bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pre‐emptive analgesia and its supraspinal mechanisms: enhanced descending inhibition and decreased descending facilitation by dexmedetomidine
Authors: You Hao‐Jun , Lei Jing , Xiao Ying , Ye Gang , Sun Zhi‐Hong , Yang Lan , Niu Nan 
Published: January 2016

Key points
Despite the clinical importance of pre‐emptive analgesia, the mechanisms by which it attenuates pain associated with central sensitization are poorly understood.
We find that fentanyl and the α2‐adrenoceptor agonist dexmedetomidine (Dex) differ significantly in their modulatory actions on noxious mechanical and noxious heat‐evoked nociception in vivo.
Unlike fentanyl, Dex modified descending control of nociception by decreasing the threshold for descending inhibition and/or increasing the threshold for descending facilitation.
Dex exhibited after‐actions on activities of thalamus in prolongation of noxious heat‐evoked paw withdrawal latency that persisted for at least 7 days.
This study provides insight into the organization of thalamic modulation in pre‐emptive analgesia.
AbstractWe investigated and compared the antinociceptive effects of intraperitoneal administration of fentanyl (2–60 μg kg−1) and dexmedetomidine (Dex, 1–10 μg kg−1; a highly selective α2‐adrenoceptor agonist) in the regulation of nociception assessed by measuring noxious paw withdrawal reflexes in rats. Fentanyl elevated noxious mechanical paw withdrawal threshold and prolonged paw withdrawal heat latency within 1–1.5 h (P < 0.05). Dex failed to affect the mechanical paw withdrawal threshold, yet significantly prolonged the paw withdrawal heat latency in a bi‐phasic manner; a short transient 1–1.5 h period followed by a second, slowly developing increase in latency that persisted for at least 7 days (P < 0.05). Lesion of the dorsolateral funiculus (DLF) did not influence fentanyl‐induced antinociceptive effects, indicating peripheral and spinal antinociceptive mechanisms. By contrast, the Dex‐induced second, but not the first, phase of the prolonged paw withdrawal heat latency was significantly blocked by the lesion of either DLF or thalamic ventromedial (VM) nuclei, and was attenuated by intracerebral administration of either atipamezole (α2‐adrenoceptor antagonist) or WAY‐100635 (5‐HT1A receptor antagonist) into the VM nuclei (P < 0.05). Upon intramuscular 5.8% saline‐induced muscle nociception, pre‐emptive injection of fentanyl enhanced mechanical hyperalgesia and blocked heat hypoalgesia, whereas Dex significantly prevented the occurrence of mechanical hyperalgesia and enhanced heat hypoalgesia. It is suggested that Dex, but not fentanyl, significantly enhances descending inhibition and/or decreases descending facilitation to modulate pain and nociception. The present study provides novel insight into thalamus‐mediated mechanisms in pre‐emptive analgesia.
A new bus lane on urban expressway with no-bay bus stop
Authors: Tian Zhao , Jia Limin 
Published: January 2016

The sharp increase in residents and vehicles causes heavy traffic pressure in many cities. To ease traffic congestion, it has been the common sense that we should develop public transit system. The priority of the bus appears particularly necessary with the rapid development of the public transport system. The bus lane is an important embodiment of the bus priority. Focusing on the problem of the unreasonable dedicated bus lane (DBL) under the lower ratio of buses, this paper proposed a new bus lane with limited physical length. And this bus lane can reduce the lane-changing conflict caused by the buses and cars running on roads without bus lanes. Based on the cellular automata (CA) traffic flow model and the lane-changing behavior of the vehicle including the optional lane-changing and the mandatory lane-changing, a three-lane traffic model with an isolated no-bay bus stop is proposed. The ordinary three-lane traffic without a bus lane and the cases of traffic with a DBL or the proposed bus lane are simulated, and the comparisons in the form of the fundamental diagrams are made among them. It is shown that the no-bay bus stop can act as a bottleneck on the traffic flow because of the mandatory lane-changing behavior. Under a certain ratio of the bus number to the total vehicles number, (1) the traffic with the proposed bus lane has less lane-changing conflict and can provide higher traffic capacity than the ordinary traffic without a bus lane, (2) compared with the DBL, the proposed bus lane is advantageous in easing congestion on the ordinary lanes when the traffic flow is high and can avoid unreasonable allocation of the road resources.
The Expression Quantitative Trait Loci in Immune Pathways and their Effect on Cutaneous Melanoma Prognosis
Authors: Vogelsang Matjaz , Martinez Carlos N. , Rendleman Justin , Bapodra Anuj , Malecek Karolina , Romanchuk Artur , Kazlow Esther , Shapiro Richard L. , Berman Russell S. , Krogsgaard Michelle , Osman Iman , Kirchhoff Tomas 
Published: January 2016

AbstractPurpose: The identification of personalized germline markers with biologic relevance for the prediction of cutaneous melanoma prognosis is highly demanded but to date, it has been largely unsuccessful. As melanoma progression is controlled by host immunity, here we present a novel approach interrogating immunoregulatory pathways using the genome-wide maps of expression quantitative trait loci (eQTL) to reveal biologically relevant germline variants modulating cutaneous melanoma outcomes.Experimental Design: Using whole genome eQTL data from a healthy population, we identified 385 variants significantly impacting the expression of 268 immune-relevant genes. The 40 most significant eQTLs were tested in a prospective cohort of 1,221 patients with cutaneous melanoma for their association with overall (OS) and recurrence-free survival using Cox regression models.Results: We identified highly significant associations with better melanoma OS for rs6673928, impacting IL19 expression (HR, 0.56; 95% CI, 0.41–0.77; P = 0.0002) and rs6695772, controlling the expression of BATF3 (HR, 1.64; 95% CI, 1.19–2.24; P = 0.0019). Both associations map in the previously suspected melanoma prognostic locus at 1q32. Furthermore, we show that their combined effect on melanoma OS is substantially enhanced reaching the level of clinical applicability (HR, 1.92; 95% CI, 1.43–2.60; P = 2.38e-5).Conclusions: Our unique approach of interrogating lymphocyte-specific eQTLs reveals novel and biologically relevant immunomodulatory eQTL predictors of cutaneous melanoma prognosis that are independent of current histopathologic markers. The significantly enhanced combined effect of identified eQTLs suggests the personalized utilization of both SNPs in a clinical setting, strongly indicating the promise of the proposed design for the discovery of prognostic or risk germline markers in other cancers. Clin Cancer Res; 22(13); 3268–80. ©2016 AACR.
Strategically Timing Inhibition of Phosphatidylinositol 3-Kinase to Maximize Therapeutic Index in Estrogen Receptor Alpha–Positive, PIK3CA-Mutant Breast Cancer
Authors: Yang Wei , Hosford Sarah R. , Dillon Lloye M. , Shee Kevin , Liu Stephanie C. , Bean Jennifer R. , Salphati Laurent , Pang Jodie , Zhang Xiaolin , Nannini Michelle A. , Demidenko Eugene , Bates Darcy , Lewis Lionel D. , Marotti Jonathan D. , Eastman Alan R. , Miller Todd W. 
Published: January 2016

Abstract
Purpose: Phosphatidylinositol 3-kinase (PI3K) inhibitors are being developed for the treatment of estrogen receptor α (ER)–positive breast cancer in combination with antiestrogens. Understanding the temporal response and pharmacodynamic effects of PI3K inhibition in ER+ breast cancer will provide a rationale for treatment scheduling to maximize therapeutic index.
Experimental Design: Antiestrogen-sensitive and antiestrogen-resistant ER+ human breast cancer cell lines and mice bearing PIK3CA-mutant xenografts were treated with the antiestrogen fulvestrant, the PI3K inhibitor GDC-0941 (pictilisib; varied doses/schedules that provided similar amounts of drug each week), or combinations. Cell viability, signaling pathway inhibition, proliferation, apoptosis, tumor volume, and GDC-0941 concentrations in plasma and tumors were temporally measured.
Results: Treatment with the combination of fulvestrant and GDC-0941, regardless of dose/schedule, was significantly more effective than that with single-agent treatments in fulvestrant-resistant tumors. Short-term, complete PI3K inhibition blocked cell growth in vitro more effectively than chronic, incomplete inhibition. Longer-term PI3K inhibition hypersensitized cells to growth factor signaling upon drug withdrawal. Different schedules of GDC-0941 elicited similar tumor responses. While weekly high-dose GDC-0941 with fulvestrant continuously suppressed PI3K signaling for 72 hours, inducing a bolus of apoptosis and inhibiting proliferation, PI3K reactivation upon GDC-0941 washout induced a proliferative burst. Fulvestrant with daily low-dose GDC-0941 metronomically suppressed PI3K for 6 to 9 hours/day, repeatedly inducing small amounts of apoptosis and temporarily inhibiting proliferation, followed by proliferative rebound compared with fulvestrant alone.
Conclusions: Continuous and metronomic PI3K inhibition elicits robust anticancer effects in ER+, PIK3CA-mutant breast cancer. Clinical exploration of alternate treatment schedules of PI3K inhibitors with antiestrogens is warranted. Clin Cancer Res; 22(9); 2250–60. ©2016 AACR.
See related commentary by Toska and Baselga, p. 2099
Ofatumumab and Lenalidomide for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia: Correlation between Responses and Immune Characteristics
Authors: Vitale Candida , Falchi Lorenzo , ten Hacken Elisa , Gao Hui , Shaim Hila , Van Roosbroeck Katrien , Calin George , O'Brien Susan , Faderl Stefan , Wang Xuemei , Wierda William G. , Rezvani Katayoun , Reuben James M. , Burger Jan A. , Keating Michael J. , Ferrajoli Alessandra 
Published: January 2016

Abstract
Purpose: We evaluated efficacy and tolerability of the combination of ofatumumab and lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), and explored whether immune system characteristics could influence the response to treatment.
Experimental Design: Thirty-four patients were enrolled in this phase II study. Ofatumumab was administered at a dose of 300 mg on day 1, 1,000 mg on days 8, 15, and 22 during course 1, 1,000 mg on day 1 during courses 3–6, and once every other course during courses 7–24 (28-day courses). Oral lenalidomide (10 mg daily) was started on day 9 and continued for as long as a clinical benefit was observed.
Results: The overall response rate was 71%. Eight patients (24%) achieved a complete remission (CR) or CR with incomplete recovery of blood counts, including 9% with minimal residual disease-negative CR. The median progression-free survival was 16 months, and the estimated 5-year survival was 53%. The most common treatment-related toxicity was neutropenia (grade &gt;2 in 18% of the 574 patient courses). The most frequent infectious complications were pneumonia and neutropenic fever (24% and 9% of patients, respectively). We observed that patients who achieved a CR had at baseline higher numbers and a better preserved function of T cells and natural killer cells compared with non-responders.
Conclusions: The combination of ofatumumab and lenalidomide is a well-tolerated regimen that induces durable responses in the majority of patients with relapsed/refractory CLL. Our correlative data suggest a role of competent immune system in supporting the efficacy of this treatment. Clin Cancer Res; 22(10); 2359–67. ©2016 AACR.
Oncogenic BRAF Deletions That Function as Homodimers and Are Sensitive to Inhibition by RAF Dimer Inhibitor LY3009120
Authors: Chen Shih-Hsun , Zhang Youyan , Van Horn Robert D. , Yin Tinggui , Buchanan Sean , Yadav Vipin , Mochalkin Igor , Wong Swee Seong , Yue Yong Gang , Huber Lysiane , Conti Ilaria , Henry James R. , Starling James J. , Plowman Gregory D. , Peng Sheng-Bin 
Published: January 2016

Abstract
We have identified previously undiscovered BRAF in-frame deletions near the αC-helix region of the kinase domain in pancreatic, lung, ovarian, and thyroid cancers. These deletions are mutually exclusive with KRAS mutations and occur in 4.21% of KRAS wild-type pancreatic cancer. siRNA knockdown in cells harboring BRAF deletions showed that the MAPK activity and cell growth are BRAF dependent. Structurally, the BRAF deletions are predicted to shorten the β3/αC-helix loop and hinder its flexibility by locking the helix in the active αC-helix-in conformation that favors dimer formation. Expression of L485-P490–deleted BRAF is able to transform NIH/3T3 cells in a BRAF dimer–dependent manner. BRAF homodimer is confirmed to be the dominant RAF dimer by proximity ligation assays in BRAF deletion cells, which are resistant to the BRAF inhibitor vemurafenib and sensitive to LY3009120, a RAF dimer inhibitor. In tumor models with BRAF deletions, LY3009120 has shown tumor growth regression, whereas vemurafenib is inactive.
Significance: This study discovered oncogenic BRAF deletions with a distinct activation mechanism dependent on the BRAF dimer formation in tumor cells. LY3009120 is active against these cells and represents a potential treatment option for patients with cancer with these BRAF deletions, or other atypical BRAF mutations where BRAF functions as a dimer. Cancer Discov; 6(3); 300–15. ©2016 AACR.
This article is highlighted in the In This Issue feature, p. 217
A systems approach to hemostasis: 4. How hemostatic thrombi limit the loss of plasma-borne molecules from the microvasculature
Authors: Welsh John D. , Muthard Ryan W. , Stalker Timothy J. , Taliaferro Joshua P. , Diamond Scott L. , Brass Lawrence F. 
Published: January 2016

Key Points
Following vessel injury, the extravasation of plasma borne molecules continues long after hemostasis occurs. Limiting molecular extravasation is driven by platelet accumulation and retraction, but not fibrin deposition.
Tympanoplasty—conchal cavum approach
Authors: Man S. Christopher , Nunez Desmond A. 
Published: January 2016

The three well recognized tympanoplasty approaches: permeatal, postaural, and endaural, each have advantages and disadvantages. The permeatal approach is suitable only for ears with adequate canal size. The postaural approach limits visualization of the posterior eardrum margin. The endaural approach limits the view of the eardrum's anterior margin. This study describes a modified endaural approach, developed to overcome these limitations. A retrospective case series review and collection of a prospective cohort of patient reported outcome data were undertaken to assess the technique. Method Standard incisions as used in an endaural approach are placed within the ear canal. The novel incision extends from the superior canal incision into the conchal cavum. This allows a flap of the thick, hairbearing skin from both the bony and cartilaginous portions of the canal to be raised, and everted, to provide an excellent view of the entire drum. Perichondrium can be harvested for grafting from the conchal cavum. The clinical charts of all patients operated on by the first author using this technique from 2010–2012 were retrospectively reviewed. The size and position of the perforation, size of the canal, whether primary or revision surgery, graft take rate, hearing results and the occurrence of chondritis/perichondritis were recorded. To investigate the morbidities and the acceptance by the patients of the incision/scar in the conchal cavum, all patients undergoing the procedure in the 8 months up to the end of August 2013 were prospectively recruited to complete a self-assessment Likert scale questionnaire recording postoperative pain, and satisfaction with the cosmesis of the operative site. The clinician recorded if there was any evidence of chondritis/perichondritis. Results A 100 % graft take rate was achieved in the 75 adults treated by the first author from 2010 to 2012 regardless of the size and position of the perforation, configuration of the canal, primary or revision surgery. Preoperative Pure Tone Audiometric (PTA) Air Bone Gap (ABG) averaged over 3 frequencies (0.5, 1 and 2 K Hz) was 19.4dB (standard deviation = 9.6, range 2 to 50). Postoperative PTA ABG average was 6.2 dB (standard deviation = 8.3, range -7 to 37), demonstrating a statistically significant post-surgery mean improvement of 13.2 dB (paired T-test, p < 0.001). Twenty-one patients who underwent the procedure in 2013, reported minimal postoperative analgesic use, and scored the acceptability of the incision scar highly (4.8 out of a maximum of 5). There was no case of chondritis/perichondritis in the 96 cases. Conclusion Whilst it is the surgeon's decision to use a permeatal, postaural or endaural approach, the endaural approach with the conchal cavum modification is an excellent alternative to the traditionally described approaches. Trial Registration Clinical trial number: NCT02000843 at ClinicalTrials.gov
Complete genome sequence of Methanospirillum hungatei type strain JF1
Authors: Gunsalus Robert P. , Cook Lauren E. , Crable Bryan , Rohlin Lars , McDonald Erin , Mouttaki Housna , Sieber Jessica R. , Poweleit Nicole , Zhou Hong , Lapidus Alla L. , Daligault Hajnalka Erzsebet , Land Miriam , Gilna Paul , Ivanova Natalia , Kyrpides Nikos , Culley David E. , McInerney Michael J. 
Published: January 2016

AbstractMethanospirillum hungatei strain JF1 (DSM 864) is a methane-producing archaeon and is the type species of the genus Methanospirillum, which belongs to the family Methanospirillaceae within the order Methanomicrobiales. Its genome was selected for sequencing due to its ability to utilize hydrogen and carbon dioxide and/or formate as a sole source of energy. Ecologically, M. hungatei functions as the hydrogen- and/or formate-using partner with many species of syntrophic bacteria. Its morphology is distinct from other methanogens with the ability to form long chains of cells (up to 100 μm in length), which are enclosed within a sheath-like structure, and terminal cells with polar flagella. The genome of M. hungatei strain JF1 is the first completely sequenced genome of the family Methanospirillaceae, and it has a circular genome of 3,544,738 bp containing 3,239 protein coding and 68 RNA genes. The large genome of M. hungatei JF1 suggests the presence of unrecognized biochemical/physiological properties that likely extend to the other Methanospirillaceae and include the ability to form the unusual sheath-like structure and to successfully interact with syntrophic bacteria.
Ambient CO2, fish behaviour and altered GABAergic neurotransmission: exploring the mechanism of CO2-altered behaviour by taking a hypercapnia dweller down to low CO2 levels
Authors: Regan Matthew D. , Turko Andy J. , Heras Joseph , Andersen Mads Kuhlmann , Lefevre Sjannie , Wang Tobias , Bayley Mark , Brauner Colin J. , Huong Do Thi Thanh , Phuong Nguyen Thanh , Nilsson Göran E. 
Published: January 2016

ABSTRACT
Recent studies suggest that projected rises of aquatic CO2 levels cause acid–base regulatory responses in fishes that lead to altered GABAergic neurotransmission and disrupted behaviour, threatening fitness and population survival. It is thought that changes in Cl− and HCO3− gradients across neural membranes interfere with the function of GABA-gated anion channels (GABAA receptors). So far, such alterations have been revealed experimentally by exposing species living in low-CO2 environments, like many oceanic habitats, to high levels of CO2 (hypercapnia). To examine the generality of this phenomenon, we set out to study the opposite situation, hypothesizing that fishes living in typically hypercapnic environments also display behavioural alterations if exposed to low CO2 levels. This would indicate that ion regulation in the fish brain is fine-tuned to the prevailing CO2 conditions. We quantified pH regulatory variables and behavioural responses of Pangasianodon hypophthalmus, a fish native to the hypercapnic Mekong River, acclimated to high-CO2 (3.1 kPa) or low-CO2 (0.04 kPa) water. We found that brain and blood pH was actively regulated and that the low-CO2 fish displayed significantly higher activity levels, which were reduced after treatment with gabazine, a GABAA receptor blocker. This indicates an involvement of the GABAA receptor and altered Cl− and HCO3− ion gradients. Indeed, Goldman calculations suggest that low levels of environmental CO2 may cause significant changes in neural ion gradients in P. hypophthalmus. Taken together, the results suggest that brain ion regulation in fishes is fine-tuned to the prevailing ambient CO2 conditions and is prone to disruption if these conditions change.
Make-Take Structure and Market Quality: Evidence from the U.S. Options Markets
Authors: Anand Amber , Hua Jian , McCormick Tim 
Published: January 2016

We examine the make-take structure, which compensates liquidity suppliers and charges liquidity demanders, in the options markets where it competes with a traditional structure that uses payments for order flow. Using the introduction of the make-take structure as an event, we find that execution costs (including fees) for liquidity demanders decline after the event for the affected options, that the make-take structure encourages market makers to improve quoted prices, and that brokers change their routing behavior to include fees in the routing decision. The decline in execution costs is consistent with the benefits of the increased quote competition from the make-take structure prevailing over the fees the structure charges to liquidity demanders. This paper was accepted by Wei Jiang, finance.
Functional organization of human SAMHD1 and mechanisms of HIV-1 restriction
Authors: Ahn Jinwoo 
Published: January 2016

Abstract
Sterile alpha motif and histidine-aspartate domain containing protein 1 (SAMHD1) is a triphosphohydrolase that catalyzes the conversion of deoxyribonucleoside triphosphate to deoxyribonucleoside and triphosphate. SAMHD1 has been a recent focus of study since it was identified as a potent human immunodeficiency virus-1 (HIV-1) restriction factor in the intrinsic antiviral immune system. Recent biochemical and biological studies have suggested that SAMHD1 restricts HIV-1 infection in non-cycling cells by limiting the pool of deoxyribonucleoside triphosphates, thereby interfering with HIV-1 reverse transcription. SAMHD1 also possesses single-stranded DNA and RNA binding activity, with reported nuclease activity, conferring additional HIV-1 restriction function. This review summarizes current knowledge regarding the structure of SAMHD1 and the regulation of its function in HIV-1 restriction.