tbuckley/cabot-search huggingface dataset:
A phosphotyrosine switch determines the antitumor activity of ERβ
Authors: Bin Yuan, Long Cheng, Huai-Chin Chiang, Xiaojie Xu, Yongjian Han, Hang Su, Lingxue Wang, Bo Zhang, Jing Lin, Xiaobing Li, Xiangyang Xie, Tao Wang, Rajeshwar R. Tekmal, Tyler J. Curiel, Zhi-Min Yuan, Richard Elledge, Yanfen Hu, Qinong Ye, Rong Li
Journal: Journal of Clinical Investigation (2014)

Estrogen receptors ERα and ERβ share considerable sequence homology yet exert opposite effects on breast cancer cell proliferation. While the proliferative role of ERα in breast tumors is well characterized, it is not clear whether the antitumor activity of ERβ can be mobilized in breast cancer cells. Here, we have shown that phosphorylation of a tyrosine residue (Y36) present in ERβ, but not in ERα, dictates ERβ-specific activation of transcription and is required for ERβ-dependent inhibition of cancer cell growth in culture and in murine xenografts. Additionally, the c-ABL tyrosine kinase and EYA2 phosphatase directly and diametrically controlled the phosphorylation status of Y36 and subsequent ERβ function. A nonphosphorylatable, transcriptionally active ERβ mutant retained antitumor activity but circumvented control by upstream regulators. Phosphorylation of Y36 was required for ERβ-mediated coactivator recruitment to ERβ target promoters. In human breast cancer samples, elevated phosphorylation of Y36 in ERβ correlated with high levels of c-ABL but low EYA2 levels. Furthermore, compared with total ERβ, the presence of phosphorylated Y36–specific ERβ was strongly associated with both disease-free and overall survival in patients with stage II and III disease. Together, these data identify a signaling circuitry that regulates ERβ-specific antitumor activity and has potential as both a prognostic tool and a molecular target for cancer therapy.
On the thymus in the differentiation of "H-2 self-recognition" by T cells: evidence for dual recognition?
Authors: R M Zinkernagel, G N Callahan, A Althage, S Cooper, P A Klein, J Klein
Journal: The Journal of Experimental Medicine (1978)

In the thymus, precursor T cells differentiate recognition structures for self that are specific for the H-2K, D, and I markers expressed by the thymic epithelium. Thus recognition of self-H-2 differentiates independently of the T cells H-2 type and independently of recognition of nonself antigen X. This is readily compatible with dual recognition by T cells but does not formally exclude a single recognition model. These conclusions derive from experiments with bone marrow and thymic chimeras. Irradiated mice reconstituted with bone marrow to form chimeras of (A X B)F1 leads to A type generate virus-specific cytotoxic T cells for infected targets A only. Therefore, the H-2 type of the host determines the H-2-restricted activity of killer T cells alone. In contrast, chimeras made by reconstituting irradiated A mice with adult spleen cells of (A X B)F1 origin generate virus-specific cytotoxic activity for infected A and B targets, suggesting that mature T cells do not change their self-specificity readily. (A X B)F1 leads to (A X C)F1 and (KAIA/DC) leads to (KAIA/DB) irradiation bone marrow chimeras responded against infected A but not B or C targets. This suggests that cytotoxicity is not generated against DC because it is abscent from the host's thymus epithelium and not against DB because it is not expressed by the reconstituting lymphoreticular system. (KBIB/DA) leads to (KCIC/DA) K, I incompatible, or completely H-2 incompatible A leads to B chimeras fail to generate any measurable virus specific cytotoxicity, indicating the necessity for I-specific helper T cells for the generation of killer T cells. Finally adult thymectomized, irradiated and bone marrow reconstituted (A X B)F1 mice, transplanted with an irradiated thymus of A origin, generate virus-specific cytotoxic T cells specific for infected A targets but not for B targets; this result formally demonstrates the crucial role of thymic epithelial cells in the differentiation of anti-self-H-2 specificities of T cells.
Abstract 4668: Pro-inflammatory lipid PAF may induce malignant potential via PAFR and phospho-FAK/STAT pathway in BRCA1-positive tubo-ovarian epithelial cells
Authors: LiFang Zhang, Dan Wang, Dale Edwards, Margarita Aponte, Weiliang Qiu, LianJin Jin, Vanitha Seethapan, Allison Vitonis, Jian Liu Wang, Samuel Mok, Christopher Crum, Daniel W. Cramer, Bin Ye
Journal: Cancer Research (2010)

Abstract The loss of BRCA1 function may induce profound transcriptional changes, phenotypic reprogramming and ultimately, generate genetically unstable tumor-initiating cells, which significantly increase the risk of breast and ovarian cancer. The molecular targets and pathways involved in early events of malignant transformation of at-risk epithelium has not been well investigated, particularly the effects of chronic inflammation. In an earlier study, we demonstrated that platelet activating factor (PAF), a potent pro-inflammatory mediator, plays a significant role in ovarian cancer progression and invasion (Cancer Research, 68:5839, 2008). Here, we extend our finding to show that PAF receptor is over expressed in BRCA1-mutated (BRCA1+) human ovarian surface epithelial cells (HOSE) by western blot and in distal fallopian tube (fimbria) epithelial cells by immunohistochemistry. In addition, PAF induced cell apoptosis only in wild type HOSE cells, and anti-apoptosis in BRCA1+ ovarian surface epithelial cells. A kinase microarray revealed that phosphor-STAT1/3/4/6 was simultaneously activated by 100 nM PAF treatment in BRCA1+ ovarian cancer cells. Induction of phosphor-STAT1 associated with PAFR and BRCA1-mutation was further confirmed in three BRCA1+ HOSE cell lines, but not in normal (HOSEE6E7) or malignant (OVCA429) ovarian epithelial cells. Co-immune precipitation revealed that PAF/PAFR coordinately activates FAK through dephosphorylation and STAT1 through phosphorylation only in BRCA1+ ovarian epithelial cells. These findings strongly suggest that potent inflammatory mediators (i.e. PAF) may play a significant role to induce malignant transformation in BRCA1-mutant ovarian epithelial cells through the FAK-STAT pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4668.
Clinical implications of E-cadherin associated hereditary diffuse gastric cancer
Authors: R C Fitzgerald
Journal: Gut (2004)

Approximately 1–3% of gastric cancers arise as a result of inherited gastric cancer predisposition syndromes. These may be of the diffuse or intestinal type. Linkage analysis has recently implicated E-cadherin mutations in an estimated 25% of families with an autosomal dominant predisposition to diffuse type gastric cancers. This subset of gastric cancer has been termed hereditary diffuse gastric cancer (HDGC).
Preventing Staphylococcus aureus infection during chronic peritoneal dialysis.
Authors: R Swartz, J Messana, B Starmann, M Weber, J Reynolds
Journal: Journal of the American Society of Nephrology (1991)

In the interest of studying the prevention of chronic peritoneal dialysis infections, serial studies of the bacterial epidemiology in peritonitis and of antibiotic prophylaxis, respectively, were carried out. For 18 months, prospective evaluation of catheter exist site cultures, performed at the time patients developed acute peritonitis, showed that Staphylococcus aureus peritonitis was associated with concordant S. aureus at the exist site in 85% of cases, significantly more frequent than that for other organisms (P less than 0.02). Furthermore, active inflammation along with concordant culture results at the exit site characterized more than 60% of S. aureus peritonitis cases, also significantly more than that for other organisms (P less than 0.01). Over the ensuing 2 yr, patients beginning chronic peritoneal dialysis with a new percutaneously placed catheter were prospectively entered into a randomized, controlled trial of long-term antibiotic prophylaxis with trimethoprim-sulfamethoxasole. Patients receiving prophylaxis tended to have fewer episodes of peritonitis; however, the lower rate of peritonitis reached statistical significance only comparing patients who were S. aureus carriers at entry into the study to patients who were not S. aureus carriers. In particular, the prophylaxis trial seemed to reduce the specific incidence of S. aureus peritonitis overall, with S. aureus appearing in only 2 of 28 total peritonitis episodes among treated patients as compared with 11 of 37 total episodes among non-treated patients (P less than 0.01). Further analysis of the time to first peritonitis suggests that the effect of prophylaxis was most prominent during the first 3 months of therapy (P less than 0.02) rather than later in the course of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Randomized Phase I Trial of Recombinant Human Keratinocyte Growth Factor Plus Chemotherapy: Potential Role as Mucosal Protectant
Authors: Neal J. Meropol, Robert A. Somer, John Gutheil, Robert J. Pelley, Manuel R. Modiano, Eric K. Rowinsky, Mace L. Rothenberg, Spencer W. Redding, Cuneyt M. Serdar, Bin Yao, Robert Heard, Lee S. Rosen
Journal: Journal of Clinical Oncology (2003)

Purpose: To evaluate the safety of recombinant human keratinocyte growth factor (KGF) when administered with fluorouracil (FU) in patients with metastatic colorectal cancer. Patients and Methods: Patients (N = 81) received KGF by intravenous (IV) bolus on days 1 to 3, followed by FU 425 mg/m 2 /d IV bolus plus leucovorin 20 mg/m 2 /d IV on days 4 to 8. KGF dose levels were 1, 10, 20, 40, 60, and 80 μg/kg/d. A randomized, placebo-controlled design was employed (2:1 randomization of KGF to placebo). Oral mucositis was assessed by examination on days 1, 4, 8, 15, and 28. In addition, patients provided daily assessments of oral symptoms using a self-administered questionnaire. Results: Skin and oral events occurred in 13 of 18 patients (eight patients, grade 1; four patients, grade 2; and one patient, grade 3) treated with 60 and 80 μg/kg of KGF and three of 11 patients treated with 40 μg/kg (grade 1). These symptoms were dose limiting in three cases (ie, in two of 10 patients treated with 80 μg/kg and in one of eight patients treated with 60 μg/kg). The frequency of grade 2 to 4 mucositis was 43% in patients treated with KGF, compared with 67% in patients treated with placebo (P = .06). Patient self-assessments of oral pain and clinical assessments of mucositis showed good correlation (Kendall’s tau = 0.75). Conclusion: KGF is generally well tolerated when administered IV at doses up to 40 μg/kg/d for 3 days before a 5-day course of FU plus leucovorin. A clinically meaningful biologic effect was also suggested in that patients treated with the epithelial growth factor KGF had a lower rate of grade 2 to 4 mucositis than did patients treated with placebo.
Neuregulin-1 as a potentially novel biomarker in acute respiratory distress syndrome
Authors: William Checkley
Journal: European Respiratory Journal (2013)

The investigation of biomarkers in clinical studies can provide insights into mechanistic pathways about a disease or condition, and may help identify potentially novel therapeutic strategies or inform about prognosis or disease progression. In this issue of the European Respiratory Journal , Finigan et al. [1] show that high levels of neuregulin-1, a potentially novel biomarker for lung injury, are found in both bronchoalveolar lavage and plasma during the inflammatory phase of acute respiratory distress syndrome (ARDS) in humans. The authors examined levels of neuregulin-1 in bronchoalveolar lavage and plasma in a group of 23 adults with ARDS obtained at day 3 after meeting consensus criteria for ARDS [2] and in five healthy volunteers free of lung disease. They were able to further examine whether levels of neuregulin-1 correlated with markers of inflammation (epidermal growth factor (EGF), interleukin (IL)-1β, IL-6, IL-8 and tumour necrosis factor (TNF)-α) and with clinical outcomes such as ventilator-free days. Specifically, they found that levels of neuregulin-1 in bronchoalveolar lavage (187 versus 86 pg·mL−1, p=0.001) and plasma (612 versus 25 pg·mL−1, p<0.001) were higher in patients with ARDS than in healthy controls. Moreover, they found that levels of neuregulin-1 in bronchoalveolar lavage were positively correlated with TNF-α (p=0.03), IL-6 (p=0.05) and IL-1β (p=0.06), and negatively correlated with ventilator-free days (p=0.02). Finally, levels of neuregulin-1 in plasma were also negatively associated with ventilator-free days (p=0.04). …
Obstetrical "Flying Squad"
Authors: E. F. Murray
Journal: BMJ (1938)

The main prognostic points elicited were as follows.Anxiety and its clinical manifestations may persist un- changed for ten years and over, and the percentage of cases in which it is converted to hypochondriasis is small.The prognosis is fairly good if the condition is of less than two years' duration, and, conversely, it is poor but not hopeless for ultimate and permanent recovery if the condition is of longer than two years' standing.On the other hand, the patient's chances of returning to work are always quite good, as only 20 per cent. of those unable to work persisted in that state.If the patient's habits or mode of life remain substantially unchanged by the anxiety the prognosis is good.The outlook in cases with markedly psychopathic personalities is poor.There was no evidence of increased susceptibility to organic disease in these patients.The difficulties and possible fallacies are discussed.
The airway epithelium in health and disease: "calm on the surface, paddling furiously underneath"
Authors: R. L Smyth
Journal: Thorax (2009)

The airway epithelium, which is exposed to antigens and microbes throughout respiration, provides an enormous and delicate interface with the external environment. In major conducting airways the epithelium is covered by surface liquid, which includes an overlying mucous layer onto which inhaled particles are trapped. The physical defence mechanisms of the airway epithelium include the mucociliary escalator and complex structures known as tight junctions which control paracellular transport of inhaled material. In response to immunological challenge, epithelial cell surfaces produce antimicrobial chemicals (such as surfactants and defensins), cytokines (particularly type I and type III interferons) and chemokines following activation of their pattern recognition receptors, including Toll-like receptors (TLRs). This leads to recruitment of immune cells including dendritic cells, T cells and B cells.

Given the speed, complexity and specificity of these responses, it is likely that, in an environment full of antigens such as the lung, epithelial surfaces will have developed mechanisms to inhibit inflammation, as has already been demonstrated for the microbe-rich milieu of the gut.1 Although it has been recognised for some time that the airway epithelium plays an important role in generating danger signals upon immunological challenge, we need to update these concepts to recognise the importance of this interface in protecting the host from unwanted responses to innocuous environmental agents. Data are now emerging which suggest that, in health, airway epithelial cells (AECs) play a critical role in regulating local immunological homeostasis. The study by Wang et al published in this issue of Thorax provides an important contribution to this body of evidence ( see page 283 ).2

The diverse array …
Spontaneous Effort Causes Occult Pendelluft during Mechanical Ventilation
Authors: Takeshi Yoshida, Vinicius Torsani, Susimeire Gomes, Roberta R. De Santis, Marcelo A. Beraldo, Eduardo L. V. Costa, Mauro R. Tucci, Walter A. Zin, Brian P. Kavanagh, Marcelo B. P. Amato
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

In normal lungs, local changes in pleural pressure (P(pl)) are generalized over the whole pleural surface. However, in a patient with injured lungs, we observed (using electrical impedance tomography) a pendelluft phenomenon (movement of air within the lung from nondependent to dependent regions without change in tidal volume) that was caused by spontaneous breathing during mechanical ventilation.To test the hypotheses that in injured lungs negative P(pl) generated by diaphragm contraction has localized effects (in dependent regions) that are not uniformly transmitted, and that such localized changes in P(pl) cause pendelluft.We used electrical impedance tomography and dynamic computed tomography (CT) to analyze regional inflation in anesthetized pigs with lung injury. Changes in local P(pl) were measured in nondependent versus dependent regions using intrabronchial balloon catheters. The airway pressure needed to achieve comparable dependent lung inflation during paralysis versus spontaneous breathing was estimated.In all animals, spontaneous breathing caused pendelluft during early inflation, which was associated with more negative local P(pl) in dependent regions versus nondependent regions (-13.0 ± 4.0 vs. -6.4 ± 3.8 cm H2O; P < 0.05). Dynamic CT confirmed pendelluft, which occurred despite limitation of tidal volume to less than 6 ml/kg. Comparable inflation of dependent lung during paralysis required almost threefold greater driving pressure (and tidal volume) versus spontaneous breathing (28.0 ± 0.5 vs. 10.3 ± 0.6 cm H2O, P < 0.01; 14.8 ± 4.6 vs. 5.8 ± 1.6 ml/kg, P < 0.05).Spontaneous breathing effort during mechanical ventilation causes unsuspected overstretch of dependent lung during early inflation (associated with reciprocal deflation of nondependent lung). Even when not increasing tidal volume, strong spontaneous effort may potentially enhance lung damage.
Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size
Authors: Sebastian Stier, Yon Ko, Randolf Forkert, Christoph Lutz, Thomas Neuhaus, Elisabeth Grünewald, Tao Cheng, David Dombkowski, Laura M. Calvi, Susan R. Rittling, David T. Scadden
Journal: The Journal of Experimental Medicine (2005)

Stem cells reside in a specialized niche that regulates their abundance and fate. Components of the niche have generally been defined in terms of cells and signaling pathways. We define a role for a matrix glycoprotein, osteopontin (OPN), as a constraining factor on hematopoietic stem cells within the bone marrow microenvironment. Osteoblasts that participate in the niche produce varying amounts of OPN in response to stimulation. Using studies that combine OPN-deficient mice and exogenous OPN, we demonstrate that OPN modifies primitive hematopoietic cell number and function in a stem cell–nonautonomous manner. The OPN-null microenvironment was sufficient to increase the number of stem cells associated with increased stromal Jagged1 and Angiopoietin-1 expression and reduced primitive hematopoietic cell apoptosis. The activation of the stem cell microenvironment with parathyroid hormone induced a superphysiologic increase in stem cells in the absence of OPN. Therefore, OPN is a negative regulatory element of the stem cell niche that limits the size of the stem cell pool and may provide a mechanism for restricting excess stem cell expansion under conditions of niche stimulation.
The Production of Asepsis in Acutely Septic Wounds by the Free Application of Pure Carbolic Acid
Authors: A. E. Maylard
Journal: BMJ (1897)

Contrary to what is generally stated, I never observed the rash on the face, thougli a suffused blush at the commence- ment of the illness was common.The white line which -remains for a few seconds on drawing the fingernail across the skin, and which is spoken of as " typical " in scarlet fever, I invariably failed to produce.If this line be pathogno- -monic of the scarlet fever rash, as some say it is, its absence would be a valuable sign to rely on in distinguishing the two rashes.Enlargement of the posterior cervical glands was a con- stant and marked feature, I think, without exception, in all the cases.In the great majority of the cases little complaint {of illness was made, and that only transitory, seldom lasting beyond the first or second day; and, with rare exceptions, the appetite was scarcely, if at all, impaired.In some few, however, convalescence was not established for a week or ten days.In one case, that of a child aged 5, the temperature rose to I00 on three or four successive days; there was considerable delirium ; pulse as rapid as 130, and there was very abundant rash, followed by conspicuous desquamation, which was general over the body, and was not completed till some weeks had elapsed.There were several other cases which resembled this one, though of lessened severity.Many of the children, including the child above-mentioned, were, despite the precautionary orders to the contrary, allowed to play in the open air during the desquamation stage, yet no harm resulted.In all the cases which were at all severe the urine was examined for albumen on different occasions, yet in not one instance was albumen present.In two cases pains in the
A new criterion by which to discriminate between patients with moderate allergic rhinitis and patients with severe allergic rhinitis based on the Allergic Rhinitis and its Impact on Asthma severity items
Authors: Antonio Valero, Montse Ferrer, Joaquín Sastre, Ana M. Navarro, Laura Monclús, Enrique Martí-Guadaño, Michael Herdman, Ignacio Dávila, Alfonso del Cuvillo, Carlos Colás, Eva Baró, Ignacio Antépara, Jordi Alonso, Joaquim Mullol
Journal: Journal of Allergy and Clinical Immunology (2007)
Rtp801, a suppressor of mTOR signaling, is an essential mediator of cigarette smoke–induced pulmonary injury and emphysema
Authors: Toshinori Yoshida, Igor Mett, Anil K Bhunia, Joel Bowman, Mario Perez, Li Zhang, Aneta Gandjeva, Lijie Zhen, Ugonma Chukwueke, Tianzhi Mao, Amy Richter, Emile Brown, Hagit Ashush, Natalie Notkin, Anna Gelfand, Rajesh K Thimmulappa, Tirumalai Rangasamy, Thomas Sussan, Gregory Cosgrove, Majd Mouded, Steven D Shapiro, Irina Petrache, Shyam Biswal, Elena Feinstein, Rubin M Tuder
Journal: Nature Medicine (2010)
Peroxisome proliferator‐activated receptor (PPAR) modulators: Diabetes and beyond*
Authors: A. Brian Jones
Journal: Medicinal Research Reviews (2001)

Abstract Peroxisome proliferator‐activated receptors (PPARs) are a class of ligand modulated transcription factors with a prominent role in the regulation of metabolic processes. This report is intended to provide a limited introduction to the PPAR field, sketched with reference to one early series of PPAR ligands. © 2001 John Wiley &amp; Sons, Inc. Med Res Rev, 21, No. 6, 540–552, 2001