tbuckley/cabot-search huggingface dataset:
Mice lacking NKCC1 are protected from development of bacteremia and hypothermic sepsis secondary to bacterial pneumonia
Authors: MyTrang Nguyen, Amy J. Pace, Beverly H. Koller
Journal: The Journal of Experimental Medicine (2007)

The contribution of the Na+-K+-Cl− transporter (NKCC1) to fluid in ion transport and fluid secretion in the lung and in other secretory epithelia has been well established. Far less is known concerning the role of this cotransporter in the physiological response of the pulmonary system during acute inflammation. Here we show that mice lacking this transporter are protected against hypothermic sepsis and bacteremia developing as a result of Klebsiella pneumoniae infection in the lung. In contrast, this protection was not observed in NKCC1−/− mice with K. pneumoniae—induced peritonitis. Although overall recruitment of cells to the lungs was not altered, the number of cells present in the airways was increased in the NKCC1−/− animals. Despite this robust inflammatory response, the increase in vascular permeability observed in this acute inflammatory model was attenuated in the NKCC1−/− animals. Our studies suggest that NKCC1 plays a unique and untoward unrecognized role in acute inflammatory responses in the lung and that specific inhibition of this NKCC isoform could be beneficial in treatment of sepsis.
Three minute, but not one minute, ischemia and nicorandil have a preconditioning effect in patients with coronary artery disease
Authors: Tetsuo Matsubara, Shinya Minatoguchi, Hitoshi Matsuo, Kenji Hayakawa, Tomonori Segawa, Yukihiko Matsuno, Sachiro Watanabe, Masazumi Arai, Yoshihiro Uno, Masanori Kawasaki, Toshiyuki Noda, Genzou Takemura, Kazuhiko Nishigaki, Hisayoshi Fujiwara
Journal: Journal of the American College of Cardiology (2000)
Relation of GIX antigen of thymocytes to envelope glycoprotein of murine leukemia virus.
Authors: Y Obata, H Ikeda, E Stockert, E A Boyse
Journal: The Journal of Experimental Medicine (1975)

Expression of Gix surface antigen on thymocytes is an inherited mendelian train of certain strains of mice. We report here the following new findings: (a) Gix antigen was found free in the serum of Gix+ mouse strains. (b) Expression vs. nonexpression of Gix antigen was invariably correlated with presence or absence of the group-specific antigen of Murine leukemia virus (MuLV) gp69/71 in the serum of mice of inbred and segregating populations. (c) Gix antigen could be removed from normal Gix+ mouse serum by precipitation with antiserum to MuLV gp 69/71. (d) Anti-gp69/71 serum was weakly cytotoxic for Gix+ thymocytes, and partially blocked the cytotoxic activity of Gix antibody for Gix+ thymocytes. (e) Purified AKR virus absorbed Gix activity, and disruption of the virions did not increase their absorbing capacity. These serological data indicate that Gix antigen is a constituent of gp69/71, the glycoprotein which is the major component of the MuLV envelope. On present evidence, Gix antigen is represented in intact virions and is probably accessible to Gix antibody.
CD4+ T Cells Contribute to the Remodeling of the Microenvironment Required for Sustained Tumor Regression upon Oncogene Inactivation
Authors: Kavya Rakhra, Pavan Bachireddy, Tahera Zabuawala, Robert Zeiser, Liwen Xu, Andrew Kopelman, Alice C. Fan, Qiwei Yang, Lior Braunstein, Erika Crosby, Sandra Ryeom, Dean W. Felsher
Journal: Cancer Cell (2010)
Incidence rate ratio
Authors: P. Sedgwick
Journal: BMJ (2010)

Researchers evaluated whether a community falls prevention service reduced the rate of falls in older people. They used a randomised controlled trial design. Participants were recruited if they were aged over 60 years, had experienced a fall while living at home or in residential care, and an emergency ambulance had been called but had not taken them to hospital. Participants were randomised to the community falls prevention service or standard medical and social care (control treatment).1

The primary outcome was rate of falls in one year of follow-up, as recorded in monthly diaries. Analysis was by intention to treat. After randomisation, 99 participants were offered the community falls prevention service and 102 participants were offered the control treatment. Diaries for the intervention group contributed 88.6 person years and those for the control group contributed 84.5 person years. The incidence rates of falls per year were 3.46 in the intervention group and 7.68 in the control group, with an incidence rate ratio equal …
Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib
Authors: Lisa A. Carey, Donald A. Berry, Constance T. Cirrincione, William T. Barry, Brandelyn N. Pitcher, Lyndsay N. Harris, David W. Ollila, Ian E. Krop, Norah Lynn Henry, Douglas J. Weckstein, Carey K. Anders, Baljit Singh, Katherine A. Hoadley, Michael Iglesia, Maggie Chon U. Cheang, Charles M. Perou, Eric P. Winer, Clifford A. Hudis
Journal: Journal of Clinical Oncology (2015)

Dual human epidermal growth factor receptor 2 (HER2) targeting can increase pathologic complete response rates (pCRs) to neoadjuvant therapy and improve progression-free survival in metastatic disease. CALGB 40601 examined the impact of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel, considering tumor and microenvironment molecular features.Patients with stage II to III HER2-positive breast cancer underwent tumor biopsy followed by random assignment to paclitaxel plus trastuzumab alone (TH) or with the addition of lapatinib (THL) for 16 weeks before surgery. An investigational arm of paclitaxel plus lapatinib (TL) was closed early. The primary end point was pCR in the breast; correlative end points focused on molecular features identified by gene expression-based assays.Among 305 randomly assigned patients (THL, n = 118; TH, n = 120; TL, n = 67), the pCR rate was 56% (95% CI, 47% to 65%) with THL and 46% (95% CI, 37% to 55%) with TH (P = .13), with no effect of dual therapy in the hormone receptor-positive subset but a significant increase in pCR with dual therapy in those with hormone receptor-negative disease (P = .01). The tumors were molecularly heterogeneous by gene expression analysis using mRNA sequencing (mRNAseq). pCR rates significantly differed by intrinsic subtype (HER2 enriched, 70%; luminal A, 34%; luminal B, 36%; P < .001). In multivariable analysis treatment arm, intrinsic subtype, HER2 amplicon gene expression, p53 mutation signature, and immune cell signatures were independently associated with pCR. Post-treatment residual disease was largely luminal A (69%).pCR to dual HER2-targeted therapy was not significantly higher than single HER2 targeting. Tissue analysis demonstrated a high degree of intertumoral heterogeneity with respect to both tumor genomics and tumor microenvironment that significantly affected pCR rates. These factors should be considered when interpreting and designing trials in HER2-positive disease.
Expression of integrins and basement membrane components by wound keratinocytes.
Authors: H Larjava, T Salo, K Haapasalmi, R H Kramer, J Heino
Journal: Journal of Clinical Investigation (1993)

Extracellular matrix proteins and their cellular receptors, integrins, play a fundamental role in keratinocyte adhesion and migration. During wound healing, keratinocytes detach, migrate until the two epithelial sheets confront, and then regenerate the basement membrane. We examined the expression of different integrins and their putative ligands in keratinocytes during human mucosal wound healing. Migrating keratinocytes continuously expressed kalinin but not the other typical components of the basement membrane zone: type IV collagen, laminin, and type VII collagen. When the epithelial sheets confronted each other, these missing basement membrane components started to appear gradually through the entire wound area. The expression of integrin beta 1 subunit was increased in keratinocytes during migration. The beta 1-associated alpha 2 and alpha 3 subunits were expressed constantly by wound keratinocytes whereas the alpha 5 subunit was present only in keratinocytes during reepithelialization. Furthermore, migrating cells started to express alpha v-integrins which were not present in the nonaffected epithelium. All keratinocytes also expressed the alpha 6 beta 4 integrin during migration. In the migrating cells, the distribution of integrins was altered. In normal mucosa, beta 1-integrins were located mainly on the lateral plasma membrane and alpha 6 beta 4 at the basal surface of basal keratinocytes in the nonaffected tissue. In wounds, integrins were found in filopodia of migrating keratinocytes, and also surrounding cells in several cell layers of the migrating sheet. The results indicate that migrating keratinocytes, in deep human wounds enlarge their integrin repertoire. The changes in integrin expression take place concomitantly with changes in the basement membrane composition, suggesting a close interplay of these two groups of molecules during wound healing.
Précis of<i>Images of Mind</i>
Authors: Michael I. Posner, Marcus E. Raichle
Journal: Behavioral and Brain Sciences (1995)

Abstract This volume explores how functional brain imaging techniques like positron emission tomography have influenced cognitive studies. The first chapter outlines efforts to relate human thought and cognition in terms of great books from the late 1800s through the present. Chapter 2 describes mental operations as they are measured in cognitive science studies. It develops a framework for relating mental operations to activity in nerve cells. In Chapter 3, the PET method is reviewed and studies are presented that use PET to map the striate cortex and to activate extrastriate motion, color, and form areas. Chapter 4 shows how top down processes involving attention can lead to activation of these same areas in the detection of targets, visual search, and visual imagery. This chapter reveals complex networks of activations. Chapters 5 and 6 deal with the presentation of words. Chapter 5 illustrates PET studies of the anatomy of visual word processing and shows how the circuitry used for generating novel uses of words changes as the task becomes automated. Chapter 6 applies high density electrical recording to explore these activations in real time and to show how a constant anatomy can be reprogrammed by task instructions to produce and perform different cognitive tasks. Chapter 7 shows how studies of brain lesions and PET converge on common networks underlying attentional functions such as visual orienting, target detection, and maintenance of the alert state. Chapters 8 and 9 apply the network approach to examine normal development of attention in infants and pathological conditions resulting from brain damage, and psychiatric pathologies of depression, schizophrenia, and attention deficit disorder. In Chapter 10, new developments such as functional MRI are discussed in terms of future developments and integration of cognitive neuroscience.
Cell Surface Expression of Epidermal Growth Factor Receptor and Her-2 with Nuclear Expression of Her-4 in Primary Osteosarcoma
Authors: Dennis P. M. Hughes, Dafydd G. Thomas, Thomas J. Giordano, Laurence H. Baker, Kevin T. McDonagh
Journal: Cancer Research (2004)

Abstract There is controversy over the role of Her-2 in osteosarcoma, with some investigators reporting association between expression and adverse outcome, whereas others point to the lack of gene amplification and membranous expression by immunohistochemistry (IHC) as inconsistent with biological significance. Her-2 normally requires pairing with epidermal growth factor receptor (EGFR), Her-3, or Her-4, but these have been less well studied in osteosarcoma. We evaluated the expression of each of these receptors in osteosarcoma and their potential to contribute to pathogenesis by examining a panel of low-passage primary osteosarcoma cell lines, comparing these with archival tumor specimens. Her-2 immunoreactivity was seen frequently in the diffuse staining pattern described previously. We observed EGFR in all samples by IHC. Her-3 expression was not observed. Her-4 expression was nuclear in distribution in all tumor samples and many cell line samples, consistent with activation and cleavage of the receptor. Quantified expression of Her-2 and EGFR mRNA by quantitative, real-time PCR in cell lines correlated with IHC for Her-2 but not for EGFR. Western blot identified full-length receptors for EGFR and Her-2 in all expected cell lines and showed Her-4 to be predominantly in the p80 form. Flow cytometry identified cell surface Her-2 and EGFR in all lines with receptor expression by IHC. We conclude that the cell surface expression of Her-2 and EGFR and the nuclear localization of the activated p80 fragment of Her-4 suggest that all three may be contributing to osteosarcoma pathogenesis. Therapy directed against this family of receptors may be beneficial for patients with osteosarcoma.
Dexamethasone modulates α2-macroglobulin and apolipoprotein E gene expression in cultured rat liver fat-storing (Ito) cells
Authors: Giuliano Ramadori, Thomas Knittel, Stefan Schwögler, Florian Bieber, Hartmut Rieder, Karl-Herrmann Meyer Zum Büschenfelde
Journal: Hepatology (1991)

Fat-storing (Ito) cells are perisinusoidal liver cells thought to play a central role in vitamin A metabolism and fibrongenesis. Glucocorticoids have been shown to be beneficial in the treatment of certain types of liver diseases by delaying the development of cirrhosis. To study the regulatory effects of dexamethasone on Ito cell gene expression, Ito cells were isolated from normal rat liver and primary cultures were established. The effect of dexamethasone on the synthesis of alpha 2-macroglobulin, apolipoprotein E, fibronectin and actin was examined. Protein synthesis was studied both at the protein level and at the RNA level by means of biosynthetic labeling, immunoprecipitation followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by Northern blot analysis of total RNA. After exposure to dexamethasone for 20 hr, alpha 2-macroglobulin protein synthesis was increased threefold, whereas apolipoprotein E expression was decreased 80%. Biosynthesis of fibronectin remained unaffected by hormone treatment. The dexamethasone effect became detectable 5 hr after beginning the exposure. Deinduction kinetic experiments showed that the glucocorticoid effect was detectable more than 12 hr after the replacement of the dexamethasone-containing culture medium by medium without the hormone. Corresponding to the data obtained at the protein level, dexamethasone increased the steady-state levels of alpha 2-macroglobulin-specific messenger RNA and reduced apolipoprotein E-specific transcripts, whereas fibronectin and actin messenger mRNA remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study
Authors: P.J. Hesketh, G. Rossi, G. Rizzi, M. Palmas, A. Alyasova, I. Bondarenko, A. Lisyanskaya, R.J. Gralla
Journal: Annals of Oncology (2014)

BackgroundNEPA is a novel oral fixed-dose combination of netupitant (NETU), a new highly selective neurokinin-1 (NK1) receptor antagonist (RA) and palonosetron (PALO), a pharmacologically and clinically distinct 5-hydroxytryptamine type 3 (5-HT3) RA. This study was designed to determine the appropriate clinical dose of NETU to combine with PALO for evaluation in the phase 3 NEPA program.Patients and methodsThis randomized, double-blind, parallel group study in 694 chemotherapy naïve patients undergoing cisplatin-based chemotherapy for solid tumors compared three different oral doses of NETU (100, 200, and 300 mg) + PALO 0.50 mg with oral PALO 0.50 mg, all given on day 1. A standard 3-day aprepitant (APR) + IV ondansetron (OND) 32 mg regimen was included as an exploratory arm. All patients received oral dexamethasone on days 1–4. The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the overall (0–120 h) phase.ResultsAll NEPA doses showed superior overall CR rates compared with PALO (87.4%, 87.6%, and 89.6% for NEPA100, NEPA200, and NEPA300, respectively versus 76.5% PALO; P < 0.050) with the highest NEPA300 dose studied showing an incremental benefit over lower NEPA doses for all efficacy endpoints. NEPA300 was significantly more effective than PALO and numerically better than APR + OND for all secondary efficacy endpoints of no emesis, no significant nausea, and complete protection (CR plus no significant nausea) rates during the acute (0–24 h), delayed (25–120 h), and overall phases. Adverse events were comparable across groups with no dose response. The percent of patients developing electrocardiogram changes was also comparable.ConclusionsEach NEPA dose provided superior prevention of chemotherapy-induced nausea and vomiting (CINV) compared with PALO following highly emetogenic chemotherapy; however, NEPA300 was the best dose studied, with an advantage over lower doses for all efficacy endpoints. The combination of NETU and PALO was well tolerated with a similar safety profile to PALO and APR + OND.
Patients With Valvular Heart Disease Presenting With Sustained Ventricular Tachyarrhythmias or Syncope
Authors: Antoni Martínez-Rubio, Yvonne Schwammenthal, Ehud Schwammenthal, Michael Block, Lutz Reinhardt, Arcadi Garcia-Alberola, Gilberto Sierra, Mohammad Shenasa, Wilhelm Haverkamp, Hans H. Scheld, Günter Breithardt, Martin Borggrefe
Journal: Circulation (1997)

Programmed ventricular stimulation is commonly used to guide therapy in post-myocardial infarction patients with sustained monomorphic ventricular tachycardia (VT) or ventricular fibrillation (VF). In patients with valvular heart disease presenting with spontaneous VT, VF, or syncope, the usefulness of this technique is still unclear. The aim of the study was to analyze whether programmed ventricular stimulation was helpful in guiding therapy and determining prognosis in 97 patients with valvular heart disease presenting with VT (60%), VF (18%), or syncope (22%).Patients were classified as having either predominant ventricular pressure or volume overload or no significant pressure or volume overload. Overall, sustained VT or VF was inducible in 38 (39%) and 19 (20%) patients, respectively. Forty-six (47%) patients were discharged on antiarrhythmic drugs, 29 (30%) received an implantable cardioverter-defibrillator, and 22 (23%) remained without therapy. With serial drug testing, inducibility was completely or partially suppressed in 18 (19%) and 9 (9%) patients, respectively. During a mean follow-up of 51 months (n=97), 17 patients (18%) died (sudden death, n=7; heart failure, n=4; noncardiac causes, n=6). One-, 2- and 3-year event-free survival for sudden death, sustained VT, or VF was 77%, 68%, and 61%, respectively. Only inducibility of VT during baseline study (P<.0003) and left ventricular volume overload (P<.008) were significant predictors of arrhythmic events. Recurrence of arrhythmic events occurred in 56% and 56% of patients with complete or partial suppression of inducibility during serial drug testing as well as in 10 of 19 (53%) patients without a change in inducibility.Although programmed ventricular stimulation seems to predict adverse outcome, serial drug testing is unreliable in guiding therapy. The type of workload imposed on the ventricles influences outcome, being worse in patients with left ventricular volume overload. Therefore, implantation of a cardioverter-defibrillator should be considered early for the management of these patients.
Long-term adenoma recurrence following wide-field endoscopic mucosal resection (WF-EMR) for advanced colonic mucosal neoplasia is infrequent: results and risk factors in 1000 cases from the Australian Colonic EMR (ACE) study
Authors: Alan Moss, Stephen J Williams, Luke F Hourigan, Gregor Brown, William Tam, Rajvinder Singh, Simon Zanati, Nicholas G Burgess, Rebecca Sonson, Karen Byth, Michael J Bourke
Journal: Gut (2014)

<h3>Objective</h3> Wide-field endoscopic mucosal resection (WF-EMR) is an alternative to surgery for treatment of advanced colonic mucosal neoplasia up to 120 mm in size, but has been criticised for its potentially high recurrence rates. We aimed to quantify recurrence at 4 months (early) and 16 months (late) following successful WF-EMR and identify its risk factors and clinical significance. <h3>Design</h3> Ongoing multicentre, prospective, intention-to-treat analysis of sessile or laterally spreading colonic lesions ≥20 mm in size referred for WF-EMR to seven academic endoscopy units. Surveillance colonoscopy (SC) was performed 4 months (SC1) and 16 months (SC2) after WF-EMR, with photographic documentation and biopsy of the scar. <h3>Results</h3> 1134 consecutive patients were enrolled when 1000 successful EMRs were achieved, of whom 799 have undergone SC1. 670 were normal. Early recurrent/residual adenoma was present in 128 (16.0%, 95% CI 13.6% to 18.7%). One case was unknown. The recurrent/residual adenoma was diminutive in 71.7% of cases. On multivariable analysis, risk factors were lesion size &gt;40 mm, use of argon plasma coagulation and intraprocedural bleeding. Of 670 with normal SC1, 426 have undergone SC2, with late recurrence present in 17 cases (4.0%, 95% CI 2.4% to 6.2%). Overall, recurrent/residual adenoma was successfully treated endoscopically in 135 of 145 cases (93.1%, 95% CI 88.1% to 96.4%). If the initial EMR was deemed successful and did not contain submucosal invasion requiring surgery, 98.1% (95% CI 96.6% to 99.0%) were adenoma-free and had avoided surgery at 16 months following EMR. <h3>Conclusions</h3> Following colonic WF-EMR, early recurrent/residual adenoma occurs in 16%, and is usually unifocal and diminutive. Risk factors were identified. Late recurrence occurs in 4%. Overall, recurrence was managed endoscopically in 93% of cases. Recurrence is not a significant clinical problem following WF-EMR, as with strict colonoscopic surveillance, it can be managed endoscopically with high success rates. <h3>Trial registration number:</h3> NCT01368289.