bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recovery time of snowshoe hare habitat after commercial thinning in boreal Quebec
Authors: Bois Guylaine , Imbeau Louis , Mazerolle Marc J. 
Published: December 2011

As short-term effects of partial cuts generally decrease available cover for snowshoe hare ( Lepus americanus Erxleben), most studies have shown negative effects of such treatments on this keystone species in boreal ecosystems. This study aims to determine the long-term impact of commercial thinning on snowshoe hare habitat, and we hypothesized that habitat quality, as well as habitat use, recovers with time since treatment. We selected stands aged 50–90 years dominated by black spruce ( Picea mariana (Mill.) Britton, Sterns & Poggenb.) in Abitibi (Quebec). We used models of habitat parameters to explain the abundance of snowshoe hare tracks and pellets in 20 commercially thinned stands treated between 1989 and 1999 and 12 control stands. Lateral cover was the dominant parameter influencing snowshoe hare habitat use. On average, commercially thinned stands had a lower lateral cover than controls (–18%). We also found that snowshoe hare use of commercially thinned stands increases with time since treatment. However, 11–18 years are needed before commercially thinned stands return to the same level of lateral cover and snowshoe hare signs as control stands. Commercial thinning is generally followed by harvesting all merchantable stems 15 years after treatment. Thus, we suggest that commercial thinning as currently practiced should be avoided if the objective is to maintain quality habitat for snowshoe hare and its associated predators.
Hedgehog Signaling Inhibition Blocks Growth of Resistant Tumors through Effects on Tumor Microenvironment
Authors: Heller Emanuela , Hurchla Michelle A. , Xiang Jingyu , Su Xinming , Chen Sara , Schneider Jochen , Joeng Kyu-Sang , Vidal Marcos , Goldberg Leah , Deng Hongju , Hornick Mary C. , Prior Julie L. , Piwnica-Worms David , Long Fanxin , Cagan Ross , Weilbaecher Katherine N. 
Published: December 2011

Abstract
Hedgehog (Hh) signaling is implicated in bone development and cellular transformation. Here we show that inhibition of Hh pathway activity inhibits tumor growth through effects on the microenvironment. Pharmacologic inhibition of the Hh effector Smoothened (Smo) increased trabecular bone in vivo and inhibited osteoclastogenesis in vitro. In addition, enhanced Hh signaling due to heterozygosity of the Hh inhibitory receptor Patched (Ptch1+/−) increased bone resorption, suggesting direct regulation of osteoclast (OC) activity by the Hh pathway. Ptch1+/− mice had increased bone metastatic and subcutaneous tumor growth, suggesting that increased Hh activation in host cells promoted tumor growth. Subcutaneous growth of Hh-resistant tumor cells was inhibited by LDE225, a novel orally bioavailable SMO antagonist, consistent with effects on tumor microenvironment. Knockdown of the Hh ligand Sonic Hh (SHH) in these cells decreased subcutaneous tumor growth and decreased stromal cell production of interleukin-6, indicating that tumor-derived Hh ligands stimulated tumor growth in a paracrine fashion. Together our findings show that inhibition of the Hh pathway can reduce tumor burden, regardless of tumor Hh responsiveness, through effects on tumor cells, OCs, and stromal cells within the tumor microenvironment. Hh may be a promising therapeutic target for solid cancers and bone metastases. Cancer Res; 72(4); 897–907. ©2011 AACR.
Molecular Pathways: Beta-Adrenergic Signaling in Cancer
Authors: Cole Steven W. , Sood Anil K. 
Published: December 2011

Abstract
Beta-adrenergic signaling has been found to regulate multiple cellular processes that contribute to the initiation and progression of cancer, including inflammation, angiogenesis, apoptosis/anoikis, cell motility and trafficking, activation of tumor-associated viruses, DNA damage repair, cellular immune response, and epithelial–mesenchymal transition. In several experimental cancer models, activation of the sympathetic nervous system promotes the metastasis of solid epithelial tumors and the dissemination of hematopoietic malignancies via β-adrenoreceptor–mediated activation of protein kinase A and exchange protein activated by adenylyl cyclase signaling pathways. Within the tumor microenvironment, β-adrenergic receptors on tumor and stromal cells are activated by catecholamines from local sympathetic nerve fibers (norepinephrine) and circulating blood (epinephrine). Tumor-associated macrophages are emerging as key targets of β-adrenergic regulation in several cancer contexts. Sympathetic nervous system regulation of cancer cell biology and the tumor microenvironment has clarified the molecular basis for long-suspected relationships between stress and cancer progression, and now suggests a highly leveraged target for therapeutic intervention. Epidemiologic studies have linked the use of β-blockers to reduced rates of progression for several solid tumors, and preclinical pharmacologic and biomarker studies are now laying the groundwork for translation of β-blockade as a novel adjuvant to existing therapeutic strategies in clinical oncology. Clin Cancer Res; 18(5); 1201–6. ©2011 AACR.
Silencing hsp25/hsp27 Gene Expression Augments Proteasome Activity and Increases CD8+ T-Cell–Mediated Tumor Killing and Memory Responses
Authors: Nagaraja Ganachari M. , Kaur Punit , Neumann William , Asea Edwina E. , Bausero María A. , Multhoff Gabriele , Asea Alexzander 
Published: December 2011

Abstract
Relatively high expression of Hsp27 in breast and prostate cancer is a predictor of poor clinical outcome. This study elucidates a hitherto unknown mechanism by which Hsp27 regulates proteasome function and modulates tumor-specific T-cell responses. Here, we showed that short-term silencing of Hsp25 or Hsp27 using siRNA or permanent silencing of Hsp25 using lentivirus RNA interference technology enhanced PA28α mRNA expression, PA28α protein expression, and proteasome activity; abrogated metastatic potential; induced the regression of established breast tumors by tumor-specific CD8+ T cells; and stimulated long-lasting memory responses. The adoptive transfer of reactive CD8+ T cells from mice bearing Hsp25-silenced tumors efficiently induced the regression of established tumors in nontreated mice which normally succumb to tumor burden. The overexpression of Hsp25 and Hsp27 resulted in the repression of normal proteasome function, induced poor antigen presentation, and resulted in increased tumor burden. Taken together, this study establishes a paradigm shift in our understanding of the role of Hsp27 in the regulation of proteasome function and tumor-specific T-cell responses and paves the way for the development of molecular targets to enhance proteasome function and concomitantly inhibit Hsp27 expression in tumors for therapeutic gain. Cancer Prev Res; 5(1); 122–37. ©2011 AACR.
The contribution of thrombin-induced platelet activation to thrombus growth is diminished under pathological blood shear conditions
Authors: Lee Hannah , Sturgeon Sharelle , Jackson Shaun , Hamilton Justin 
Published: December 2011

SummaryDeveloping novel anti-platelet therapies is an important clinical strategy for the prevention of arterial thromboses which cause heart attacks and most strokes. Thrombin activates platelets via protease-activated receptors (PARs), and PAR antagonists are currently under investigation as antithrombotics. Yet despite these clinical advances, the importance of PARs to platelet activation during thromboses formed under pathological conditions has not been investigated. To this end, we examined the role of PAR-dependent platelet activation in thrombus formation in the presence of elevated blood shear rates. We used two in vivo thrombosis models and an ex vivo whole blood flow approach in PAR4-/-mice, whose platelets are unresponsive to thrombin, to show that the contribution of PAR-mediated platelet activation to thrombosis is diminished at pathological blood shear rates as a direct result of decreased incorporation of thrombin-activated platelets into growing thrombi. Our ex vivo observations were replicated in human whole blood treated with a PAR1 antagonist. These results define a novel, shear-regulated role for thrombin/PAR-dependent platelet activation during thrombosis and provide important insights into the conditions under which PAR antagonists may best be used for the prevention of acute coronary syndromes.
Continental Shelf Wave Propagation in the Mid-Atlantic Bight: A General Dispersion Relation
Authors: Schulz William J. , Mied Richard P. , Snow Charlotte M. 
Published: December 2011

Abstract
The authors address the propagation of continental shelf waves in the Mid-Atlantic Bight. An analytical model of the bathymetry in the region is constructed by representing the continental shelf as a gently sloping bottom, which deepens linearly with offshore distance to the place where it meets the continental slope. Seaward of that point, the bathymetry is modeled with an exponentially decaying function of distance. The linearized, barotropic equations of hydrostatic motion, subject to the long-wave approximation, yield separate shelf and slope solutions, which are matched at the shelf break to specify the eigenfunctions. The associated eigenvalues define the dispersion relations for each of the modes. Wavenumber–frequency pairs derived from NOAA sea surface height stations along the coast are plotted on the first-mode dispersion curve, and the agreement is good. The theory also shows good agreement with the wave data of D. P. Wang.
Paradoxical absence of a prothrombotic phenotype in a mouse model of severe hyperhomocysteinemia
Authors: Dayal Sanjana , Chauhan Anil K. , Jensen Melissa , Leo Lorie , Lynch Cynthia M. , Faraci Frank M. , Kruger Warren D. , Lentz Steven R. 
Published: December 2011

Abstract
Hyperhomocysteinemia confers a high risk for thrombotic vascular events, but homocysteine-lowering therapies have been ineffective in reducing the incidence of secondary vascular outcomes, raising questions regarding the role of homocysteine as a mediator of cardiovascular disease. Therefore, to determine the contribution of elevated homocysteine to thrombosis susceptibility, we studied Cbs−/− mice conditionally expressing a zinc-inducible mutated human CBS (I278T) transgene. Tg-I278T Cbs−/− mice exhibited severe hyperhomocysteinemia and endothelial dysfunction in cerebral arterioles. Surprisingly, however, these mice did not display increased susceptibility to arterial or venous thrombosis as measured by photochemical injury in the carotid artery, chemical injury in the carotid artery or mesenteric arterioles, or ligation of the inferior vena cava. A survey of hemostatic and hemodynamic parameters revealed no detectible differences between control and Tg-I278T Cbs−/− mice. Our data demonstrate that severe elevation in homocysteine leads to the development of vascular endothelial dysfunction but is not sufficient to promote thrombosis. These findings may provide insights into the failure of homocysteine-lowering trials in secondary prevention from thrombotic vascular events.
CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development
Authors: Finney Brenda A. , Schweighoffer Edina , Navarro-Núñez Leyre , Bénézech Cecile , Barone Francesca , Hughes Craig E. , Langan Stacey A. , Lowe Kate L. , Pollitt Alice Y. , Mourao-Sa Diego , Sheardown Steve , Nash Gerard B. , Smithers Nicholas , Reis e Sousa Caetano , Tybulewicz Victor L. J. , Watson Steve P. 
Published: December 2011

AbstractThe C-type lectin receptor CLEC-2 signals through a pathway that is critically dependent on the tyrosine kinase Syk. We show that homozygous loss of either protein results in defects in brain vascular and lymphatic development, lung inflation, and perinatal lethality. Furthermore, we find that conditional deletion of Syk in the hematopoietic lineage, or conditional deletion of CLEC-2 or Syk in the megakaryocyte/platelet lineage, also causes defects in brain vascular and lymphatic development, although the mice are viable. In contrast, conditional deletion of Syk in other hematopoietic lineages had no effect on viability or brain vasculature and lymphatic development. We show that platelets, but not platelet releasate, modulate the migration and intercellular adhesion of lymphatic endothelial cells through a pathway that depends on CLEC-2 and Syk. These studies found that megakaryocyte/platelet expression of CLEC-2 and Syk is required for normal brain vasculature and lymphatic development and that platelet CLEC-2 and Syk directly modulate lymphatic endothelial cell behavior in vitro.
Rapid effects of extrafine beclomethasone dipropionate/formoterol fixed combination inhaler on airway inflammation and bronchoconstriction in asthma: a randomised controlled trial
Authors: O'Connor Brian J , Collarini Sara , Poli Gianluigi , Brindicci Caterina , Spinola Monica , Acerbi Daniela , Barnes Peter J , Leaker Brian 
Published: December 2011

Abstract

Background
The dose-dependent anti-inflammatory effects of a recent fixed combination of extrafine beclomethasone dipropionate/formoterol (BDP/F) were investigated using non-invasive markers of inflammation, exhaled nitric oxide (NO) and adenosine monophosphate (AMP) provocative challenge. The aim was to assess the onset of the anti-inflammatory action of low and high doses and evaluate the suitability of non-invasive assessments to demonstrate dose response.

Methods
Steroid naïve adult out-patients with mild asthma, sensitive to AMP with baseline exhaled NO > 25 parts per billion entered a double-blind, placebo-controlled, 3-way, cross-over study. Patients were randomised to low dose (1 actuation) or high dose (4 actuations) extrafine BDP/F 100/6 μg, or placebo administered twice daily on Days 1 and 2 and once in the morning on Day 3 of each period. Exhaled NO was measured pre-dose on Day 1, then 2 and 4 hours post-administration on Day 3. The AMP challenge was performed 4 hours post-administration on Day 3 and forced expiratory volume in 1 second (FEV1, L) was measured from 0 to 4 hours post-dose on Day 1. Endpoints were NO at 2 and 4 hours, AMP challenge at 4 hours after the fifth dose on Day 3 and FEV1 area under the curve from 0 to 4 h post-dose on Day 1. Analysis of covariance was performed for NO and FEV1 and analysis of variance for AMP challenge.

Results
Eighteen patients were randomised and completed the study. Exhaled NO was significantly lower for both doses of extrafine BDP/F versus placebo at 2 and 4 hours (high dose LS mean difference: -22.5 ppb, p < 0.0001 and -20.5 ppb, p < 0.0001; low dose: -14.1 ppb, p = 0.0006 and -12.1 ppb, p = 0.0043) with a significant dose response (p = 0.0342 and p = 0.0423). Likewise, AMP challenge revealed statistically significant differences between both doses of extrafine BDP/F and placebo (high dose LS mean difference: 4.8 mg/mL, p < 0.0001; low dose: 3.7 mg/mL, p < 0.0001), and a significant dose response (p = 0.0185). FEV1 was significantly improved versus placebo for both doses (high dose LS mean difference: 0.2 L, p = 0.0001; low dose: 0.2 L p = 0.0001), but without a significant dose response.

Conclusions
The fixed combination inhaler of extrafine BDP/F has early dose-dependent anti-inflammatory effects with a rapid onset of bronchodilatation in mild asthmatic patients.

Trial Registration
ClinicalTrials.gov: NCT01343745
Video-assisted thoracoscopic surgery is more favorable than thoracotomy for administration of adjuvant chemotherapy after lobectomy for non-small cell lung cancer
Authors: Jiang Guanchao , Yang Fan , Li Xiao , Liu Jun , Li Jianfeng , Zhao Hui , Li Yun , Wang Jun 
Published: December 2011

Abstract

Background
Video-assisted thoracoscopic surgery (VATS) lobectomy is a newly developed type of surgery for lung cancer and has been demonstrated obvious minimally-invasive advantages compared with traditional thoracotomy. Theoretically, that less trauma leads to quicker recovery and may facilitate administration of adjuvant chemotherapy. We tested this hypothesis in this study.

Methods
One hundred and ten NSCLC patients underwent lobectomy and adjuvant chemotherapy from June 2004 to June 2010 was analyzed. The baseline characteristic criteria, variables related to surgery and accomplishing status of chemotherapy were analyzed.

Results
All 110 patients underwent lobectomy through VATS (n = 54) or thracotomy (n = 56) and adjuvant chemotherapy. There was no significant difference in patients' age, preoperative pulmonary function, co-morbidity, pathologic staging between the two groups, whereas, blood loss, operation time and postoperative complications, chest tube duration and length of stay were less in VATS group. There were no significant differences in time to initiation chemotherapy. Cases in VATS group received more cycles of chemotherapy (3.6 vs. 3.0, p = 0.002). A higher proportion of patients received full dose on schedule in VATS group (57.4% vs. 33.9%, p = 0.013) and a higher proportion of patients completed ≥75% planed dose, (88.9% vs. 71.4%, p = 0.022); slightly higher proportion of patients in thoracotomy group had grade 3 or more toxicity (20.4% vs. 35.7%, p = 0.074).

Conclusions
Patients underwent lobectomy by VATS have better compliance and fewer delayed or reduced dose on adjuvant chemotherapy than those by thoracotomy.
High dose intermittent sorafenib shows improved efficacy over conventional continuous dose in renal cell carcinoma
Authors: Wang Xiaoen , Zhang Liang , Goldberg S Nahum , Bhasin Manoj , Brown Victoria , Alsop David C , Signoretti Sabina , Mier James W , Atkins Michael B , Bhatt Rupal S 
Published: December 2011

Abstract

Background
Renal cell carcinoma (RCC) responds to agents that inhibit vascular endothelial growth factor (VEGF) pathway. Sorafenib, a multikinase inhibitor of VEGF receptor, is effective at producing tumor responses and delaying median progression free survival in patients with cytokine refractory RCC. However, resistance to therapy develops at a median of 5 months. In an effort to increase efficacy, we studied the effects of increased sorafenib dose and intermittent scheduling in a murine RCC xenograft model.

Methods
Mice bearing xenografts derived from the 786-O RCC cell line were treated with sorafenib according to multiple doses and schedules: 1) Conventional dose (CD) continuous therapy; 2) high dose (HD) intermittent therapy, 3) CD intermittent therapy and 4) HD continuous therapy. Tumor diameter was measured daily. Microvessel density was assessed after 3 days to determine the early effects of therapy, and tumor perfusion was assessed serially by arterial spin labeled (ASL) MRI at day 0, 3, 7 and 10.

Results
Tumors that were treated with HD sorafenib exhibited slowed tumor growth as compared to CD using either schedule. HD intermittent therapy was superior to CD continous therapy, even though the total dose of sorafenib was essentially equivalent, and not significantly different than HD continuous therapy. The tumors exposed to HD sorafenib had lower microvessel density than the untreated or the CD groups. ASL MRI showed that tumor perfusion was reduced to a greater extent with the HD sorafenib at day 3 and at all time points thereafter relative to CD therapy. Further the intermittent schedule appeared to maintain RCC sensitivity to sorafenib as determined by changes in tumor perfusion.

Conclusions
A modification of the sorafenib dosing schedule involving higher dose intermittent treatment appeared to improve its efficacy in this xenograft model relative to conventional dosing. MRI perfusion imaging and histologic analysis suggest that this benefit is related to enhanced and protracted antiangiogenic activity. Thus, better understanding of dosing and schedule issues may lead to improved therapeutic effectiveness of VEGF directed therapy in RCC and possibly other tumors.
Modulation of spinal cord synaptic activity by tumor necrosis factor α in a model of peripheral neuropathy
Authors: Spicarova Diana , Nerandzic Vladimir , Palecek Jiri 
Published: December 2011

Abstract

Background
The cytokine tumor necrosis factor α (TNFα) is an established pain modulator in both the peripheral and central nervous systems. Modulation of nociceptive synaptic transmission in the spinal cord dorsal horn (DH) is thought to be involved in the development and maintenance of several pathological pain states. Increased levels of TNFα and its receptors (TNFR) in dorsal root ganglion (DRG) cells and in the spinal cord DH have been shown to play an essential role in neuropathic pain processing. In the present experiments the effect of TNFα incubation on modulation of primary afferent synaptic activity was investigated in a model of peripheral neuropathy.

Methods
Spontaneous and miniature excitatory postsynaptic currents (sEPSC and mEPSCs) were recorded in superficial DH neurons in acute spinal cord slices prepared from animals 5 days after sciatic nerve transection and in controls.

Results
In slices after axotomy the sEPSC frequency was 2.8 ± 0.8 Hz, while neurons recorded from slices after TNFα incubation had significantly higher sEPSC frequency (7.9 ± 2.2 Hz). The effect of TNFα treatment was smaller in the slices from the control animals, where sEPSC frequency was 1.2 ± 0.2 Hz in slices without and 2.0 ± 0.5 Hz with TNFα incubation. Tetrodotoxin (TTX) application in slices from axotomized animals and after TNFα incubation decreased the mEPSC frequency to only 37.4 ± 6.9% of the sEPSC frequency. This decrease was significantly higher than in the slices without the TNFα treatment (64.4 ± 6.4%). TTX application in the control slices reduced the sEPSC frequency to about 80% in both TNFα untreated and treated slices. Application of low concentration TRPV1 receptors endogenous agonist N-oleoyldopamine (OLDA, 0.2 μM) in slices after axotomy induced a significant increase in mEPSC frequency (175.9 ± 17.3%), similar to the group with TNFα pretreatment (158.1 ± 19.5%).

Conclusions
Our results indicate that TNFα may enhance spontaneous transmitter release from primary afferent fibres in the spinal cord DH by modulation of TTX-sensitive sodium channels following sciatic nerve transection. This nerve injury also leads to enhanced sensitivity of presynaptic TRPV1 receptors to endogenous agonist. Modulation of presynaptic receptor activity on primary sensory terminals by TNFα may play an important role in neuropathic pain development.