tbuckley/cabot-search huggingface dataset:
Comparative effects of hypoxia and ischemia in the isolated, blood-perfused dog heart: evaluation of left ventricular diastolic chamber distensibility and wall thickness.
Authors: R M Wyman, E R Farhi, O H Bing, R G Johnson, R M Weintraub, W Grossman
Journal: Circulation Research (1989)

To compare the effects of hypoxia and ischemia on left ventricular (LV) diastolic function, we studied 17 isolated, isovolumic dog hearts by measuring LV diastolic chamber distensibility (LV end diastolic pressure at constant volume), wall thickness, and myocardial pH in response to hypoxia at constant coronary flow or pressure versus global ischemia (zero coronary blood flow). Hypoxic perfusates consisted of methemoglobin-containing red blood cells suspended in lactated Ringer's solution. Brief cross-clamping of the coronary perfusion line was used to assess the contribution of coronary turgor to chamber distensibility and wall thickness. With hypoxia, left ventricles showed a significant early (5 minutes) decrease in diastolic distensibility and an increase in wall thickness, at either constant coronary perfusion pressure or flow. The increase in wall thickness was independent of hypoxia-induced changes in coronary turgor. In contrast, global ischemia produced an early increase in LV diastolic chamber distensibility and a decrease in wall thickness. When global ischemia was continued beyond 60 minutes, a decrease in LV chamber distensibility developed. This diastolic contracture was not associated with an increase in LV wall thickness. Myocardial pH decreased slightly during 15 minutes of hypoxia and markedly with 15 minutes of global ischemia. Thus, LV diastolic chamber distensibility decreased during 15 minutes of hypoxia, while an increase in distensibility was seen during global ischemia of similar duration. During hypoxia, these changes were associated with increased LV wall thickness, at either constant coronary perfusion pressure or constant coronary flow. Prolonged ischemia led to diastolic contracture without an increase in wall thickness.(ABSTRACT TRUNCATED AT 250 WORDS)
Being able to adapt to variable stimuli: the key driver in injury and illness prevention?
Authors: Philip Glasgow, Christopher M Bleakley, Nicola Phillips
Journal: British Journal of Sports Medicine (2012)

The capacity of the human body to adapt and flourish in a wide range of environmental conditions is well recognised. Indeed, it is this ability to effectively adapt physiologically, psychologically and genetically that makes us successful as a species. Significant attention has been given to the long-term adaptation to environmental factors, for example, the ‘mismatch hypothesis’ of evolutionary medicine.1 Of particular note, however, is the capacity to make rapid changes at neurophysiological and behavioural levels in response to alterations in environmental constraints. The ability to effectively modify responses under a broad spectrum of conditions is central to effective sporting performance and to long-term health outcomes. Simply speaking, the ability of humans to respond to a variety of challenges is what makes us stand out.

The traditional dogma that injury or illness results from the failure to attain a single ‘ideal’ (specific movement pattern, nutritional status and anatomical alignment) has been challenged.2 The multifactorial nature of the majority of conditions has resulted in a general acceptance that a reductionist approach is often inadequate to describe the nuanced clinical presentation of many sporting injuries.3 The dynamic and frequently non-linear relationship between risk factors and injury incidence is, perhaps, better understood in relation to the ability of the individual to adapt to various challenges.
THYMUS CELL MATURATION
Authors: Irving L. Weissman
Journal: The Journal of Experimental Medicine (1973)

Outer thymic cortical large lymphocytes were labeled by transcapsular administration of tritiated thymidine. By 2-4 days after labeling, small and medium labeled lymphocyte descendants were found throughout the cortex and in the medulla. The labeled cortical lymphocytes undergo pycnosis after parenteral administration of hydrocortisone 24 h previously, but their (labeled) medullary descendants do not. In addition, parenteral administration of hydrocortisone at the time of surface labeling results in the absence of the appearance of labeled medullary descendants.
Phylogenomic Analyses Support the Monophyly of Taphrinomycotina, including <i>Schizosaccharomyces</i> Fission Yeasts
Authors: Yu Liu, Jessica W. Leigh, Henner Brinkmann, Melanie T. Cushion, Naiara Rodriguez-Ezpeleta, Hervé Philippe, B. Franz Lang
Journal: Molecular Biology and Evolution (2008)

Abstract Several morphologically dissimilar ascomycete fungi including Schizosaccharomyces, Taphrina, Saitoella, Pneumocystis, and Neolecta have been grouped into the taxon Taphrinomycotina (Archiascomycota or Archiascomycotina), originally based on rRNA phylogeny. These analyses lack statistically significant support for the monophyly of this grouping, and although confirmed by more recent multigene analyses, this topology is contradicted by mitochondrial phylogenies. To resolve this inconsistency, we have assembled phylogenomic mitochondrial and nuclear data sets from four distantly related taphrinomycotina taxa: Schizosaccharomyces pombe, Pneumocystis carinii, Saitoella complicata, and Taphrina deformans. Our phylogenomic analyses based on nuclear data (113 proteins) conclusively support the monophyly of Taphrinomycotina, diverging as a sister group to Saccharomycotina + Pezizomycotina. However, despite the improved taxon sampling, Taphrinomycotina continue to be paraphyletic with the mitochondrial data set (13 proteins): Schizosaccharomyces species associate with budding yeasts (Saccharomycotina) and the other Taphrinomycotina group as a sister group to Saccharomycotina + Pezizomycotina. Yet, as Schizosaccharomyces and Saccharomycotina species are fast evolving, the mitochondrial phylogeny may be influenced by a long-branch attraction (LBA) artifact. After removal of fast-evolving sequence positions from the mitochondrial data set, we recover the monophyly of Taphrinomycotina. Our combined results suggest that Taphrinomycotina is a legitimate taxon, that this group of species diverges as a sister group to Saccharomycotina + Pezizomycotina, and that phylogenetic positioning of yeasts and fission yeasts with mitochondrial data is plagued by a strong LBA artifact.
Enhanced Activation of Epidermal Growth Factor Receptor Caused by Tumor-Derived E-Cadherin Mutations
Authors: Anja Bremm, Axel Walch, Margit Fuchs, Jörg Mages, Justus Duyster, Gisela Keller, Christine Hermannstädter, Karl-Friedrich Becker, Sandra Rauser, Rupert Langer, Claus Hann von Weyhern, Heinz Höfler, Birgit Luber
Journal: Cancer Research (2008)

Abstract Mutations of the tumor suppressor E-cadherin and overexpression of the receptor tyrosine kinase epidermal growth factor receptor (EGFR) are among the most frequent genetic alterations associated with diffuse-type gastric carcinoma. Accumulating evidence suggests a functional relationship between E-cadherin and EGFR that regulates both proteins. We report that somatic mutation of E-cadherin is associated with increased activation of EGFR followed by enhanced recruitment of the downstream acting signaling components growth factor receptor binding protein 2 and Shc, and activation of Ras. Reduced complex formation of mutant E-cadherin — with an in frame deletion of exon 8 in the extracellular domain resulting in reduced adhesion and increased motility — with EGFR was observed compared with wild-type E-cadherin. We conclude that reduced binding of mutant E-cadherin to EGFR in a multicomponent complex or reduced stability of the complex may enhance EGFR surface motility, thereby facilitating EGFR dimerization and activation. Furthermore, reduced surface localization due to enhanced internalization of mutant E-cadherin compared with the wild-type protein was observed. The internalization of EGFR was decreased in response to epidermal growth factor stimulation in cells expressing mutant E-cadherin, suggesting that mutation of E-cadherin also influences the endocytosis of EGFR. Moreover, we show increased activation of EGFR in gastric carcinoma samples with mutant E-cadherin lacking exons 8 or 9. In summary, we describe activation of EGFR by mutant E-cadherin as a novel mechanism in tumor cells that explains the enhanced motility of tumor cells in the presence of an extracellular mutation of E-cadherin. [Cancer Res 2008;68(3):707–14]
A quantitative analysis of antigen-presenting cell function: activated B cells stimulate naive CD4 T cells but are inferior to dendritic cells in providing costimulation.
Authors: D J Cassell, R H Schwartz
Journal: The Journal of Experimental Medicine (1994)

Ligation of CD28 on CD4 Th1 clones and freshly isolated mixtures of naive and memory CD4 T cells triggered their T cell receptors (TCR) is sufficient to induce the costimulatory signals necessary for interleukin 2 (IL-2) production by these cells. CTLA-4-reactive ligands expressed on antigen-presenting cells (APC) are critical in providing costimulatory signals to these T cell populations. We demonstrate that these activation characteristics apply equally to purified naive CD4 T cells. Because B cell blasts express CTLA-4-reactive ligands and high levels of adhesion and major histocompatibility complex class II molecules, they would be expected to engage both the TCR and CD28 and consequently stimulate IL-2 production by naive CD4 T cells. Using purified populations of cells in limiting dilution cultures, we have carried out a quantitative analysis of the interaction between naive CD4 T cells and either activated B or dendritic cells. We demonstrate that B cell blasts stimulate a high frequency of naive CD4 T cells. Slight differences in TCR signaling efficiency between the two APC types were observed. Even at optimal peptide concentrations, however, the amount of IL-2 made by individual T cells was fourfold lower in response to B cell blasts than to dendritic cells. This relative deficiency of activated B cells was due to their inability to optimally costimulate naive CD4 T cells.
Prediagnostic Plasma Folate and the Risk of Death in Patients With Colorectal Cancer
Authors: Brian M. Wolpin, Esther K. Wei, Kimmie Ng, Jeffrey A. Meyerhardt, Jennifer A. Chan, Jacob Selhub, Edward L. Giovannucci, Charles S. Fuchs
Journal: Journal of Clinical Oncology (2008)

Although previous studies have demonstrated an inverse relationship between folate intake and colorectal cancer risk, a recent trial suggests that supplemental folic acid may accelerate tumorigenesis among patients with a history of colorectal adenoma. Therefore, high priority has been given to research investigating the influence of folate on cancer progression in patients with colorectal cancer.To investigate whether prediagnostic levels of plasma folate are associated with colorectal cancer-specific and overall mortality, we performed a prospective, nested observational study within two large US cohorts: the Nurses' Health Study and Health Professionals Follow-Up Study. We measured folate levels among 301 participants who developed colorectal cancer 2 or more years after their plasma was collected and compared participants using Cox proportional hazards models by quintile of plasma folate.Higher levels of plasma folate were not associated with an increased risk of colorectal cancer-specific or overall mortality. Compared with participants in the lowest quintile of plasma folate, those in the highest quintile experienced a multivariable-adjusted hazard ratio for colorectal cancer-specific mortality of 0.42 (95% CI, 0.20 0.88) and overall mortality of 0.46 (95% CI, 0.24 0.88). When the analysis was limited to participants whose plasma was collected within 5 years of cancer diagnosis, no detrimental effect of high plasma folate was noted. In subgroup analyses, no subgroup demonstrated worse survival among participants with higher plasma folate levels.In two large prospective cohorts, higher prediagnostic levels of plasma folate were not associated with an increased risk of colorectal cancer-specific or overall mortality.
gp100/pmel 17 Is a Murine Tumor Rejection Antigen: Induction of “Self”-reactive, Tumoricidal T Cells Using High-affinity, Altered Peptide Ligand
Authors: Willem W. Overwijk, Allan Tsung, Kari R. Irvine, Maria R. Parkhurst, Theresa J. Goletz, Kangla Tsung, Miles W. Carroll, Chunlei Liu, Bernard Moss, Steven A. Rosenberg, Nicholas P. Restifo
Journal: The Journal of Experimental Medicine (1998)

Many tumor-associated antigens are nonmutated, poorly immunogenic tissue differentiation antigens. Their weak immunogenicity may be due to "self"-tolerance. To induce autoreactive T cells, we studied immune responses to gp100/pmel 17, an antigen naturally expressed by both normal melanocytes and melanoma cells. Although a recombinant vaccinia virus (rVV) encoding the mouse homologue of gp100 was nonimmunogenic, immunization of normal C57BL/6 mice with the rVV encoding the human gp100 elicited a specific CD8(+) T cell response. These lymphocytes were cross-reactive with mgp100 in vitro and treated established B16 melanoma upon adoptive transfer. To understand the mechanism of the greater immunogenicity of the human version of gp100, we characterized a 9-amino acid (AA) epitope, restricted by H-2Db, that was recognized by the T cells. The ability to induce specific T cells with human but not mouse gp100 resulted from differences within the major histocompatibility complex (MHC) class I-restricted epitope and not from differences elsewhere in the molecule, as was evidenced by experiments in which mice were immunized with rVV containing minigenes encoding these epitopes. Although the human (hgp10025-33) and mouse (mgp10025-33) epitopes were homologous, differences in the three NH2-terminal AAs resulted in a 2-log increase in the ability of the human peptide to stabilize "empty" Db on RMA-S cells and a 3-log increase in its ability to trigger interferon gamma release by T cells. Thus, the fortuitous existence of a peptide homologue with significantly greater avidity for MHC class I resulted in the generation of self-reactive T cells. High-affinity, altered peptide ligands might be useful in the rational design of recombinant and synthetic vaccines that target tissue differentiation antigens expressed by tumors.
Intensified and protective CD4+ T cell immunity in mice with anti–dendritic cell HIV gag fusion antibody vaccine
Authors: Christine Trumpfheller, Jennifer S. Finke, Carolina B. López, Thomas M. Moran, Bruno Moltedo, Helena Soares, Yaoxing Huang, Sarah J. Schlesinger, Chae Gyu Park, Michel C. Nussenzweig, Angela Granelli-Piperno, Ralph M. Steinman
Journal: The Journal of Experimental Medicine (2006)

Current human immunodeficiency virus (HIV) vaccine approaches emphasize prime boost strategies comprising multiple doses of DNA vaccine and recombinant viral vectors. We are developing a protein-based approach that directly harnesses principles for generating T cell immunity. Vaccine is delivered to maturing dendritic cells in lymphoid tissue by engineering protein antigen into an antibody to DEC-205, a receptor for antigen presentation. Here we characterize the CD4+ T cell immune response to HIV gag and compare efficacy with other vaccine strategies in a single dose. DEC-205–targeted HIV gag p24 or p41 induces stronger CD4+ T cell immunity relative to high doses of gag protein, HIV gag plasmid DNA, or recombinant adenovirus-gag. High frequencies of interferon (IFN)-γ– and interleukin 2–producing CD4+ T cells are elicited, including double cytokine-producing cells. In addition, the response is broad because the primed mice respond to an array of peptides in different major histocompatibility complex haplotypes. Long-lived T cell memory is observed. After subcutaneous vaccination, CD4+ and IFN-γ–dependent protection develops to a challenge with recombinant vaccinia-gag virus at a mucosal surface, the airway. We suggest that a DEC-targeted vaccine, in part because of an unusually strong and protective CD4+ T cell response, will improve vaccine efficacy as a stand-alone approach or with other modalities.
Oral Anticoagulation Thresholds
Authors: Kathleen E. Brummel, Sara G. Paradis, Richard F. Branda, Kenneth G. Mann
Journal: Circulation (2001)

Background Monitoring patients on oral anticoagulation is essential to prevent hemorrhage and recurrent thrombosis. We studied tissue factor–induced whole-blood coagulation in patients on warfarin therapy with similar international normalized ratios (INRs). Methods and Results Contact pathway–suppressed whole-blood coagulation initiated with tissue factor was studied in 8 male subjects (group W) and in 1 individual multiple times (subject A). Coagulation profiles for group W showed that subjects with similar INRs had widely varying clot times (6.2 to 23 minutes) and thrombin–antithrombin III (TAT) profiles with rates of 25 to 40 nmol · L −1 · min −1 and maximum levels varying from 192 to 349 nmol/L. The normal control group exhibited clot times of 5.7±0.3 minutes and TAT rates of 57±13 nmol · L −1 · min −1 , reaching maximum levels of 742±91 nmol/L. Subject A, who was stably anticoagulated at an INR of 2.1±0.4 for 6 months, had widely ranging profiles with clot times of 9.0 to 22.7 minutes, TAT maximums varying from 141 to 345 nmol/L, and TAT formation rates of 10 to 57 nmol · L −1 · min −1 . INR did not correlate with TAT formation. Platelet activation was decreased by anticoagulants but also displayed variability. Fibrinopeptide A generation showed threshold variability independent of the INR. Factor VIII levels were increased ( P =0.03) in group W (204±34.4%) compared with normal control subjects (149.4±37.4%). A significant correlation was identified between increasing factor VIII levels and years on warfarin therapy ( r =0.78, P =0.01), suggesting a possible factor VIII compensatory mechanism. Conclusions These results suggest that control of anticoagulation in patients to a set INR therapeutic range may be less secure than anticipated. Patients with similar INRs show significant individual variability in their tissue factor coagulation response, suggesting different risks to anticoagulation when confronted with underlying vascular anomalies.
On Over-Operating in Gynaecology
Authors: W. Duncan
Journal: BMJ (1895)

On Sunday, the 28th ult., the Militarsanitatsverein of Ziirich and the Samaritervereine of Aussersihl, Birmensdorf, and Wiedikon went through a series of evolutions on a con- siderable scale by way of practice in the event of war.Their field of operations was the rather difficult ground lying between the villages of Uitikon, Birmensdorf, and Urdorf, and the scorching sun that prevailed throughout the day put their service to a severe trial.By 7 A.M. 100 male and female members of all sections were on the ground, those of the Damensektionen (lady sections) being in great force.Under the command of First Lieutenant Dr. Kruker- Wegmann the personnel was distributed into three main bodies, each of which had its special head, The various subordinate posts were then filled up and the day's practice commenced.The principal Verbandsplatz (rendezvous for surgical treatment) was the Lowen estate, near Uitikon; another rendezvous of the kind was in a. field a quarter of an hour's march distant, and the third Verbandsplatz was considered as the line of battle, in the vicinity of Urdorf, not far from the banks of the Reppisch.Those two latter Platze were entrusted to the sanitary instructors, Dr. Erne and Dr. Jager, and three surgeons, Dr. Eberle, Dr. Bryner, and Dr. Schmid, were on duty with the respective main bodies.Each of these latter took up
Proceedings from the Third National Institutes of Health International Congress on Advances in Uterine Leiomyoma Research: comprehensive review, conference summary and future recommendations
Authors: James H. Segars, Estella C. Parrott, Joan D. Nagel, Xiaoxiao Catherine Guo, Xiaohua Gao, Linda S. Birnbaum, Vivian W. Pinn, Darlene Dixon
Journal: Human Reproduction Update (2014)

BACKGROUNDUterine fibroids are the most common gynecologic tumors in women of reproductive age yet the etiology and pathogenesis of these lesions remain poorly understood. Age, African ancestry, nulliparity and obesity have been identified as predisposing factors for uterine fibroids. Symptomatic tumors can cause excessive uterine bleeding, bladder dysfunction and pelvic pain, as well as associated reproductive disorders such as infertility, miscarriage and other adverse pregnancy outcomes. Currently, there are limited noninvasive therapies for fibroids and no early intervention or prevention strategies are readily available. This review summarizes the advances in basic, applied and translational uterine fibroid research, in addition to current and proposed approaches to clinical management as presented at the 'Advances in Uterine Leiomyoma Research: 3rd NIH International Congress'. Congress recommendations and a review of the fibroid literature are also reported.
Phase II Trial of Pleural Photodynamic Therapy and Surgery for Patients With Non–Small-Cell Lung Cancer With Pleural Spread
Authors: Joseph S. Friedberg, Rosemarie Mick, James P. Stevenson, Timothy Zhu, Theresa M. Busch, Daniel Shin, Debbie Smith, Melissa Culligan, Andreea Dimofte, Eli Glatstein, Stephen M. Hahn
Journal: Journal of Clinical Oncology (2004)

Purpose Non—small-cell lung cancer (NSCLC) with pleural spread is incurable, with median survival rates ranging from 6 to 9 months. Surgery alone fails to locally control this disease or extend survival beyond the accepted treatment, palliative chemotherapy. Methods We conducted a phase II trial to evaluate the effects on local control and survival of combining surgery with intraoperative photodynamic therapy (PDT), a light-based cancer treatment, in patients with NSCLC with pleural spread. Patients received porfimer sodium (2 mg/kg), 24 hours before surgery, at which time all gross tumor was resected and followed by illumination of the hemithorax with 630 nm light to a measured dose of 30 J/cm 2 . Photosensitizer levels in tumor and surrounding normal tissue were measured. Results Twenty-two patients with NSCLC were enrolled; 17 underwent complete debulking and PDT, three underwent partial debulking/PDT, and two patients were unresectable. Local control of pleural disease at 6 months was achieved in 11 of 15 (73.3%; 95% CI, 44.9% to 92.2%) assessable patients. Median overall survival for all 22 patients was 21.7 months (95% CI, 17.7 to 25.8 months). Measured levels of porfimer sodium in tumor were greater than those measured in normal tissues, with ratios ranging from 1.19 to 22.42. Conclusion Our results indicate surgery and PDT can be performed safely with very good local control. The median survival of 21.7 months, calculated from the time of surgery and PDT is encouraging. Further evaluation of this therapy is warranted.
Targeting the Hedgehog Pathway in Cancer: Can the Spines Be Smoothened?: Figure 1.
Authors: Laurie Ailles, Lillian L. Siu
Journal: Clinical Cancer Research (2011)

Aberrant Hedgehog (Hh) pathway signaling has been suggested to play a role in the development of multiple solid tumors and hematologic malignancies. GDC-0449 is a novel first-in-human, first-in-class smoothened (SMO) inhibitor, which has completed its phase I evaluation and achieved proof of concept in tumors with Hh pathway mutations.