tbuckley/cabot-search huggingface dataset:
NF-κB and p53 Are the Dominant Apoptosis-inducing Transcription Factors Elicited by the HIV-1 Envelope
Authors: Jean-Luc Perfettini, Thomas Roumier, Maria Castedo, Nathanael Larochette, Patricia Boya, Brigitte Raynal, Vladimir Lazar, Fabiola Ciccosanti, Roberta Nardacci, Josef Penninger, Mauro Piacentini, Guido Kroemer
Journal: The Journal of Experimental Medicine (2004)

The coculture of cells expressing the HIV-1 envelope glycoprotein complex (Env) with cells expressing CD4 results into cell fusion, deregulated mitosis, and subsequent cell death. Here, we show that NF-κB, p53, and AP1 are activated in Env-elicited apoptosis. The nuclear factor κB (NF-κB) super repressor had an antimitotic and antiapoptotic effect and prevented the Env-elicited phosphorylation of p53 on serine 15 and 46, as well as the activation of AP1. Transfection with dominant-negative p53 abolished apoptosis and AP1 activation. Signs of NF-κB and p53 activation were also detected in lymph node biopsies from HIV-1–infected individuals. Microarrays revealed that most (85%) of the transcriptional effects of HIV-1 Env were blocked by the p53 inhibitor pifithrin-α. Macroarrays led to the identification of several Env-elicited, p53-dependent proapoptotic transcripts, in particular Puma, a proapoptotic “BH3-only” protein from the Bcl-2 family known to activate Bax/Bak. Down modulation of Puma by antisense oligonucleotides, as well as RNA interference of Bax and Bak, prevented Env-induced apoptosis. HIV-1–infected primary lymphoblasts up-regulated Puma in vitro. Moreover, circulating CD4+ lymphocytes from untreated, HIV-1–infected donors contained enhanced amounts of Puma protein, and these elevated Puma levels dropped upon antiretroviral therapy. Altogether, these data indicate that NF-κB and p53 cooperate as the dominant proapoptotic transcription factors participating in HIV-1 infection.
Fibrin induces release of von Willebrand factor from endothelial cells.
Authors: J A Ribes, C W Francis, D D Wagner
Journal: Journal of Clinical Investigation (1987)

Addition of fibrinogen to human umbilical vein endothelial cells in culture resulted in release of von Willebrand factor (vWf) from Weibel-Palade bodies that was temporally related to formation of fibrin in the medium. Whereas no release occurred before gelation, the formation of fibrin was associated with disappearance of Weibel-Palade bodies and development of extracellular patches of immunofluorescence typical of vWf release. Release also occurred within 10 min of exposure to preformed fibrin but did not occur after exposure to washed red cells, clot liquor, or structurally different fibrin prepared with reptilase. Metabolically labeled vWf was immunopurified from the medium after release by fibrin and shown to consist of highly processed protein lacking pro-vWf subunits. The contribution of residual thrombin to release stimulated by fibrin was minimized by preparing fibrin clots with nonstimulatory concentrations of thrombin and by inhibiting residual thrombin with hirudin or heating. We conclude that fibrin formed at sites of vessel injury may function as a physiologic secretagogue for endothelial cells causing rapid release of stored vWf.
Increased responsiveness of B. cells in the murine MRL/lpr model of lupus nephritis to interleukin-1 beta.
Authors: T V Lebedeva, A K Singh
Journal: Journal of the American Society of Nephrology (1995)

The high-level production of immunoglobulin G (IgG), anti-DNA antibodies, and id-H130-expressing antibodies has been correlated with both the presence and the severity of nephritis in the murine MRL/lpr lupus model. Although evidence suggests that interleukin-1 (IL-1) could be an important factor in the immunopathogenesis of murine lupus nephritis, its influence on B cell hyperactivity is poorly understood. The in vitro responsiveness of B cells derived from lupus-prone old and young MRL/lpr and healthy C3H/HeJ mice to exogenous IL-1 beta was examined. B cells derived from MRL/lpr mice, and particularly old MRL/lpr mice, were hyperresponsive to exogenous IL-1 beta, demonstrating a marked increase in IgG production with 50 pg/mL concentrations of IL-1 beta as compared with control medium. Whereas MRL/lpr B cells demonstrated remarkable unresponsiveness to high concentrations of IL-1 beta. By contrast, B cells derived from C3H/HeJ mice and cultured with IL-1 beta showed virtually no alteration in IgG production. In addition, B cells derived from old MRL/lpr mice and cultured with IL-1 beta showed a significant increase in the production of anti-DNA and id-H130-expressing antibodies. Collectively, these observations demonstrate increased B cell responsiveness to exogenous IL-1 beta and suggest that heightened IL-1 bioactivity in the murine MRL/lpr lupus model may influence high-level IgG and autoantibody production.
Pearly penile papules: Still no reason for uneasiness
Authors: Cornelis J.A. Hogewoning, Maaike C.G. Bleeker, Adriaan J.C. van den Brule, Feja J. Voorhorst, Rick E. van Andelb, Elle K. Risse, Theo M. Starink, Chris J.L.M. Meijer
Journal: Journal of the American Academy of Dermatology (2003)
PWE-039 Routine water soluble contrast swallow has limited clinical value in the detection of anastomotic leaks following oesophagectomy
Authors: S Love, S Bruce, T S Athwal, N Howes, M Hartley
Journal: Gut (2012)

<h3>Introduction</h3> Water-soluble contrast swallow (WSCS) is performed following oesophagectomy to assess anastomotic integrity before commencing oral intake. This study, the largest in the UK to date, challenges the routine use of WSCS following oesophagectomy. <h3>Methods</h3> All patients undergoing open transthoracic oesophagectomy for oesophageal cancer with intrathoracic anastomosis, within a supra-regional upper GI cancer centre, were registered on a prospective database between 2006 and 2011. WSCS results, anastomotic leak rate and the modality of leak detection were analysed. <h3>Results</h3> During the study period, 116 oesophagectomies were performed. WSCS was undertaken in 97 (84%) cases on a median of day 5 (range 3–8) post operatively; 95 (98%) WSCS reported no evidence of a leak, two studies reported a leak and one study was equivocal. WSCS was not performed in 19 (16%) cases; 10 patients developed early clinical signs suggestive of an anastomotic leak and were immediately imaged by CT, eight had a prolonged ITU stay due to cardiorespiratory complications while one patient died peri-operatively. There were 6 (5%) anastomotic leaks of which three patients had immediate CT due to clinical deterioration while three patients had routine WSCS. WSCS was followed by CT in two patients due to a positive or equivocal finding. One patient had no WSCS evidence of a leak but then developed sepsis and CT confirmed a leak. Clinical signs suggestive of a leak were evident in all patients within 7 days post-operatively. <h3>Conclusion</h3> Routine WSCS has limited value in the detection of anastomotic leak following oesophagectomy. All patients with an anastomotic leak developed significant clinical signs of a leak that were subsequently confirmed by CT imaging. WSCS altered the management in just 2% of cases. <h3>Competing interests</h3> None declared.
A cell-penetrating ARF peptide inhibitor of FoxM1 in mouse hepatocellular carcinoma treatment
Authors: Galina A. Gusarova, I-Ching Wang, Michael L. Major, Vladimir V. Kalinichenko, Timothy Ackerson, Vladimir Petrovic, Robert H. Costa
Journal: Journal of Clinical Investigation (2006)

The forkhead box m1 (Foxm1) transcription factor is essential for initiation of carcinogen-induced liver tumors; however, whether FoxM1 constitutes a therapeutic target for liver cancer treatment remains unknown. In this study, we used diethylnitrosamine/phenobarbital treatment to induce hepatocellular carcinomas (HCCs) in either WT mice or Arf(-/-)Rosa26-FoxM1b Tg mice, in which forkhead box M1b (FoxM1b) is overexpressed and alternative reading frame (ARF) inhibition of FoxM1 transcriptional activity is eliminated. To pharmacologically reduce FoxM1 activity in HCCs, we subjected these HCC-bearing mice to daily injections of a cell-penetrating ARF(26-44) peptide inhibitor of FoxM1 function. After 4 weeks of this treatment, HCC regions displayed reduced tumor cell proliferation and angiogenesis and a significant increase in apoptosis within the HCC region but not in the adjacent normal liver tissue. ARF peptide treatment also induced apoptosis of several distinct human hepatoma cell lines, which correlated with reduced protein levels of the mitotic regulatory genes encoding polo-like kinase 1, aurora B kinase, and survivin, all of which are transcriptional targets of FoxM1 that are highly expressed in cancer cells and function to prevent apoptosis. These studies indicate that ARF peptide treatment is an effective therapeutic approach to limit proliferation and induce apoptosis of liver cancer cells in vivo.
Recent Evolution of the Human Pathogen Cryptococcus neoformans by Intervarietal Transfer of a 14-Gene Fragment
Authors: Laura A. Kavanaugh, James A. Fraser, Fred S. Dietrich
Journal: Molecular Biology and Evolution (2006)

The availability of the whole-genome sequence from the 2 known varieties of the human pathogenic fungus Cryptococcus neoformans provides an opportunity to study the relative contribution of divergence and introgression during the process of speciation in a genetically tractable organism. At the genomic level, these varieties are nearly completely syntenic, share approximately 85-90% nucleotide identity, and are believed to have diverged approximately 18 MYA. Via a comparative genomic approach, we identified a 14-gene region (approximately 40 kb) that is nearly identical between the 2 varieties that resulted from a nonreciprocal transfer event from var. grubii to var. neoformans approximately 2 MYA. The majority of clinical and environmental var. neoformans strains from around the world contain this sequence obtained from var. grubii. This introgression event likely occurred via an incomplete intervarietal sexual cycle, creating a hybrid intermediate where mobile elements common to both lineages mediated the exchange. The subsequent duplication in laboratory strains of a fragment of this same genomic region supports evolutionary theories that instabilities in subtelomeric regions promote adaptive evolution through gene amplification and subsequent adaptation. Along with a more ancient predicted transfer event in C. neoformans and a recently reported example from Saccharomyces cerevisiae, these data indicate that DNA exchange between closely related sympatric varieties or species may be a recurrent theme in the evolution of fungal species. It further suggests that although evolutionary divergence is the primary force driving speciation, rare introgression events also play a potentially important role.
Oncogenic B-RAF Signaling in Melanoma Impairs the Therapeutic Advantage of Autophagy Inhibition
Authors: Jane L. Armstrong, Marco Corazzari, Shaun Martin, Vittoria Pagliarini, Laura Falasca, David S. Hill, Nicola Ellis, Salim Al Sabah, Christopher P.F. Redfern, Gian Maria Fimia, Mauro Piacentini, Penny E. Lovat
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Metastatic melanoma is characterized by extremely poor survival rates and hence novel therapies are urgently required. The ability of many anticancer drugs to activate autophagy, a lysosomal-mediated catabolic process which usually promotes cell survival, suggests targeting the autophagy pathway may be a novel means to augment therapy. Experimental Design: Autophagy and apoptosis were assessed in vitro in human melanoma cell lines in response to clinically achievable concentrations of the endoplasmic reticulum (ER) stress-inducing drugs fenretinide or bortezomib, and in vivo using a s.c. xenograft model. Results: Autophagy was activated in response to fenretinide or bortezomib in B-RAF wild-type cells, shown by increased conversion of LC3 to the autophagic vesicle-associated form (LC3-II) and redistribution to autophagosomes and autolysosomes, increased acidic vesicular organelle formation and autophagic vacuolization. In contrast, autophagy was significantly reduced in B-RAF–mutated melanoma cells, an effect attributed partly to oncogenic B-RAF. Rapamycin treatment was unable to stimulate LC3-II accumulation or redistribution in the presence of mutated B-RAF, indicative of de-regulated mTORC1-dependent autophagy. Knockdown of Beclin-1 or ATG7 sensitized B-RAF wild-type cells to fenretinide- or bortezomib-induced cell death, demonstrating a pro-survival function of autophagy. In addition, autophagy was partially reactivated in B-RAF–mutated cells treated with the BH3 mimetic ABT737 in combination with fenretinide or bortezomib, suggesting autophagy resistance is partly mediated by abrogated Beclin-1 function. Conclusions: Our findings suggest inhibition of autophagy in combination with ER stress-inducing agents may represent a means by which to harness autophagy for the therapeutic benefit of B-RAF wild-type melanoma. Clin Cancer Res; 17(8); 2216–26. ©2011 AACR.
The IL-6R α chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo
Authors: Aysefa Doganci, Tatjana Eigenbrod, Norbert Krug, George T. De Sanctis, Michael Hausding, Veit J. Erpenbeck, El-Bdaoui Haddad, Edgar Schmitt, Tobias Bopp, Karl-J. Kallen, Udo Herz, Steffen Schmitt, Cornelia Luft, Olaf Hecht, Jens M. Hohlfeld, Hiroaki Ito, Norihiro Nishimoto, Kazuyuki Yoshizaki, Tadamitsu Kishimoto, Stefan Rose-John, Harald Renz, Markus F. Neurath, Peter R. Galle, Susetta Finotto
Journal: Journal of Clinical Investigation (2005)

The cytokine IL-6 acts via a specific receptor complex that consists of the membrane-bound IL-6 receptor (mIL-6R) or the soluble IL-6 receptor (sIL-6R) and glycoprotein 130 (gp130). In this study, we investigated the role of IL-6R components in asthma. We observed increased levels of sIL-6R in the airways of patients with allergic asthma as compared to those in controls. In addition, local blockade of the sIL-6R in a murine model of late-phase asthma after OVA sensitization by gp130–fraction constant led to suppression of Th2 cells in the lung. By contrast, blockade of mIL-6R induced local expansion of Foxp3-positive CD4+CD25+ Tregs with increased immunosuppressive capacities. CD4+CD25+ but not CD4+CD25– lung T cells selectively expressed the IL-6R α chain and showed IL-6–dependent STAT-3 phosphorylation. Finally, in an in vivo transfer model of asthma in immunodeficient Rag1 mice, CD4+CD25+ T cells isolated from anti–IL-6R antibody–treated mice exhibited marked immunosuppressive and antiinflammatory functions. IL-6 signaling therefore controls the balance between effector cells and Tregs in the lung by means of different receptor components. Furthermore, inhibition of IL-6 signaling emerges as a novel molecular approach for the treatment of allergic asthma.
Antibody to Hepatitis-Associated Antigen
Authors: Jerrold J. Lander
Journal: JAMA (1972)

Serum samples from a human population group in the Washington, DC, area and from a chimpanzee colony in Arizona were tested for antibody to hepatitis-associated antigen (anti-HAA) by the redioimmunoprecipitation technique. Anti-HAA was detected in 64 of 324 (20%) persons tested; an age-specific increase in frequency and geometric mean titer of anti-HAA was observed. There was no difference in frequency between males and females. Forty-six of 81 chimpanzees tested were found to have anti-HAA; the frequency of this antibody also increased with age. IgM and IgG anti-HAA were measured in ten patients who developed anti-HAA after what was thought to be primary exposure to HAA. IgM and IgG anti-HAA were detected in all ten patients. No specific patterns of IgM or IgG anti-HAA response were detected.
Response to Letters Regarding Article, “Comparison of Clinical Interpretation With Visual Assessment and Quantitative Coronary Angiography in Patients Undergoing Percutaneous Coronary Intervention in Contemporary Practice: The Assessing Angiography (A2) Project”
Authors: Brahmajee K. Nallamothu, John A. Spertus, Alexandra J. Lansky, David J. Cohen, Philip G. Jones, Faraz Kureshi, Gregory J. Dehmer, Joseph P. Drozda, Mary Norine Walsh, John E. Brush, Gerald C. Koenig, Thad F. Waites, D. Scott Gantt, George Kichura, Richard A. Chazal, Peter K. O’Brien, C. Michael Valentine, John S. Rumsfeld, Johan H.C. Reiber, Joann G. Elmore, Richard A. Krumholz, W. Douglas Weaver, Harlan M. Krumholz
Journal: Circulation (2013)
Enhanced Myocardial Contractility and Increased Ca <sup>2+</sup> Transport Function in Transgenic Hearts Expressing the Fast-Twitch Skeletal Muscle Sarcoplasmic Reticulum Ca <sup>2+</sup> -ATPase
Authors: Evgeny Loukianov, Yong Ji, Ingrid L. Grupp, Darryl L. Kirkpatrick, Debra L. Baker, Tanya Loukianova, Gunter Grupp, Jonathan Lytton, Richard A. Walsh, Muthu Periasamy
Journal: Circulation Research (1998)

Abstract —In this study, we investigated whether the fast-twitch skeletal muscle sarco(endo)plasmic reticulum Ca 2+ transport pump (SERCA1a) can functionally substitute the cardiac SERCA2a isoform and how its overexpression affects cardiac contractility. For this purpose, we generated transgenic (TG) mice that specifically overexpress SERCA1a in the heart, using the cardiac-specific α-myosin heavy chain promoter. Ectopic expression of SERCA1a resulted in a 2.5-fold increase in the amount of total SERCA protein. At the same time, the level of the endogenous SERCA2a protein was decreased by 50%, whereas the level of other muscle proteins, including calsequestrin, phospholamban, actin, and tropomyosin, remained unchanged. The steady-state level of SERCA phosphoenzyme intermediate was increased 2.5-fold, and the maximal velocity of Ca 2+ uptake was increased 1.7-fold in TG hearts, demonstrating that the overexpressed protein is functional. Although the basal cytosolic calcium signal was decreased by 38% in TG cardiomyocytes, the amplitude of cytosolic calcium signal was increased by 71.8%. The rate of calcium resequestration was also increased in TG myocytes, which was reflected by a 51.6% decrease in the normalized time to 80% decay of calcium signal. This resulted in considerably increased peak rates of myocyte shortening and relengthening (50.0% and 66.6%, respectively). Cardiac functional analysis using isolated work-performing heart preparations revealed significantly faster rates of contraction and relaxation in TG hearts (41.9% and 39.5%, respectively). The time to peak pressure and the time to half-relaxation were shorter (29.1% and 32.7%, respectively). In conclusion, our study demonstrates that the SERCA1a pump can functionally substitute endogenous SERCA2a, and its overexpression significantly enhances Ca 2+ transport and contractile function of the myocardium. These results also demonstrate that the SERCA pump level is a critical determinant of cardiac contractility.
The long shadow of cerebral localization
Authors: R. Richardson
Journal: Journal of the Royal Society of Medicine (2006)

I am distinctly puzzled by Saad Shafqat's article on cerebral localization (December 2005 JRSM1). The foundations of cerebral localization are generally accepted to have been laid by Paul Broca2 and, more significantly, by Gustav Fritsch and Eduard Hitzig3 and David Ferrier.4

Dr Shafqat goes on to say `The problem, unfortunately, is that lesion localization became an end in itself'. Oh? Within 5 years William Macewen was operating on abscesses of the brain that he had successfully located. He was soon followed by the likes of Victor Horsley, Charles Harrison Frazier and Harvey Cushing, all active before the end of the first decade of the 20th century. Besides abscesses, tumours and epilepsy were tackled by a handful of men with pretty satisfactory results considering the state of surgery at the time.5

Before computerized tomography and magnetic resonance scanning appeared on the scene, Walter Dandy had devised pneumoventriculography and Egas Moniz had introduced arterial encephalography.
Emerging pathogens: the epidemiology and evolution of species jumps
Authors: Mark E.J. Woolhouse, Daniel T. Haydon, Rustom Antia
Journal: Trends in Ecology & Evolution (2005)

Novel pathogens continue to emerge in human, domestic animal, wildlife and plant populations, yet the population dynamics of this kind of biological invasion remain poorly understood. Here, we consider the epidemiological and evolutionary processes underlying the initial introduction and subsequent spread of a pathogen in a new host population, with special reference to pathogens that originate by jumping from one host species to another. We conclude that, although pathogen emergence is inherently unpredictable, emerging pathogens tend to share some common traits, and that directly transmitted RNA viruses might be the pathogens that are most likely to jump between host species. Novel pathogens continue to emerge in human, domestic animal, wildlife and plant populations, yet the population dynamics of this kind of biological invasion remain poorly understood. Here, we consider the epidemiological and evolutionary processes underlying the initial introduction and subsequent spread of a pathogen in a new host population, with special reference to pathogens that originate by jumping from one host species to another. We conclude that, although pathogen emergence is inherently unpredictable, emerging pathogens tend to share some common traits, and that directly transmitted RNA viruses might be the pathogens that are most likely to jump between host species.
Fibrin degradation products and menstruation.
Authors: I S Menon
Journal: BMJ (1970)

Classification).There were 27 spontaneous deliveries, 8 forceps deliveries, and 9 caes- arean sections.In brief, there was a sharp fall in C.V.P. on delivery of the child in every case.During the third stage of labour the C.V.P. ranged from -2 to + 9 cm.H20 (zero level was the sternal angle).Each pa- tient received ergometrine 0-25 mg. or 0-5 mg.intravenously, sometimes before and sometimes after placental separation.Placental separation and the injection of ergometrine produced small and transient rises in C.V.P. (never more than 3 cm.H20 and never lasting for more than 4 minutes).Blood loss was measured at these deliveries and was of the anticipated magnitude.1 2 It is believed that the direct effects of ergo- metrine on the veins were to a variable extent cancelled out by the effects of haemorrhage.