tbuckley/cabot-search huggingface dataset:
AI-03 * TARGETING ANGIOGENESIS WITHOUT INCREASING THE STROMAL CELL RESPONSE OR INVASION USING ABT-898, A THROMBOSPONDIN TYPE 1 REPEAT PEPTIDE
Authors: E. Bae, L. Smith, G. Muller-Greven, R. Yamada, K. Joshi, M. Nakano-Okuno, X. Feng, D. Hambardzumyan, I. Nakano, C. L. Gladson
Journal: Neuro-Oncology (2014)

Anti-angiogenic therapy is a promising therapeutic approach for highly vascularized tumors including glioblastoma (GBM). Nonetheless, the efficacy of Bevacizumab - a monoclonal antibody to VEGF-A - is limited only to progression-free survival but not overall survival, due at least in part to the induction of a more invasive phenotype. Here, we investigated the anti-tumor effect of a thrombospondin-1&2 mimetic peptide, ABT-898, on intracerebral xenografts derived from primary patient GBM neurospheres in the nude mouse. ABT-898 treatment of xenograft tumors (80 mg/kg/day i.p.) prolonged mouse survival. Unlike Bevacizumab-treated mouse brain tumors, ABT-898-treated tumors did not exhibit a detectable increase in the number of invasive foci or phospho-Met expression, indicating no induction of an invasive phenotype. As stromal cells are thought to promote tumor cell invasion, we quantitated infiltration of Iba1+ activated microglial/macrophages into the tumor. Although Bevacizumab therapy significantly increased the number of recruited Iba1+ cells into the tumors, the number of Iba1+ cells in the ABT-898-treated tumors was not increased as compared to the vehicle-treated xenograft tumors. Supporting this finding, the migration of microglia cells (BV2), was significantly inhibited by ABT898 in a dose-dependent manner, and the inhibition was reversed by CD36-neutralizing antibody. This suggests that recruitment of tumor invasion-promoting microglia/macrophage can be regulated by ABT898 and this regulation is in part CD36-dependent. In addition, treatment with ABT898 significantly reduced vessel density in xenograft tumors. In vitro ABT898 induced apoptosis of brain endothelial cells (ECs) and inhibited tubulomorphogenesis in collagen gels, both in a dose-dependent manner, and both were reversed by treatment with CD36 neutralizing antibody, Collectively, these data suggest that ABT-898 offers the novel advantage over Bevacizumab of decreasing stromal cell recruitment to the tumor and thus should be considered as an alternative anti-angiogenic therapy for GBM.
Changes in use of hormone replacement therapy after the report from the Women's Health Initiative: cross sectional survey of users
Authors: B. Lawton
Journal: BMJ (2003)

In 2002 the Women's Health Initiative reported the results of a study on the effects of combined oestrogen plus progestogen on healthy postmenopausal women. They found increased rates of breast cancer, coronary heart disease, stroke, and venous thromboembolism and decreased rates of hip fracture and colorectal disease but no “global” benefit. They concluded that combined oestrogen and progestogen is not suitable for the prevention of chronic diseases.1 The subsequent extensive media coverage came at a time when the prevalence,2 3 duration,2 4 and use of hormone replacement therapy (HRT) for the prevention of chronic disease had been increasing.2 4 After the report, government regulatory authorities issued advice to health professionals and women, and guidelines relating to the postmenopausal use of hormone replacement therapy were updated.5 We examined changes in HRT use since the publication of the report.

Between January 2000 and November 2002, 3500 women were screened from 23 general practices in four New Zealand centres as part of the recruitment process for the …
A novel small molecule inhibits STAT3 phosphorylation and DNA binding activity and exhibits potent growth suppressive activity in human cancer cells
Authors: Li Lin, Stephanie Deangelis, Elizabeth Foust, James Fuchs, Chenglong Li, Pui-Kai Li, Eric B Schwartz, Gregory B Lesinski, Don Benson, Jiagao Lü, Dale Hoyt, Jiayuh Lin
Journal: Molecular Cancer (2010)

Targeting Signal Transducer and Activator of Transcription 3 (STAT3) signaling is an attractive therapeutic approach for most types of human cancers with constitutively activated STAT3. A novel small molecular STAT3 inhibitor, FLLL32 was specifically designed from dietary agent, curcumin to inhibit constitutive STAT3 signaling in multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cells. FLLL32 was found to be a potent inhibitor of STAT3 phosphorylation, STAT3 DNA binding activity, and the expression of STAT3 downstream target genes in vitro, leading to the inhibition of cell proliferation as well as the induction of Caspase-3 and PARP cleavages in human multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cell lines. However, FLLL32 exhibited little inhibition on some tyrosine kinases containing SH2 or both SH2 and SH3 domains, and other protein and lipid kinases using a kinase profile assay. FLLL32 was also more potent than four previously reported JAK2 and STAT3 inhibitors as well as curcumin to inhibit cell viability in these cancer cells. Furthermore, FLLL32 selectively inhibited the induction of STAT3 phosphorylation by Interleukin-6 but not STAT1 phosphorylation by IFN-γ. Our findings indicate that FLLL32 exhibits potent inhibitory activity to STAT3 and has potential for targeting multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cells expressing constitutive STAT3 signaling.
Pulmonary Function in Diaphragmatic Paralysis
Authors: M. McCredie, F. W. Lovejoy, N. L. Kaltreider
Journal: Thorax (1962)

Retinoic acids, a group of natural and synthetic vitamin A derivatives, have potent antiproliferative and anti-inflammatory properties. Recently, retinoic acids were reported to inhibit Th1 cytokine production. We investigated the effects of retinoic acid on lupus nephritis in a model of NZB/NZW F<sub>1</sub> (NZB/W F<sub>1</sub>) mice. Three-month-old NZB/W F<sub>1</sub> mice were separated into two groups: one treated with all-<i>trans</i>-retinoic acid (ATRA; 0.5 mg i.p., three times weekly for 7 mo) and one with saline as a control. Compared with controls, ATRA-treated mice survived longer and exhibited a significant reduction of proteinuria, renal pathological findings including glomerular IgG deposits, and serum anti-DNA Abs. Splenomegaly was less marked in the treated mice than in controls. Transcripts encoding IFN-γ, IL-2, and IL-10 in splenic CD4<sup>+</sup> T cells were significantly reduced in treated mice compared with controls. We conclude that treatment with ATRA in SLE-prone NZB/W F<sub>1</sub> mice significantly alleviates autoimmune renal disorder and prolongs survival; this may thus represent a novel approach to the treatment of patients with lupus nephritis.
A Founder Mutation in Presenilin 1 Causing Early-Onset Alzheimer Disease in Unrelated Caribbean Hispanic Families
Authors: Eleni S. Athan
Journal: JAMA (2001)

][3] Mutations in presenilin 1 are known to be responsible for a large proportion of familial early-onset AD [4][5][6][7] and are typically completely penetrant.Presenilin 1 mutations have been described in
One-year follow-up of a randomised controlled trial on added splinting to eccentric exercises in chronic midportion Achilles tendinopathy
Authors: S de Jonge, R J de Vos, H T M Van Schie, J A N Verhaar, A Weir, J L Tol
Journal: British Journal of Sports Medicine (2008)

Objective The study examined whether the addition of a night splint to eccentric exercises is beneficial for functional outcome in chronic midportion Achilles tendinopathy. Design One-year follow-up of a randomised controlled single blinded clinical trial. Setting Sports medicine department in a general hospital. Patients 58 patients (70 tendons) were included. Interventions All patients completed a 12-week heavy load eccentric training programme. One group received a night splint in addition to eccentric exercises. Main outcome measurements Outcome scores were: Victorian Institute of Sport Assessment—Achilles (VISAA) score, subjective patient satisfaction and neovascularisation score measured with power Doppler ultrasonography (PDU). Results For both groups the VISA-A score increased significantly (from 50 to 76 (p&lt;0.01) in the eccentric group and from 49 to 78 (p&lt;0.01) in the night splint group). No significant differences in the VISA-A score were found between the groups from baseline to one year (p = 0.32). The presence of neovessels at baseline did not predict a change in the VISA-A score after one year in the whole group (p = 0.71). Conclusion Eccentric exercises with or without a night splint improved functional outcome at one year follow-up. At follow-up there was no significant difference in clinical outcome when a night splint was used in addition to an eccentric exercise programme. Between 3 months and one year follow-up, a continuing increase in the VISA-A score was found. Assessment of the neovascularisation score with PDU at baseline has no prognostic value on long-term clinical outcome.
Long-Term Clinical Outcome After a First Angiographically Confirmed Coronary Stent Thrombosis
Authors: Jochem W. van Werkum, Antonius A.C.M. Heestermans, Fleur I. de Korte, Johannes C. Kelder, Maarten-Jan Suttorp, Benno J.W.M. Rensing, Bastiaan Zwart, B. R. Guus Brueren, Jacques J. Koolen, Jan-Henk E. Dambrink, Arnoud W.J. van't Hof, Freek W.A. Verheugt, Jurriën M. ten Berg
Journal: Circulation (2009)

Background— There are limited data on the long-term clinical outcome after an angiographically confirmed (definite) stent thrombosis (ST). Methods and Results— Four hundred thirty-one consecutive patients with a definite ST were enrolled in this multicenter registry. The primary end point was the composite of cardiac death and definite recurrent ST. Secondary end points were all-cause death, cardiac death, definite recurrent ST, definite and probable recurrent ST, any myocardial infarction, and any target-vessel revascularization. The primary end point occurred in 111 patients after a median follow-up of 27.1 months. The estimated cumulative event rates at 30 days and 1, 2, and 3 years were 18.0%, 23.6%, 25.2%, and 27.9%, respectively. The cumulative incidence rates of definite recurrent ST, definite or probable recurrent ST, any myocardial infarction, and any target-vessel revascularization were 18.8%, 20.1%, 21.3%, and 32.0%, respectively, at the longest available follow-up. Independent predictors for the primary end point were diabetes mellitus, total stent length, severe calcification, American College of Cardiology/American Heart Association B2-C lesions, TIMI (Thrombolysis In Myocardial Infarction) flow grade &lt;3 after percutaneous coronary intervention, and left ventricular ejection fraction &lt;45%. The implantation of an additional coronary stent during the first ST was also associated with unfavorable outcome. Clinical outcome was not affected by the type of previously implanted stent (drug-eluting or bare-metal stent) or the category of ST (early versus late). Conclusions— The long-term clinical outcome after a first definite ST is unfavorable, with a high mortality and recurrence rate. Diabetes mellitus, left ventricular ejection fraction &lt;45%, long total stent length, complex coronary lesions, TIMI flow grade &lt;3 after percutaneous coronary intervention, and implantation of an additional coronary stent during the emergent percutaneous coronary intervention for the ST were associated with this unfavorable outcome.
p38-MAPK Signals Survival by Phosphorylation of Caspase-8 and Caspase-3 in Human Neutrophils
Authors: Maria Alvarado-Kristensson, Fredrik Melander, Karin Leandersson, Lars Rönnstrand, Christer Wernstedt, Tommy Andersson
Journal: The Journal of Experimental Medicine (2004)

Neutrophil apoptosis occurs both in the bloodstream and in the tissue and is considered essential for the resolution of an inflammatory process. Here, we show that p38–mitogen-activated protein kinase (MAPK) associates to caspase-8 and caspase-3 during neutrophil apoptosis and that p38-MAPK activity, previously shown to be a survival signal in these primary cells, correlates with the levels of caspase-8 and caspase-3 phosphorylation. In in vitro experiments, immunoprecipitated active p38-MAPK phosphorylated and inhibited the activity of the active p20 subunits of caspase-8 and caspase-3. Phosphopeptide mapping revealed that these phosphorylations occurred on serine-364 and serine-150, respectively. Introduction of mutated (S150A), but not wild-type, TAT-tagged caspase-3 into primary neutrophils made the Fas-induced apoptotic response insensitive to p38-MAPK inhibition. Consequently, p38-MAPK can directly phosphorylate and inhibit the activities of caspase-8 and caspase-3 and thereby hinder neutrophil apoptosis, and, in so doing, regulate the inflammatory response.
Effects of cimetidine and carbenoxolone on gastric mucus.
Authors: M D Ene, J R Clamp, C J Roberts
Journal: Gut (1988)

The effect of cimetidine on normal human gastric mucus has been compared with that of carbenoxolone, a drug believed to enhance mucus production. Each drug was given for two weeks, the gastric contents aspirated over a timed period and the results assessed in unstimulated and pentagastrin stimulated secretions. The volume, dry weight and the carbohydrate contents of non-diffusable glycoconjugates, high molecular mass glycoproteins and glycopolypeptides were investigated. Both drugs reduced the volumes of stimulated secretions. This was statistically significant after cimetidine. More importantly neither drug affected the amount of non-diffusable glycoconjugates, so that the concentration remained the same or increased. Both drugs reduced the monosaccharide content of the high molecular mass fractions. This reached significance for the stimulated secretion after cimetidine. As the carbohydrate content of the glycopolypeptides was unchanged this indicated the presence of a non-mucin glycoprotein or protein. Overall there was no fundamental difference between the results for cimetidine and carbenoxolone.
Effect of spatial variations in shear on diffusion at the wall of an arterial branch.
Authors: M H Friedman, L W Ehrlich
Journal: Circulation Research (1975)

The effect of spatially varying shear on transport to the wall of a two-dimensional branch was examined, using oxygen as the test solute and the results of earlier fluid mechanical calculations to provide the shear profiles in a region characterizing the aortic bifurcation. The numerical technique employed allowed both blood-phase and mural resistances to solute uptake to be treated simultaneously and self-consistently. The calculated profiles of wall concentration and mural flux were significantly different from those which would have obtained if the shear had been uniform. The calculations suggest that, even when solute is rapidly taken up from the blood, the occasional high-shear and flow-development sites encountered along the arterial tree prevent the diffusion boundary layer adjacent to the wall from thickening to the point at which nutrition is compromised. The indirect effect of arterial geometry on transport, consequent to its direct effect on the magnitude and the distribution of the relevant hemodynamic variables, was illustrated using the branch area ratio as the geometric parameter. The shapes of the flux and interfacial concentration profiles along the branch wall were markedly dependent on the extent to which wall shear affected intimal permeability.
Fate of the Rectal Stump After Subtotal Colectomy for Ulcerative Colitis in the Era of Ileal Pouch–Anal Anastomosis
Authors: Semeret Munie, Neil Hyman, Turner Osler
Journal: JAMA Surgery (2013)

Total proctocolectomy with ileal pouch-anal anastomosis is considered the procedure of choice for patients requiring elective surgery for ulcerative colitis, but some patients undergoing subtotal colectomy with end ileostomy are satisfied with an ileostomy and do not choose to undergo later pelvic pouch surgery. The need and timing for completion proctectomy in this setting are uncertain.To assess the long-term fate of the retained rectum compared with the morbidity associated with completion proctectomy in patients who underwent subtotal colectomy for ulcerative colitis.Retrospective review of a prospective database in an academic medical center.Patients who underwent subtotal colectomy with ileostomy for ulcerative colitis from July 1, 1990, to December 31, 2010.Proctectomy, surgical complications, and symptoms from the retained rectum.One hundred eight patients underwent subtotal colectomy for ulcerative colitis during the study period: 73 for acute disease, 18 for advanced age and/or comorbidities, and 17 to avoid the risk of sexual dysfunction or infertility. Of these patients, 71 (65.7%) underwent subsequent ileal pouch-anal anastomosis, 2 died of other causes, and 3 were lost to follow-up. Of the remaining 32 patients, 20 chose rectal stump surveillance and 12 underwent elective proctectomy. Median follow-up was 13.8 years. No difference was noted in age, sex, surgical complications, pad use, or urinary dysfunction between the 2 groups. Only 8 of 20 patients in the surveillance group were compliant with follow-up endoscopy, and 13 were able to maintain their rectum; 2 required proctectomy at 11 and 16 years, respectively, for rectal cancer; neither has developed recurrent disease. One patient in each group reported erectile dysfunction.Management of the retained rectum after subtotal colectomy remains an important issue even in the era of ileal pouch-anal anastomosis. Considering the risk of rectal cancer, the low success rate of long-term rectal preservation, and the safety of surgery, a more aggressive approach to early completion proctectomy seems justified in this situation.
Antimicrobial peptaibols, novel suppressors of tumor cells, targeted calcium-mediated apoptosis and autophagy in human hepatocellular carcinoma cells
Authors: Mei Shi, Hong-Na Wang, Shu-Tao Xie, Yan Luo, Cai-Yun Sun, Xiu-Lan Chen, Yu-Zhong Zhang
Journal: Molecular Cancer (2010)

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common cancers in the world which is highly chemoresistant to currently available chemotherapeutic agents. Thus, novel therapeutic targets are needed to be sought for the successful treatment of HCC. Peptaibols, a family of peptides synthesized non-ribosomally by the Trichoderma species and other fungi, exhibit antibiotic activities against bacteria and fungi. Few studies recently showed that peptaibols exerted cytotoxicity toward human lung epithelial and breast carcinoma cells. However, the mechanism involved in peptaibol-induced cell death remains poorly understood. Results Here, we showed that Trichokonin VI (TK VI), a peptaibol from Trichoderma pseudokoningii SMF2, induced growth inhibition of HCC cells in a dose-dependent manner. It did not obviously impair the viability of normal liver cells at lower concentration. Moreover, the suppression of cell viability resulted from the programmed cell death (PCD) with characteristics of apoptosis and autophagy. An influx of Ca 2+ triggered the activation of μ-calpain and proceeded to the translocation of Bax to mitochondria and subsequent promotion of apoptosis. On the other hand, typically morphological characteristics consistent with autophagy were also observed by punctate distribution of MDC staining and the induction of LC3-II, including extensive autophagic vacuolization and enclosure of cell organelles by these autophagosomes. More significantly, specific depletion of Bak expression by small RNA interfering (siRNA) could partly attenuate TK VI-induced autophagy. However, siRNA against Bax led to increased autophagy. Conclusion Taken together, these findings showed for the first time that peptaibols were novel regulators involved in both apoptosis and autophagy, suggesting that the class of peptaibols might serve as potential suppressors of tumor cells.
The response of human bone marrow to chronic cigarette smoking
Authors: S.F. van Eeden, J.C. Hogg
Journal: European Respiratory Journal (2000)

Chronic cigarette smoking in humans causes leukocytosis. Animal studies show that chronic smoking shortens the transit time of polymorphonuclear leukocytes (PMNLs) through the bone marrow. The present study examines the response of human bone marrow to chronic cigarette smoking. Three characteristics of peripheral blood PMNLs that indicate active bone marrow release (band cell counts, surface L-selectin expression and myeloperoxidase (MPO) content), were measured in 38 healthy chronic smokers (23+/-5 pack-yrs) and 15 age- and sex-matched nonsmoking controls. The total white cell (6.8+/-0.3x10(9) versus 5.3+/-0.2x10(9) cells x L(-1), p&lt;0.0001) and PMNL (4.2+/-0.18x10(9) versus 3.2+/-0.1x10(9) cells x L(-1), p&lt;0.003) counts were higher in smokers as were the percentage (4.8+/-0.6 versus 1.1+/-0.2, p&lt;0.0001) and total number (0.21+/-0.04x10(9) versus 0.03+/-0.001x10(9) cells x L(-1), p&lt;0.01) of band cells. Flow cytometry showed that the mean fluorescence intensity (MFI) of L-selectin (3.2+/-0.2 versus 2.6+/-0.1, p&lt;0.05) on PMNLs was higher in smokers. There was no difference in the baseline or N-formyl-methionyl-leucyl-phenylalanine-stimulated expression of CD63 or CD18/CD11b (surface markers of PMNL activation) between smokers and controls. The MPO content of PMNLs was higher in smokers (3.4+/-0.3 versus 1.7+/-0.2 MFI, p&lt;0.05). Smokers with a low (&lt;75% of the predicted value) diffusing capacity of the lung for carbon monoxide had higher PMNL MPO levels than smokers with a diffusing capacity of &gt;75% pred (p&lt;0.05). In conclusion, chronic smoking causes phenotypic changes in circulating polymorphonuclear leukocytes that are characteristic of chronic stimulation of the bone marrow and it is speculated that the increased number of immature polymorphonuclear leukocytes contributes to the chronic lung inflammation associated with cigarette smoking.
Newer Cytotoxic Agents: Attacking Cancer Broadly
Authors: Beverly A. Teicher
Journal: Clinical Cancer Research (2008)

Abstract The plasticity and instability of the cancer genome is impressive and is characterized by gene amplifications and deletions, rearrangements, and many silent and active mutations. Although targeted therapeutics have had effect in some diseases, there remains a large role for new cytotoxic agents that have the potential to be broadly active across multiple cancers. Platinum-based regimens are the basis for treatment of several common tumors. Satraplatin and picoplatin are newer platinum complexes that form bulkier lesions in DNA than their forerunners. Microtubules are a key target for anticancer agents. Vinca alkaloid and similar compounds fragment these critical structures, whereas taxanes stabilize them. Vinflunine is a new fluorinated Vinca alkaloid derivative with vascular disrupting effects, as well as antitumor effects. Epothilones are a new class of microtubule stabilizers. Mitosis has been targeted directly and indirectly by many anticancer agents. The aurora kinases are new targets in this class. Inhibitors of aurora kinases are likely to be cytotoxic. Finally, protein regulation is essential for cellular integrity. With the approval of bortezomib (Velcade, PS-341), the proteosome, a master protein regulator, has been validated as an anticancer target. The five articles in this issue of CCR Focus present the current status of these next generation cytotoxic agents.