tbuckley/cabot-search huggingface dataset:
Inhaled synthetic surfactant abolishes the early allergen-induced response in asthma
Authors: K.S. Babu, D.A. Woodcock, S.E. Smith, J.N. Staniforth, S.T. Holgate, J.H. Conway
Journal: European Respiratory Journal (2003)

Allergen-induced inhibition of pulmonary surfactant in asthma may promote airway oedema and consequently potentiate the severity of the asthmatic response. A randomised, single-blind, cross-over study of an inhaled synthetic phospholipid dry-powder surfactant (Pumactant) was conducted in atopic, asthmatic subjects with previously documented early and late asthmatic responses (EAR and LAR) to an inhaled allergen. This was conducted to evaluate the role of exogenous surfactant administration on EAR and LAR. A total of seven subjects had complete evaluable data and received the full dose of Pumactant. Asthmatic subjects inhaled two separate doses of 400 mg Pumactant prior to an allergen exposure. The first dose was administered 8 h in advance and the second dose 30 min in advance. The dosage occurred through a purpose-built administration device. This was followed by a standard bronchial-provocation test, and forced expiratory volume in one second (FEV 1 ) was measured at regular intervals over a 10-h period. Pumactant was well tolerated and, surprisingly, abolished the EAR but not the LAR in all seven subjects. The mean area under the curve between 0–2 h (EAR) following bronchial provocation test was 0.08 for the Pumactant treatment group (PT) and 13.29 for the no treatment (NT) group. The maximum drop in FEV 1 for EAR was 4.19% and 23.98% in the PT and the NT group, respectively. The demonstration of inhibition of the early asthmatic response by exogenous surfactant, provides the first evidence that pulmonary surfactant dysfunction may also contribute to the very early asthmatic response to allergen. Exogenous surfactant administration could serve as a useful adjunct in controlling the early allergen-induced symptoms in patients with allergic asthma.
Airflow Obstruction after Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Jason W. Chien, Paul J. Martin, Ted A. Gooley, Mary E. Flowers, Susan R. Heckbert, W. Garrett Nichols, Joan G. Clark
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Despite advances in the management of myeloablative allogeneic hematopoietic stem cell transplants, airflow obstruction (AFO) remains a significant complication. We conducted a 12-year study to examine the recent epidemiology of AFO and its associated mortality. Using the rate of percent predicted FEV1 decline after transplant, we defined AFO as a more than 5% per year decline in percent predicted FEV1 with the lowest post-transplant FEV1/FVC ratio less than 0.8. New obstruction was more frequent than previous estimates (26% overall, 32% among patients with chronic graft-versus-host disease [GVHD]) and was significantly associated with older age at transplant, lower pretransplant FEV1/FVC ratio, history of both acute and chronic GVHD, and respiratory viral infection within the first 100 days after transplant. AFO was associated with significant attributable mortality rates of 9% at 3 years, 12% at 5 years, and 18% at 10 years after transplant, which were much higher for the subpopulation of patients with chronic GVHD (22% at 3 years, 27% at 5 years, and 40% at 10 years). These results suggest that the incidence of AFO may have been underestimated previously, and its presence significantly increases the mortality of long-term survivors of myeloablative allogeneic hematopoietic stem cell transplant patients.
Urine Proteomics to Detect Biomarkers for Chronic Allograft Dysfunction
Authors: Lui[Combining Acute Accent]s F. Quintana, Amanda Sole[Combining Acute Accent]-Gonzalez, Susana G. Kalko, Elisenda Ban[Combining Tilde]on-Maneus, Manel Sole[Combining Acute Accent], Fritz Diekmann, Alex Gutierrez-Dalmau, Joaquin Abian, Josep M. Campistol
Journal: Journal of the American Society of Nephrology (2008)

Despite optimal immunosuppressive therapy, more than 50% of kidney transplants fail because of chronic allograft dysfunction. A noninvasive means to diagnose chronic allograft dysfunction may allow earlier interventions that could improve graft half-life. In this proof-of-concept study, we used mass spectrometry to analyze differences in the urinary polypeptide patterns of 32 patients with chronic allograft dysfunction (14 with pure interstitial fibrosis and tubular atrophy and 18 with chronic active antibody-mediated rejection) and 18 control subjects (eight stable recipients and 10 healthy control subjects). Unsupervised hierarchical clustering showed good segregation of samples in groups corresponding mainly to the four biomedical conditions. Moreover, the composition of the proteome of the pure interstitial fibrosis and tubular atrophy group differed from that of the chronic active antibody-mediated rejection group, and an independent validation set confirmed these results. The 14 protein ions that best discriminated between these two groups correctly identified 100% of the patients with pure interstitial fibrosis and tubular atrophy and 100% of the patients with chronic active antibody-mediated rejection. In summary, this study establishes a pattern for two histologic lesions associated with distinct graft outcomes and constitutes a first step to designing a specific, noninvasive diagnostic tool for chronic allograft dysfunction.
Recent insights into the role of NF-kappaB in ovarian carcinogenesis
Authors: Ayesha B Alvero
Journal: Genome Medicine (2010)

The NF-κBs are a family of ubiquitously expressed transcription factors that have been described to be responsible for the establishment of an inflammatory response. Studies in the past decade have also demonstrated this family's role in the initiation and progression of hematological and solid tumors. Recently, research has uncovered a specific role for NF-κBs in the development and maintenance of ovarian cancer.
Suicide Ideation in Adult Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study
Authors: Christopher J. Recklitis, Lisa R. Diller, Xiaochun Li, Julie Najita, Leslie L. Robison, Lonnie Zeltzer
Journal: Journal of Clinical Oncology (2009)

To evaluate risk of suicide ideation (SI) after childhood cancer, prevalence of SI in a cohort of adult survivors of pediatric cancers was compared with prevalence in a sibling comparison group. The relationship of SI to cancer treatment and current health was examined, and the hypothesis that poor physical health is significantly associated with suicidality, after adjusting for depression, was specifically tested.Nine thousand one hundred twenty-six adult survivors of childhood cancer and 2,968 siblings enrolled onto the Childhood Cancer Survivor Study completed a survey describing their demographics and medical and psychological functioning, including SI in the prior week.Of survivors, 7.8% reported SI compared with 4.6% of controls (odds ratio = 1.79; 95% CI, 1.4 to 2.4). Suicidality was unrelated to age, age at diagnosis, sex, cancer therapy, recurrence, time since diagnosis, or second malignancy. SI was associated with primary CNS cancer diagnosis, depression, and poor health outcomes including chronic conditions, pain, and poor global health rating. A logistic regression analysis showed that poor current physical health was significantly associated with SI even after adjusting for cancer diagnosis and depression.Adult survivors of childhood cancers are at increased risk for SI. Risk of SI is related to cancer diagnosis and post-treatment mental and physical health, even many years after completion of therapy. The association of suicidal symptoms with physical health problems is important because these may be treatable conditions for which survivors seek follow-up care and underscores the need for a multidisciplinary approach to survivor care.
THE SURGICAL ANATOMY AND OPERATIVE TREATMENT OF TUBERCULOUS GLANDS OF NECK
Authors: W. G. Sutcliffe
Journal: BMJ (1905)

CASE X.Treated by Mr. Fletcher.Male, aged 41.Much pruritus every night when warm in bed.After painless action of bowels, a feeling of burning comes on, with dull aching pain across the back and down the thighs, which varies in degree, but never quite goes.Posterior ulcer discovered.Lactic acid applied.Pruritus disappeared and other symptoms gradually lessened as ulcer healed.Well in one month.Examples of Cases where the Whole Circumference of the Lining Membrane was Dzisected Off.CASE XI.Female, aged about 40, single; seen November, I90Z.Pruritus ani for many years.Patient was in a thin, miserable, nervous condition, unable to sleep on account of the irritation.Inside the external sphincter the whole circumference of the bowel was practically denuded of epithelium.The affected ring of tissue was dissected off, and the upper edge sewn to the skin.Healing was slow in this instance, but the condition of pruritus ani gradually disappeared.This patient developed a fissure nearly two years after, which was operated on in November, 1904.No return of pruritus.CASE XII.Male, aged 40.Pruritus ani for twenty-five years.Much worse of late.No treatment has done any good.Suffers from insomnia caused by itching.Typical external appearance.Inside the sphincter the entire circumference of the bowel was denuded of epithelium.The internal " pruritic area" was dissected off, the patient being anaesthe- tized, and the upper edge sewn to the skin margin.The condition of pruritus gradaally disappeared, and when the patient left the home three weeks later he was practically well of it.Seen since and says he is a different man.Sleeps well and eats well.There was some slight contraction of the orifice, but this was easily got rid of by using a conical vulcanite bougie for a few times. CASE XIII.Male, aged 28.Pruritus ani for years.The whole circumference of the lining membrane was affected, this was dissected off and the upper edge sewn to the skin margin.WVell in three weeks.CASE XIV.Female, aged 54.Pruritus ani for three years.Skin around anus excoriated, white and sodden.Ulcers found laterally and posteriorly.Membrane dissected off.Well in three weeks. CASE XV.Male, aged 54.Pruritus ani for years.Skin around anus white and sodden-looking.Ulcers found.Ring of membrane dissected off.Well in five weeks.
Growth Regulation of Prostatic Stromal Cells by Prostate-Specific Antigen
Authors: D M Sutkowski, R L Goode, J Baniel, C Teater, P Cohen, A M McNulty, H M Hsiung, G W Becker, B L Neubauer
Journal: JNCI Journal of the National Cancer Institute (1999)

Prostate-specific antigen (PSA) is a serine protease that can cleave insulin-like growth factor-binding protein-3 (IGFBP3), thereby decreasing its affinity for insulin-like growth factor-I (IGF-I). Dissociation of the IGF-I-IGFBP3 complex renders IGF-I available to bind to its receptor and stimulates cellular proliferation. We evaluated the potential for PSA to modulate the effects of IGF-I and IGFBP3 on the proliferation of human benign prostatic hyperplasia (BPH)-derived fibromuscular stromal cells in primary cultures.We cultured BPH-derived stromal cells for 48 hours in serum-free RPMI-1640 medium supplemented with 0.2% bovine serum albumin and studied the effects of IGF-I, IGFBP3, PSA, and ZnCl(2) at varying concentrations. Differences in cell growth between control and treated cultures were evaluated by use of Dunnett's test. Concentration-related trends were evaluated by linear regression of log-transformed concentrations of test reagents on BPH-derived stromal cell number responses. Statistical tests were two-sided.We observed a concentration-dependent proliferative response of BPH-derived stromal cells to IGF-I. IGFBP3 inhibited this response in a concentration-dependent fashion. IGFBP3 alone had no effect on stromal cell proliferation. When stromal cells were incubated with PSA alone or with PSA, IGF-I, and IGFBP3, an increase in stromal cell numbers that was dependent on PSA concentration was evident in both instances. Zinc, an endogenous inhibitor of PSA enzymatic activity, was able to attenuate the stimulatory effect of PSA at intraprostatic physiologic concentrations.These results are consistent with the idea that PSA can modulate in vitro interactions between IGF-I and IGFBP3 and suggest that PSA may play a role in the regulation of human prostatic fibromuscular cell growth.
State anxiety responses to 60 minutes of cross training: Figure 1
Authors: B S Hale, K R Koch, J S Raglin
Journal: British Journal of Sports Medicine (2002)

Objectives: Significant reductions in state anxiety following bouts of aerobic exercise have been consistently noted, whereas changes are generally absent after acute resistance training. However, the influence of a single exercise session involving both modes on state anxiety has not been examined. Methods: To address this, state anxiety responses to 60 minutes of cross training were examined in 16 collegiate athletes (12 women, four men). Each subject completed two cross training exercise sessions (30 minutes of resistance training, 30 minutes of bicycle ergometry) in which the order of the exercises was reversed, with a minimum of one week between sessions. Each exercise mode was completed at about 70% of maximum. State anxiety (SAI-Y1) was assessed five minutes before, and 0, 10, and 60 minutes after exercise. Results: Repeated measures analysis of variance showed a significant (p&lt;0.05) main effect for time. However, the main effect for order and the order by time interaction were not significant. Post hoc analysis showed that state anxiety was reduced (p&lt;0.05) from baseline (mean (SD) = 34.8 (7.9)) at 10 minutes (32.1 (7.5)) and 60 minutes (30.4 (5.9)) after exercise, but not at 0 minutes (33.8 (6.9)). Conclusions: The results indicate that combined sessions of aerobic and resistance exercise are associated with reductions in state anxiety, and that the order in which the exercise is completed does not influence this response.
Canonical Wnt/β-catenin Signaling Drives Human Schwann Cell Transformation, Progression, and Tumor Maintenance
Authors: Adrienne L. Watson, Eric P. Rahrmann, Branden S. Moriarity, Kwangmin Choi, Caitlin B. Conboy, Andrew D. Greeley, Amanda L. Halfond, Leah K. Anderson, Brian R. Wahl, Vincent W. Keng, Anthony E. Rizzardi, Colleen L. Forster, Margaret H. Collins, Aaron L. Sarver, Margaret R. Wallace, Stephen C. Schmechel, Nancy Ratner, David A. Largaespada
Journal: Cancer Discovery (2013)

Genetic changes required for the formation and progression of human Schwann cell tumors remain elusive. Using a Sleeping Beauty forward genetic screen, we identified several genes involved in canonical Wnt signaling as potential drivers of benign neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). In human neurofibromas and MPNSTs, activation of Wnt signaling increased with tumor grade and was associated with downregulation of β-catenin destruction complex members or overexpression of a ligand that potentiates Wnt signaling, R-spondin 2 (RSPO2). Induction of Wnt signaling was sufficient to induce transformed properties in immortalized human Schwann cells, and downregulation of this pathway was sufficient to reduce the tumorigenic phenotype of human MPNST cell lines. Small-molecule inhibition of Wnt signaling effectively reduced the viability of MPNST cell lines and synergistically induced apoptosis when combined with an mTOR inhibitor, RAD-001, suggesting that Wnt inhibition represents a novel target for therapeutic intervention in Schwann cell tumors.
Acute Psychiatric Services in the General Hospital: I. Implications for Psychiatry in Emergency Admissions
Authors: MORRIS E. CHAFETZ, HOWARD T. BLANE, JAMES J. MULLER
Journal: American Journal of Psychiatry (1966)

At Massachusetts General Hospital, visits to the psychiatric service increased from one percent of total visits in 1952 to three percent in 1961. This probably reflects an increase in acknowledgment of psychiatric disturbance rather than an actual rise in its incidence. The increase in emergency psychiatric admissions to general hospitals—which are now often used as "the poor man's family doctor"—has many implications for the future practice of psychiatry.
Targeting tumour necrosis factor receptor 1 assembly reverses Th17-mediated colitis through boosting a Th2 response
Authors: Shin-Huei Fu, Ming-Hong Lin, Li-Tzu Yeh, Yen-Ling Wang, Ming-Wei Chien, Shih-Hua Lin, Deh-Ming Chang, Huey-Kang Sytwu
Journal: Gut (2014)

Objective The soluble preligand assembly domain (PLAD) of tumour necrosis factor receptor 1 (TNFR1) interferes with receptor trimerisation to block downstream signalling, and mediates Th17 suppression. We explored the therapeutic potential of recombinant PLAD.Fc protein on a spontaneous experimental colitis. Design A T-cell-specific BLIMP-1 knockout mouse model with mixed Th1/Th17 responses, resembling human Crohn's disease (CD) was established, and its colitogenic phenotype was characterised. Mice, 9 weeks old, were treated with PLAD.Fc protein at 5 mg/kg of body weight twice per week for 16 weeks, and presence of colitis was monitored by the appearance of diarrhoea, weight loss, and by histological colonic scoring. Activation status, cytokine profiles, and transcription factors in T cells were further analysed. Results The colitogenic phenotype in BLIMP-1 knockout mice was alleviated when an interleukin (IL)-23 knockdown transgene was introduced, indicating a therapeutic potential by downregulating IL-23-Th17 axis in these knockout mice. In PLAD.Fc-treated group, the mouse body weight remained stable and only mild disease scores were revealed. The percentage of naive CD4 T cells was increased and that of effector/memory CD4 T cells was decreased after PLAD.Fc-treatment. Moreover, the levels of IFN-γ, IL-17, IL-21, IL-22, IL-23R, granulocyte-macrophage colony-stimulating factor (GM-CSF) and TNF-α were diminished. Strikingly, Th2-associated cytokines (IL-4, IL-13 and IL-10) in sera, as well as percentages of Th2 cells, were increased in PLAD.Fc-treated mice. However, PLAD.Fc-mediated suppression of effector phenotypes in Th1/Th17 was abrogated after neutralising IL-10. Conclusions The Th2 cytokine milieu induced by PLAD.Fc rebalanced T-helper cell subsets and conferred a protection against colitis in BLIMP-1 knockout mice.
Abstract 1753: GLPG1790: The first Ephrin (EPH) receptor tyrosine kinase inhibitor for the treatment of triple negative breast cancer
Authors: Philippe Pujuguet, Filip Beirinckx, Carole Delachaume, Jacques Huck, Ellen Van der Aar, Reginald Brys, Luc Van Rompaey, Piet Wigerinck, Laurent Saniere
Journal: Cancer Research (2014)

Abstract Receptor tyrosine kinases define a clinically relevant class of targets in the field of cancer. Here we report the discovery of a pre-clinical drug candidate directed against the EPH receptor family. Members of this family of receptor tyrosine kinases are over-expressed in diverse cancer types. GLPG1790 is a small molecule, nanomolar inhibitor of various EPH receptors kinases. The compound displayed a remarkable efficacy by once-daily oral administration in a mouse EPHA2 expressing xenograft model (MDA-MB-231). A rapid dose-dependent reduction of tumor growth was achieved, with full inhibition at the oral dose of 30 mg/kg/d. GLPG1790 efficacy at this dose was similar to that of Paclitaxel administered at its maximum tolerated dose. A series of experiments was initiated to confirm the mechanism of action of this compound. GLPG1790 inhibits human EPHA2 kinase activity with an IC50 of 11 nM in a biochemical assay. In the human MDA-MB-231 breast cancer cell line, that expresses a high level of EPHA2 protein, GLPG1790 inhibits receptor phosphorylation with an IC50 of 260 nM, and anchorage-independent growth with similar potency. In addition, in vivo target engagement was demonstrated in the mouse MDA-MB-231 xenograft model. GLPG1790 inhibited EPHA2 receptor phosphorylation after single oral administration of 30 and 100 mg/kg doses. The extent of the effects observed on EPHA2 phosphorylation correlated with intra-tumoral GLPG1790 concentration. Moreover, the MAPK pathway, known to be a major driver of proliferation of this cell line, was inhibited both in in vitro cellular assays and in xenograft target engagement studies. Flow cytometric analyses revealed a cell cycle arrest at the G0/G1 phase for MDA-MB-231 cells treated with GLPG1790. EPHA2 knock-down-based experiments further support the EPH-driven mode of action of GLPG1790. All together these data stimulate the development of GLPG1790 in triple negative breast cancer. This novel mechanism of action is under investigation in other cancer types overexpressing EPH's (melanoma, pancreatic, ovarian, prostatic and colorectal cancers). Citation Format: Philippe Pujuguet, Filip Beirinckx, Carole Delachaume, Jacques Huck, Ellen Van der Aar, Reginald Brys, Luc Van Rompaey, Piet Wigerinck, Laurent Saniere. GLPG1790: The first Ephrin (EPH) receptor tyrosine kinase inhibitor for the treatment of triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1753. doi:10.1158/1538-7445.AM2014-1753
Brain evolution in<i>Homo:</i>The “radiator” theory
Authors: Dean Falk
Journal: Behavioral and Brain Sciences (1990)

Abstract The “radiator” theory of brain evolution is proposed to account for “mosaic evolution” whereby brain size began to increase rapidly in the genus Homo well over a million years after bipedalism had been selected for in early hominids. Because hydrostatic pressures differ across columns of fluid depending on orientation (posture), vascular systems of early bipeds became reoriented so that cranial blood flowed preferentially to the vertebral plexus instead of the internal jugular vein in response to gravity. The Hadar early hominids and robust australopithecines partly achieved this reorientation with a dramatically enlarged occipital/marginal sinus system. On the other hand, hominids in the gracile australopithecine through Homo lineage delivered blood to the vertebral plexus via a widespread network of veins that became more elaborate through time. Mastoid and parietal emissary veins are representatives of this network, and increases in their frequencies during hominid evolution are indicative of its development. Brain size increased with increased frequencies of mastoid and parietal emissary veins in the lineage leading to and including Homo , but remained conservative in the robust australopithecine lineage that lacked the network of veins. The brain is an extremely heatsensitive organ and emissary veins in humans have been shown to cool the brain under conditions of hyperthermia. Thus, the network of veins in the lineage leading to Homo acted as a radiator that released a thermal constraint on brain size. The radiator theory is in keeping with the belief that basal gracile and basal robust australopithecines occupied distinct niches, with the former living in savanna mosaic habitats that were subject to hot temperatures and intense solar radiation during the day.