerhans cells (LC) have been studied in tissue culture and compared to spleen dendritic cells (DC). LC comprised 3% of the starting cell suspensions and were distinguished from keratinocytes by cytology and reactivity with anti-Ia and anti-Mac-1 monoclonal antibodies. The LC were nonadherent, had a low buoyant density, did not proliferate, and could be enriched to 10-50% purity. LC continued to exhibit Ia and Mac-1 antigens for 4 d in culture. However, LC rapidly lost Birbeck granules, Fc receptors, F4/80 antigen, and cytochemical reactivity for nonspecific esterase and membrane ATPase. As a result, the ultrastructure and phenotype of cultured LC became remarkably similar to lymphoid DC. Stimulatory capacity for T cell proliferative responses (oxidative mitogenesis and the mixed leukocyte reaction) was monitored daily. Initially, stimulatory capacity was very weak, even though LC expressed substantial levels of Ia antigens. After 2-3 d in culture, LC had become 3-10 times more potent than spleen DC. 30 LC could induce significant responses in cultures of 3 X 10(5) responding T cells. Removal of Ia+ LC at the start of culture ablated the development of stimulatory activity, but exposure to 1,500 rad of ionizing irradiation did not. Mixing experiments showed that contaminating Ia- epidermal cells did not alter the function of Ia+ stimulators. Therefore, LC seem to be immunologically immature, but acquire many of the features of spleen DC during culture. We suggest that functioning lymphoid DC may, in general, be derived from less mature precursors located in nonlymphoid tissues.
Comment on Shah et al. Cardiovascular Complications and Mortality After Diabetes Diagnosis for South Asian and Chinese Patients: A Population-Based Cohort Study. Diabetes Care 2013;36:2670–2676
Authors: Therese Tillin, Naveed Sattar, Nita Forouhi, Alun D. Hughes, Nish Chaturvedi
Journal: Diabetes Care (2014)

Shah et al. (1) suggest that the consequences of new-onset diabetes may be less severe in South Asian and Chinese patients and accounts for equivalent (South Asians) or lower (Chinese) risks of cardiovascular disease compared with Europeans with diabetes. They claim that missing data on key cardiovascular disease risk factors, in particular smoking, could not account for such ethnic differences. These assertions may be overstated.

In the British Southall And Brent REvisited (SABRE) population-based cohort, with detailed risk factor assessment, diabetes, whether newly diagnosed or established, was associated with a greater risk of both coronary heart disease and stroke mortality in migrant British South Asians than in comparable …
Iron uptake controls the generation of <i>Leishmania</i> infective forms through regulation of ROS levels
Authors: Bidyottam Mittra, Mauro Cortez, Andrew Haydock, Gowthaman Ramasamy, Peter J. Myler, Norma W. Andrews
Journal: The Journal of Experimental Medicine (2013)

During its life cycle, Leishmania undergoes extreme environmental changes, alternating between insect vectors and vertebrate hosts. Elevated temperature and decreased pH, conditions encountered after macrophage invasion, can induce axenic differentiation of avirulent promastigotes into virulent amastigotes. Here we show that iron uptake is a major trigger for the differentiation of Leishmania amazonensis amastigotes, independently of temperature and pH changes. We found that iron depletion from the culture medium triggered expression of the ferrous iron transporter LIT1 (Leishmania iron transporter 1), an increase in iron content of the parasites, growth arrest, and differentiation of wild-type (WT) promastigotes into infective amastigotes. In contrast, LIT1-null promastigotes showed reduced intracellular iron content and sustained growth in iron-poor media, followed by cell death. LIT1 up-regulation also increased iron superoxide dismutase (FeSOD) activity in WT but not in LIT1-null parasites. Notably, the superoxide-generating drug menadione or H2O2 was sufficient to trigger differentiation of WT promastigotes into fully infective amastigotes. LIT1-null promastigotes accumulated superoxide radicals and initiated amastigote differentiation after exposure to H2O2 but not to menadione. Our results reveal a novel role for FeSOD activity and reactive oxygen species in orchestrating the differentiation of virulent Leishmania amastigotes in a process regulated by iron availability.
IL-7 receptor α expressing B cells act proinflammatory in collagen-induced arthritis and are inhibited by sympathetic neurotransmitters
Authors: Georg Pongratz, Judith M Anthofer, Madlen Melzer, Sven Anders, Susanne Grässel, Rainer H Straub
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> The sympathetic nervous system (SNS) as well as the interleukin (IL)-7/IL-7 receptor (IL-7R) system play a role in the pathogenesis of arthritis. However, the target cells and mechanisms involved are not fully resolved. The goal of this study was to determine if B cells are influenced by IL-7 and to investigate the possible interplay between the SNS and the IL-7/IL-7R system on B cells in arthritis. <h3>Methods</h3> Collagen type II-induced arthritis (CIA) in DBA1 mice. ELISA to determine specific anti-CII antibodies. Fluorescence activated cell sorting (FACS) analysis to determine IL-7R+ cells and intracellular phosphorylated signal transducer and activator of transcription 5 (pSTAT5). Immunohistochemistry to show IL-7R+ B cells in rheumatoid arthritis (RA) and osteoarthritis (OA) synovial tissue. <h3>Results</h3> IL-7 stimulated IL-7R+ mature B cells act proinflammatory (increased clinical score, increased anticollagen type II antibodies) after cell transfer in CIA. The sympathetic neurotransmitter norepinephrine abrogates this effect. Expression of IL-7Rα is increased when B cells are activated (anti-CD40 or lipopolysaccharide) in vitro and stimulating the IL-7R induces intracellular accumulation of pSTAT5. α- And β-adrenergic agonists show no influence on expression levels of IL-7R on activated B cells; however, intracellular IL-7R downstream signalling is abrogated via the β2-adreonceptor (β2AR) agonist terbutaline. IL-7R and β2AR are also expressed on B cells in synovial tissue from RA and OA patients. <h3>Conclusions</h3> These data indicate that IL7R+ B cells have a proinflammatory role in arthritis which can be inhibited by the sympathetic neurotransmitter norepinephrine via inhibition of IL-7R signalling.
High Glucose Impairs Voltage-Gated K <sup>+</sup> Channel Current in Rat Small Coronary Arteries
Authors: Yanping Liu, Ken Terata, Nancy J. Rusch, David D. Gutterman
Journal: Circulation Research (2001)

Hyperglycemia is associated with impaired endothelium-dependent dilation that is due to quenching of NO by superoxide (O 2 · − ). In small coronary arteries (CAs), dilation depends more on smooth muscle hyperpolarization, such as that mediated by voltage-gated K + (Kv) channels. We determined whether high glucose enhances O 2 ·− production and reduces microvascular Kv channel current and functional responses. CAs from Sprague-Dawley rats were incubated 24 hours in medium containing either normal glucose (NG, 5.5 mmol/L d -glucose), high glucose (HG, 23 mmol/L d -glucose), or l -glucose (LG, 5.5 mmol/L d -glucose and 17 mmol/L l -glucose). O 2 ·− production was increased in HG arteries. Whole-cell patch clamping showed a reduction of 4-aminopyridine (4-AP)–sensitive current (Kv current) from smooth muscle cells of HG CAs versus NG CAs or versus LG CAs (peak density was 9.95±5.3 pA/pF for HG versus 27.8±6.8 pA/pF for NG and 28.5±5.2 pA/pF for LG; P &lt;0.05). O 2 ·− generation (xanthine+xanthine oxidase) decreased K + current density, with no further reduction by 4-AP. Partial restoration was observed with superoxide dismutase and catalase. Constriction to 3 mmol/L 4-AP was reduced in vessels exposed to HG (13±5%, P &lt;0.05) versus NG (30±7%) or LG (34±4%). Responses to KCl and nifedipine were not different among groups. Superoxide dismutase and catalase increased contraction to 4-AP in HG CAs. This is the first direct evidence that exposure of CAs to HG impairs Kv channel activity. We speculate that this O 2 ·− -induced impairment may reduce vasodilator responsiveness in the coronary circulation of subjects with coronary disease or its risk factors.
A cytogeneticist's perspective on genomic microarrays
Authors: L. G. Shaffer
Journal: Human Reproduction Update (2004)

The identification of cytogenetic imbalance is an important component of clinical genetics. About 1 in 154 newborns has a chromosome abnormality. Conventional cytogenetic analysis has enabled the identification of microscopic alterations of the chromosomes. The development of fluorescence in situ hybridization (FISH) and other molecular methodologies has made possible the identification of submicroscopic aberrations. An additional development was comparative genomic hybridization (CGH), a method that directly compares two genomes for DNA copy differences. As first developed, the substrate for CGH analysis is normal metaphase chromosomes. Recently, CGH has been applied to microarrays (array CGH) constructed from large insert clones to identify chromosome imbalance. Array CGH has many advantages over conventional cytogenetic and molecular cytogenetic techniques. Array CGH can be comprehensive (genome‐wide), high resolution, amenable to automation, rapid, and sensitive. We anticipate that array CGH will be employed in the clinical cytogenetics laboratory in the near future and will lead to the identification of the chromosomal basis of new syndromes and existing genetic conditions.
THE ROLE OF THE THYROID GLAND IN EXPERIMENTAL TRAUMATIC SHOCK
Authors: Jack H. Oppenheimer, Henry M. Wise, David A. Lasley
Journal: Journal of Clinical Investigation (1958)

Comparatively little attention has been paid to the role of the thyroid gland in shock.Hamolsky, Gierlach, and Jensen (1) demonstrated that the I'll' uptake of rats subjected to tourniquet shock was depressed early in shock and that the con- version of radioiodide to the organic form was depressed late in shock.Money (2) showed that bleeding caused a depression in the four hour up- take of I'8l in rats.Because of the meager body of information re- lating to this problem, it was our purpose to study several aspects of thyroid function in a traumatic shock preparation developed at the Army Chemical Center.This preparation involves the cre- ation of uniformly lethal soft tissue wounds by the detonation of high explosive charges on the hind extremities of Texas Angora goats.Al- though this method of creating traumatic shock involves multiple variables including blood loss, infection, and soft tissue damage, the clinical picture in the wounded animals is surprisingly uni- form and simulates conditions actually prevailing on the battlefield.Additional communications will document the physiological alterations in this preparation and will present evidence that a toxic factor, possibly related to bacterial metabolism, plays a prominent role in the demise of these animals.
Presentation of a Self-peptide in Two Distinct Conformations by a Disease-associated HLA-B27 Subtype
Authors: Kai W. Wucherpfennig
Journal: The Journal of Experimental Medicine (2004)

The MHC locus on human chromosome 6 harbors the most polymorphic genes in the human genome, and the large number of alleles in human populations has permitted key structural features of MHC class I and class II genes that influence susceptibility to several human autoimmune diseases to be delineated
Communicating With Realism and Hope: Incurable Cancer Patients' Views on the Disclosure of Prognosis
Authors: Rebecca G. Hagerty, Phyllis N. Butow, Peter M. Ellis, Elizabeth A. Lobb, Susan C. Pendlebury, Natasha Leighl, Craig Mac Leod, Martin H.N. Tattersall
Journal: Journal of Clinical Oncology (2005)

To identify preferences for the process of prognostic discussion among patients with incurable metastatic cancer and variables associated with those preferences.One hundred twenty-six (58%) of 218 patients invited onto the study participated. Eligible patients were the consecutive metastatic cancer patients of 30 oncologists, who were diagnosed within 6 weeks to 6 months before recruitment, over 18 years of age, and without known mental illness. Patients completed a postal survey measuring patient preferences for the manner of delivery of prognostic information, including how doctors might instill hope.Ninety-eight percent of patients wanted their doctor to be realistic, provide an opportunity to ask questions, and acknowledge them as an individual when discussing prognosis. Doctor behaviors rated the most hope giving included offering the most up to date treatment (90%), appearing to know all there is to know about the patient's cancer (87%), and saying that pain will be controlled (87%). The majority of patients indicated that the doctor appearing to be nervous or uncomfortable (91%), giving the prognosis to the family first (87%), or using euphemisms (82%) would not facilitate hope. Factor analysis revealed six general styles and three hope factors; the most strongly endorsed styles were realism and individualized care and the expert/positive/collaborative approach. A range of demographic, psychological, and disease factors were associated with preferred general and hope-giving styles, including anxiety, information-seeking behavior, expected survival, and age.The majority of patients preferred a realistic and individualized approach from the cancer specialist and detailed information when discussing prognosis.
The Impact of Membrane Permeability and Dialysate Purity on Cardiovascular Outcomes
Authors: Gulay Asci, Huseyin Töz, Mehmet Ozkahya, Soner Duman, Meltem Sezis Demirci, Mustafa Cirit, Savas Sipahi, Hamad Dheir, Devrim Bozkurt, Fatih Kircelli, Ebru Sevinc Ok, Sinan Erten, Muhittin Ertilav, Timur Kose, Ali Basci, Jochen G. Raimann, Nathan W. Levin, Ercan Ok
Journal: Journal of the American Society of Nephrology (2013)

The effects of high-flux dialysis and ultrapure dialysate on survival of hemodialysis patients are incompletely understood. We conducted a randomized controlled trial to investigate the effects of both membrane permeability and dialysate purity on cardiovascular outcomes. We randomly assigned 704 patients on three times per week hemodialysis to either high- or low-flux dialyzers and either ultrapure or standard dialysate using a two-by-two factorial design. The primary outcome was a composite of fatal and nonfatal cardiovascular events during a minimum 3 years follow-up. We did not detect statistically significant differences in the primary outcome between high- and low-flux (HR=0.73, 95% CI=0.49 to 1.08, P=0.12) and between ultrapure and standard dialysate (HR=0.90, 95% CI=0.61 to 1.32, P=0.60). Posthoc analyses suggested that cardiovascular event-free survival was significantly better in the high-flux group compared with the low-flux group for the subgroup with arteriovenous fistulas, which constituted 82% of the study population (adjusted HR=0.61, 95% CI=0.38 to 0.97, P=0.03). Furthermore, high-flux dialysis associated with a lower risk for cardiovascular events among diabetic subjects (adjusted HR=0.49, 95% CI=0.25 to 0.94, P=0.03), and ultrapure dialysate associated with a lower risk for cardiovascular events among subjects with more than 3 years of dialysis (adjusted HR=0.55, 95% CI=0.31 to 0.97, P=0.04). In conclusion, this trial did not detect a difference in cardiovascular event-free survival between flux and dialysate groups. Posthoc analyses suggest that high-flux hemodialysis may benefit patients with an arteriovenous fistula and patients with diabetes and that ultrapure dialysate may benefit patients with longer dialysis vintage.
Targeting Medulloblastoma: Small-Molecule Inhibitors of the Sonic Hedgehog Pathway as Potential Cancer Therapeutics
Authors: Justyna Romer, Tom Curran
Journal: Cancer Research (2005)

Abstract Medulloblastoma is the most common malignant pediatric brain tumor for which no satisfactory treatments exist. The Sonic Hedgehog signaling pathway seems to play an important role in the pathology of this disease. Here we review our recent demonstration that a small-molecule inhibitor of this pathway can regress tumors that arise in a transgenic mouse model of medulloblastoma. These and other findings suggest that inhibitors of Sonic Hedgehog signaling may offer an effective way to target some malignancies.
Pharmacokinetic targeting of intravenous busulfan reduces conditioning regimen related toxicity following allogeneic hematopoietic cell transplantation for acute myelogenous leukemia
Authors: Joseph Pidala, Jongphil Kim, Claudio Anasetti, Mohamed A Kharfan-Dabaja, Taiga Nishihori, Teresa Field, Janelle Perkins, Lia Perez, Hugo F Fernandez
Journal: Journal of Hematology & Oncology (2010)

Optimal conditioning therapy for hematopoietic cell transplantation (HCT) in acute myelogenous leukemia (AML) remains undefined. We retrospectively compared outcomes of a consecutive series of 51 AML patients treated with oral busulfan (1 mg/kg every 6 hours for 4 days) and cyclophosphamide (60 mg/kg IV × 2 days) - (Bu/Cy) with 100 consecutive AML patients treated with pharmacokinetic targeted IV busulfan (AUC < 6000 μM/L*min per day × 4 days) and fludarabine (40 mg/m2 × 4 days) - (t-IV Bu/Flu). The Bu/Cy and t-IV Bu/Flu groups significantly differed according to donor relation, stem cell source, aGVHD prophylaxis, remission status, primary vs. secondary disease, median age, and % blasts prior to HCT (p < 0.01 for each). Conditioning with t-IV Bu/Flu reduced early toxicity including idiopathic pneumonia syndrome (IPS) and hepatic veno-occlusive disease (VOD). Additionally, the trajectory of early NRM (100 day: 16% vs. 3%, and1 year: 25% vs. 15% for Bu/Cy and t-IV Bu/Flu, respectively) favored t-IV Bu/Flu. Grade II-IV aGVHD (48% vs. 82%, p < 0.0001), as well as moderate/severe cGVHD (7% vs. 40%, p < 0.0001) differed between the Bu/Cy and t-IV Bu/Flu groups, due to the predominance of peripheral blood stem cells in the t-IV Bu/Flu group. Pharmacokinetic targeting of intravenous busulfan in combination with fludarabine is associated with reduced conditioning regimen related toxicity compared to oral busulfan and cyclophosphamide. However, multivariable analysis did not demonstrate significant differences in overall survival (p = 0.78) or non-relapse mortality (p = 0.6) according to conditioning regimen delivered.
Mechanisms of Resistance to Crizotinib in Patients with <i>ALK</i> Gene Rearranged Non–Small Cell Lung Cancer
Authors: Robert C. Doebele, Amanda B. Pilling, Dara L. Aisner, Tatiana G. Kutateladze, Anh T. Le, Andrew J. Weickhardt, Kimi L. Kondo, Derek J. Linderman, Lynn E. Heasley, Wilbur A. Franklin, Marileila Varella-Garcia, D. Ross Camidge
Journal: Clinical Cancer Research (2012)

Patients with anaplastic lymphoma kinase (ALK) gene rearrangements often manifest dramatic responses to crizotinib, a small-molecule ALK inhibitor. Unfortunately, not every patient responds and acquired drug resistance inevitably develops in those who do respond. This study aimed to define molecular mechanisms of resistance to crizotinib in patients with ALK(+) non-small cell lung cancer (NSCLC).We analyzed tissue obtained from 14 patients with ALK(+) NSCLC showing evidence of radiologic progression while on crizotinib to define mechanisms of intrinsic and acquired resistance to crizotinib.Eleven patients had material evaluable for molecular analysis. Four patients (36%) developed secondary mutations in the tyrosine kinase domain of ALK. A novel mutation in the ALK domain, encoding a G1269A amino acid substitution that confers resistance to crizotinib in vitro, was identified in two of these cases. Two patients, one with a resistance mutation, exhibited new onset ALK copy number gain (CNG). One patient showed outgrowth of epidermal growth factor receptor (EGFR) mutant NSCLC without evidence of a persistent ALK gene rearrangement. Two patients exhibited a KRAS mutation, one of which occurred without evidence of a persisting ALK gene rearrangement. One patient showed the emergence of an ALK gene fusion-negative tumor compared with the baseline sample but with no identifiable alternate driver. Two patients retained ALK positivity with no identifiable resistance mechanism.Crizotinib resistance in ALK(+) NSCLC occurs through somatic kinase domain mutations, ALK gene fusion CNG, and emergence of separate oncogenic drivers.