tbuckley/cabot-search huggingface dataset:
Dominant Role of the p110β Isoform of PI3K over p110α in Energy Homeostasis Regulation by POMC and AgRP Neurons
Authors: Hind Al-Qassab, Mark A. Smith, Elaine E. Irvine, Julie Guillermet-Guibert, Marc Claret, Agharul I. Choudhury, Colin Selman, Kaisa Piipari, Melanie Clements, Steven Lingard, Keval Chandarana, Jimmy D. Bell, Gregory S. Barsh, Andrew J.H. Smith, Rachel L. Batterham, Michael L.J. Ashford, Bart Vanhaesebroeck, Dominic J. Withers
Journal: Cell Metabolism (2009)

PI3K signaling is thought to mediate leptin and insulin action in hypothalamic pro-opiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, key regulators of energy homeostasis, through largely unknown mechanisms. We inactivated either p110α or p110β PI3K catalytic subunits in these neurons and demonstrate a dominant role for the latter in energy homeostasis regulation. In POMC neurons, p110β inactivation prevented insulin- and leptin-stimulated electrophysiological responses. POMCp110β null mice exhibited central leptin resistance, increased adiposity, and diet-induced obesity. In contrast, the response to leptin was not blocked in p110α-deficient POMC neurons. Accordingly, POMCp110α null mice displayed minimal energy homeostasis abnormalities. Similarly, in AgRP neurons, p110β had a more important role than p110α. AgRPp110α null mice displayed normal energy homeostasis regulation, whereas AgRPp110β null mice were lean, with increased leptin sensitivity and resistance to diet-induced obesity. These results demonstrate distinct metabolic roles for the p110α and p110β isoforms of PI3K in hypothalamic energy regulation.
Neural respiratory drive during apnoeic events in obstructive sleep apnoea
Authors: Y. M. Luo, H. D. Wu, J. Tang, C. Jolley, J. Steier, J. Moxham, N. S. Zhong, M. I. Polkey
Journal: European Respiratory Journal (2007)

For a given neural drive, oesophageal pressure during apnoeic episodes may differ from that during airflow, since inspiratory airflow and increased lung volume both reduce pressure generation. It was, therefore, hypothesised that diaphragm electromyography (EMG) may provide additional data to oesophageal pressure when used for the assessment of neural drive in patients with obstructive sleep apnoea, whose breathing is associated with variable airflow and changes in lung volume. Neural respiratory drive was assessed using diaphragm EMG recorded from multipair oesophageal electrodes in 12 patients with obstructive sleep apnoea. Oesophageal pressure was also recorded. The mean± sd inspiratory oesophageal pressure swing was 11.0±3.7 cmH 2 O during wakefulness, 38.2±15.7 cmH 2 O at the end of the apnoea and reduced to 28.5±10.4 cmH 2 O at the beginning of arousal. The mean peak inspiratory diaphragm EMG signal was 21.8±6.5 μV during wakefulness, 38.6±14.0 μV at the end of the apnoea and further increased to 59.6±32.0 μV at the beginning of arousal. It was concluded that the pattern of neural drive assessed by oesophageal pressure differs from that measured by diaphragm electromyography during apnoeic events and, therefore, that diaphragm electromyography may be a useful adjunct to measurement of oesophageal pressure for the assessment of neural drive in patients with obstructive sleep apnoea.
Stroma-Derived Matrix Metalloproteinase (MMP)-2 Promotes Membrane Type 1-MMP–Dependent Tumor Growth in Mice
Authors: Kaori Taniwaki, Hiroshi Fukamachi, Kiyoshi Komori, Yohei Ohtake, Takahiro Nonaka, Takeharu Sakamoto, Takayuki Shiomi, Yasunori Okada, Takeshi Itoh, Shigeyoshi Itohara, Motoharu Seiki, Ikuo Yana
Journal: Cancer Research (2007)

Matrix metalloproteinase-2 (MMP-2) is a stroma-derived MMP belonging to the type IV collagenase family. It is believed to mediate tumor cell behavior by degrading deposits of type IV collagen, a major component of the basement membrane. The membrane type 1-MMP (MT1-MMP) is a highly potent activator of MMP-2 and is expressed in many tumor and stromal cells. However, the roles played by stromal MMP-2 in tumor progression in vivo remain poorly understood. We established a colon epithelial cell line from an Mt1-mmp(-/-) mouse strain and transfected these cells with an inducible expression system for MT1-MMP (MT1rev cells). Following s.c. implantation into Mmp-2(+/+) mice and induction of MT1-MMP expression, MT1rev cells grew rapidly, whereas they grew very slowly in Mmp-2(-/-) mice, even in the presence of MT1-MMP. This MT1-MMP-dependent tumor growth of MT1rev cells was enhanced in Mmp-2(-/-) mice as long as MMP-2 was supplied via transfection or coimplantation of MMP-2-positive fibroblasts. MT1rev cells cultured in vitro in a three-dimensional collagen gel matrix also required the MT1-MMP/MMP-2 axis for rapid proliferation. MT1rev cells deposit type IV collagen primarily at the cell-collagen interface, and these deposits seem scarce at sites of invasion and proliferation. These data suggest that cooperation between stroma-derived MMP-2 and tumor-derived MT1-MMP may play a role in tumor invasion and proliferation via remodeling of the tumor-associated basement membrane. To our knowledge, this is the first study demonstrating that MT1-MMP-dependent tumor growth in vivo requires stromal-derived MMP-2. It also suggests that MMP-2 represents a potential target for tumor therapeutics.
Shortened Head-Up Tilting Test Guided by Systolic Pressure Reductions in Neurocardiogenic Syncope
Authors: Mariavittoria Pitzalis, Francesco Massari, Pietro Guida, Massimo Iacoviello, Filippo Mastropasqua, Brian Rizzon, Cinzia Forleo, Paolo Rizzon
Journal: Circulation (2002)

Background — Asymptomatic reductions in arterial pressure have been reported to occur before the onset of tilt-induced syncope. We investigated the predictive value of these reductions for a positive tilt result. Methods and Results — In a first study, 238 consecutive healthy subjects with unexplained syncope underwent a passive tilt table test. Finger systolic arterial pressure (SAP) recordings made it possible to calculate how many of the beat-to-beat SAP values during the first 15 minutes of tilt were lower than the lowest value recorded at baseline. Neurocardiogenic syncope was diagnosed in 73 subjects; 28 fainted after 15 minutes of tilt and experienced more pressure reductions than did the subjects with a negative test (328±400 versus 119±284; P &lt;0.01). More than 14 SAP reductions during the first 15 minutes of tilt allowed us to predict a positive test with 93% sensitivity, 58% specificity, and positive and negative predictive values of 28% and 98%, respectively. In a second prospective study (80 consecutive subjects), the online analysis of this criterion by visually inspecting a Finapres monitor showed 80% sensitivity, 85% specificity, and positive and negative predictive values of 57% and 94%. Conclusions — In healthy subjects with unexplained syncope, the evaluation of SAP reductions during the first 15 minutes of tilt is a marker of systolic pressure instability preceding syncope and constitutes a simple and good predictor of tilt outcome that could be used to guide test duration.
Ulcerative enteritis and liver disease in a patient with coeliac disease.
Authors: P Lance, B G Gazzard
Journal: Gut (1983)

We report a fatal case of adult coeliac disease complicated by ulcerative enteritis and chronic liver disease. Macroscopically the liver was characterised by multiple, small depressions over the whole surface. The portal tracts were infiltrated by mononuclear cells and also scattered, large atypical cells of uncertain origin. Neither feature has been reported previously.
Prognosis of Non–Small Cell Lung Cancer Patients by Detecting Circulating Cancer Cells in the Peripheral Blood with Multiple Marker Genes
Authors: Yuh-Pyng Sher, Jin-Yuan Shih, Pan-Chyr Yang, Steve R. Roffler, Yi-Wen Chu, Cheng-Wen Wu, Chia-Li Yu, Konan Peck
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Current lung cancer staging and prognosis methods are based on imaging methods, which may not be sensitive enough for early and accurate detection of metastasis. This study aims to validate the use of a panel of markers for circulating cancer cell detection to improve the accuracy of cancer staging, prognosis, and as a rapid assessment of therapeutic response. Experimental Design: We analyzed the National Cancer Institute-Cancer Genome Anatomy Project database to identify potential marker genes for the detection of circulating cancer cells in peripheral blood. Nested real-time quantitative PCR and a scoring method using cancer cell load Lc were employed to correlate the amount of circulating cancer cells with clinical outcomes in 54 non–small cell lung cancer (NSCLC) patients. The Kaplan-Meier method was employed for analysis of prognostic variables. Results: A panel of four marker genes was identified and experimentally validated. With these marker genes, we achieved an overall positive detection rate of 72% for circulating cancer cells in the peripheral blood of NSCLC patients. Patients who had higher Lc values had worse outcomes and shorter survival times. Patients with poor therapeutic response were revealed by positive detection of circulating cancer cells after therapy. The results correlated well with the patients' survival time. Conclusion: Circulating cancer cell detection by a panel of markers and the Lc scoring method can supplement the current tumor, node, metastasis staging method for improved prognosis and for rapid assessment of therapeutic response. Together, they may facilitate the design of better therapeutic strategies for the treatment of NSCLC patients.
Anti-viral activity induced by culturing lymphocytes with tumor-derived or virus-transformed cells. Enhancement of human natural killer cell activity by interferon and antagonistic inhibition of susceptibility of target cells to lysis.
Authors: G Trinchieri, D Santoli
Journal: The Journal of Experimental Medicine (1978)

Interferon, induced in lymphocytes either with viruses or cell lines, increases severalfold the natural cytotoxicity of human lymphocytes on target cell lines. Cell separation experiments support the hypothesis that interferon enhances the activity of natural killer cells rather than generating a new population of effector cells. In mixed culture of lymphocytes and cell lines in which endogenous interferon is produced, interferon mediates an enhancement of cytotoxicity that represents up to 70-90% of the observed cytotoxicity. The effect of interferon on target cells is antagonistic to the effect on the lymphocytes: the susceptibility to cell-mediated lysis of various cells upon pretreatment with interferon is decreased and in some cases almost completely suppressed. Interferon renders target cells resistant to natural killer cells acting by an intracellular mechanism which requires RNA and protein synthesis. While normal fibroblasts are protected, virus-infected cells and most tumor cells usually are not protected by interferon. Interferon by stimulating very efficient nonspecific cytotoxic cells and by protecting at the same time normal cells from lysis, might render the natural killer cell system an inducible selective defense mechanism against tumor and virus-infected cells.
Clinical outcome and B cell depletion in patients with rheumatoid arthritis receiving rituximab monotherapy in comparison with patients receiving concomitant methotrexate
Authors: K Owczarczyk, M Hellmann, G Fliedner, T Rohrs, K Maizus, D Passon, M Hallek, A Rubbert
Journal: Annals of the Rheumatic Diseases (2008)

In line with the current licensing indications, rituximab (RTX), a monoclonal anti-CD20 antibody1 can be administered solely in combination with methotrexate (MTX).2 However, some patients are ineligible for this treatment due to contraindications to or intolerance of MTX, resulting in an unmet need for alternative treatment protocols.

The aim of our study was to determine the efficacy, safety and kinetics of B cell depletion3 following a single course of RTX as a monotherapy.

In total, 40 patients with active rheumatoid arthritis (RA) were followed. Twenty patients received rituximab as a monotherapy having previously failed or been intolerant of MTX and other …
LOX-1-MT1-MMP axis is crucial for RhoA and Rac1 activation induced by oxidized low-density lipoprotein in endothelial cells
Authors: Koichi Sugimoto, Toshiyuki Ishibashi, Tatsuya Sawamura, Nobutaka Inoue, Masashi Kamioka, Hironori Uekita, Hiroshi Ohkawara, Takayuki Sakamoto, Nobuo Sakamoto, Yasuo Okamoto, Yoh Takuwa, Akemi Kakino, Yoshiko Fujita, Takeshi Tanaka, Tamio Teramoto, Yukio Maruyama, Yasuchika Takeishi
Journal: Cardiovascular Research (2009)

AimsRhoA and Rac1 activation plays a key role in endothelial dysfunction. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a major receptor for oxidized low-density lipoprotein (ox-LDL) in endothelial cells (ECs). Membrane type 1 matrix metalloproteinase (MT1-MMP) has been shown to be involved in atherogenesis. This study was conducted to investigate the role of the LOX-1-MT1-MMP axis in RhoA and Rac1 activation in response to ox-LDL in ECs.
RETRACTED: Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial
Authors: Naoyuki Nakao, Ashio Yoshimura, Hiroyuki Morita, Masyuki Takada, Tsuguo Kayano, Terukuni Ideura
Journal: The Lancet (2003)
Tumor Endothelial Cells with Distinct Patterns of TGFβ-Driven Endothelial-to-Mesenchymal Transition
Authors: Lin Xiao, Dae Joong Kim, Clayton L. Davis, James V. McCann, James M. Dunleavey, Alissa K. Vanderlinden, Nuo Xu, Samantha G. Pattenden, Stephen V. Frye, Xia Xu, Mark Onaitis, Elizabeth Monaghan-Benson, Keith Burridge, Andrew C. Dudley
Journal: Cancer Research (2015)

Abstract Endothelial-to-mesenchymal transition (EndMT) occurs during development and underlies the pathophysiology of multiple diseases. In tumors, unscheduled EndMT generates cancer-associated myofibroblasts that fuel inflammation and fibrosis, and may contribute to vascular dysfunction that promotes tumor progression. We report that freshly isolated subpopulations of tumor-specific endothelial cells (TEC) from a spontaneous mammary tumor model undergo distinct forms of EndMT in response to TGFβ stimulation. Although some TECs strikingly upregulate α smooth muscle actin (SMA), a principal marker of EndMT and activated myofibroblasts, counterpart normal mammary gland endothelial cells (NEC) showed little change in SMA expression after TGFβ treatment. Compared with NECs, SMA+ TECs were 40% less motile in wound-healing assays and formed more stable vascular-like networks in vitro when challenged with TGFβ. Lineage tracing using ZsGreenCdh5-Cre reporter mice confirmed that only a fraction of vessels in breast tumors contain SMA+ TECs, suggesting that not all endothelial cells (EC) respond identically to TGFβ in vivo. Indeed, examination of 84 TGFβ-regulated target genes revealed entirely different genetic signatures in TGFβ-stimulated NEC and TEC cultures. Finally, we found that basic FGF (bFGF) exerts potent inhibitory effects on many TGFβ-regulated genes but operates in tandem with TGFβ to upregulate others. ECs challenged with TGFβ secrete bFGF, which blocks SMA expression in secondary cultures, suggesting a cell-autonomous or lateral-inhibitory mechanism for impeding mesenchymal differentiation. Together, our results suggest that TGFβ-driven EndMT produces a spectrum of EC phenotypes with different functions that could underlie the plasticity and heterogeneity of the tumor vasculature. Cancer Res; 75(7); 1244–54. ©2015 AACR.
Genetic variation in insulin-like growth factors and brain tumor risk
Authors: Stefan Lönn, Nathaniel Rothman, William R. Shapiro, Howard A. Fine, Robert G. Selker, Peter M. Black, Jay S. Loeffler, Amy A. Hutchinson, Peter D. Inskip
Journal: Neuro-Oncology (2008)

Many studies support a role for insulin-like growth factors (IGFs) in the regulation of tumor cell biology. We hypothesized that single-nucleotide polymorphisms (SNPs) in IGF genes are risk factors for glioma and meningioma. To test the hypothesis, we examined associations of brain tumor risk with nine variants in five IGF genes in a hospital-based case-control study. The study was conducted at hospitals in Boston, Phoenix, and Pittsburgh between 1994 and 1998. Eligible cases were individuals (18 years or older) newly diagnosed with glioma or meningioma. Controls were selected among patients who were admitted to the same hospitals for a variety of nonmalignant conditions and frequency matched to cases by hospital, age, sex, race, and distance from residence. The present analysis was restricted to non-Hispanic whites. DNA was extracted from blood samples collected from 354 glioma cases, 133 meningioma cases, and 495 control individuals. We evaluated nine SNPs in five IGF genes (IGF1, IGF1R, IGF2, IGF2R, and IGFBP3). The majority of the analyzed IGF SNPs did not display statistically significant associations with glioma or meningioma. For glioma, one IGF1R SNP (rs2272037) indicated a possible association. No indications of association were seen for glioblastoma, but for low-grade gliomas, the odds ratio under a dominant model was 0.56 (95% confidence interval [CI], 0.35-0.90) for IGF1 rs6220, 2.98 (95% CI, 1.65-5.38) for IGF1R rs2272037, and 1.60 (95% CI, 0.90-2.83) for IGF1R rs2016347. Overall, our results do not provide strong evidence of associations of brain tumor risk with IGF polymorphic variants but identify several associations for glioma that warrant further examination in other, larger studies.
Doxorubicin Eliminates Myeloid-Derived Suppressor Cells and Enhances the Efficacy of Adoptive T-Cell Transfer in Breast Cancer
Authors: Darya Alizadeh, Malika Trad, Neale T. Hanke, Claire B. Larmonier, Nona Janikashvili, Bernard Bonnotte, Emmanuel Katsanis, Nicolas Larmonier
Journal: Cancer Research (2013)

Abstract Myeloid-derived suppressor cells (MDSC) expand in tumor-bearing hosts and play a central role in cancer immune evasion by inhibiting adaptive and innate immunity. They therefore represent a major obstacle for successful cancer immunotherapy. Different strategies have thus been explored to deplete and/or inactivate MDSC in vivo. Using a murine mammary cancer model, we demonstrated that doxorubicin selectively eliminates MDSC in the spleen, blood, and tumor beds. Furthermore, residual MDSC from doxorubicin-treated mice exhibited impaired suppressive function. Importantly, the frequency of CD4+ and CD8+ T lymphocytes and consequently the effector lymphocytes or natural killer (NK) to suppressive MDSC ratios were significantly increased following doxorubicin treatment of tumor-bearing mice. In addition, the proportion of NK and cytotoxic T cell (CTL) expressing perforin and granzyme B and of CTL producing IFN-γ was augmented by doxorubicin administration. Of therapeutic relevance, this drug efficiently combined with Th1 or Th17 lymphocytes to suppress tumor development and metastatic disease. MDSC isolated from patients with different types of cancer were also sensitive to doxorubicin-mediated cytotoxicity in vitro. These results thus indicate that doxorubicin may be used not only as a direct cytotoxic drug against tumor cells, but also as a potent immunomodulatory agent that selectively impairs MDSC-induced immunosuppression, thereby fostering the efficacy of T-cell–based immunotherapy. Cancer Res; 74(1); 104–18. ©2013 AACR.
Novel Cardioprotective Role of a Small Heat-Shock Protein, Hsp20, Against Ischemia/Reperfusion Injury
Authors: Guo-Chang Fan, Xiaoping Ren, Jiang Qian, Qunying Yuan, Persoulla Nicolaou, Yang Wang, W. Keith Jones, Guoxiang Chu, Evangelia G. Kranias
Journal: Circulation (2005)

Heat-shock proteins (Hsps) have been shown to render cardioprotection from stress-induced injury; however, little is known about the role of another small heat-shock protein, Hsp20, which regulates activities of vasodilation and platelet aggregation, in cardioprotection against ischemia injury. We recently reported that increased expression of Hsp20 in cardiomyocytes was associated with improved contraction and protection against beta-agonist-induced apoptosis.To investigate whether overexpression of Hsp20 exerts protective effects in both ex vivo and in vivo ischemia/reperfusion (I/R) injury, we generated a transgenic (TG) mouse model with cardiac-specific overexpression of Hsp20 (10-fold). TG and wild-type (WT) hearts were then subjected to global no-flow I/R (45 minutes/120 minutes) using the Langendorff preparation. TG hearts exhibited improved recovery of contractile performance over the whole reperfusion period. This improvement was accompanied by a 2-fold decrease in lactate dehydrogenase released from the TG hearts. The extent of infarction and apoptotic cell death was also significantly decreased, which was associated with increased protein ratio of Bcl-2/Bax and reduced caspase-3 activity in TG hearts. Furthermore, in vivo experiments of 30-minute myocardial ischemia, via coronary artery occlusion, followed by 24-hour reperfusion, showed that the infarct region-to-risk region ratio was 8.1+/-1.1% in TG hearts (n=7), compared with 19.5+/-2.1% in WT hearts (n=11, P<0.001).Our data demonstrate that increased Hsp20 expression in the heart protects against I/R injury, resulting in improved recovery of cardiac function and reduced infarction. Thus, Hsp20 may constitute a new therapeutic target for ischemic heart diseases.
Response to Letter Regarding Article “Effects of the Selective Estrogen Receptor Modulator Raloxifene on Coronary Outcomes in the Raloxifene Use for the Heart Trial: Results of Subgroup Analyses by Age and Other Factors”
Authors: Peter Collins, Lori Mosca, Mary Jane Geiger, Messan G. Amewou-Atisso, Mark B. Effron, Sherie Dowsett, Deborah Grady, Marcel Kornitzer, Elizabeth Barrett-Connor, Nanette K. Wenger
Journal: Circulation (2009)

Use for the Heart Trial: Results of Subgroup Analyses by Age and Other Factors"We thank Dr Choi and colleagues for their correspondence and intriguing hypothesis.Unfortunately, we do not have the additional data with which to confidently test the hypothesis stated.We do not have robust osteoporosis data in the Raloxifene Use for the Heart (RUTH) study; we did not systematically measure bone mineral density.In addition, few women (Ͻ10% before data lock) reported osteoporosis as a secondary condition.Approximately 15% reported postbaseline use of bone-active agents.For reported fractures, we did not collect data on whether or not the study participant was osteoporotic.Therefore, with such small numbers, these would not be informative (or even appropriate) subgroup analyses.Although we all believe this is a very interesting hypothesis, we cannot address this question with data from the RUTH trial.