bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sphingosine 1-phosphate receptor modulation attenuate mechanical allodynia in mouse model of chronic complex regional pain syndrome by suppressing pathogenic astrocyte activation
Authors: Lee Byung Joo , Kim Jun Young , Cho Hyung-jung , Park Donghwi 
Published: January 2020

Background and objectivesFTY720 ((2-amino-2-)2-[4-octylphenyl]ethyl)-1,3-propanediol) is an Food and Drug Administration (FDA)-approved immunomodulatory drug for treating multiple sclerosis. It inhibits lymphocyte egression from lymphoid tissues by downregulating sphingosine-1 phosphate receptor (S1PR). To date, there has been no study on the effects of FTY720 on the chronic stage of the complex regional pain syndrome (CRPS) rodent model, despite its antiallodynic effect in previous studies. Thus, the aim of this study is to investigate the effect of FTY720 in a chronic stage of the CRPS mouse model.MethodThe authors used a mouse model of CRPS, involving tibia fracture/cast immobilization, to test the efficacy of intrathecal FTY720 (2.5 or 25 ng daily; 6 days) or vehicle during the chronic (7 weeks after fracture) stage of CRPS.ResultsIntrathecal recombinant FTY720 administration was antiallodynic in the chronic stage of the CRPS mouse model, and such an effect of FTY720 developed by modulating astrocyte activation in the spinal cord. Additionally, according to the in vitro data, the FTY720 treatment inhibited S1P-induced increase in the nitric oxide production and suppression of the NF-κB pathway, by inhibiting the phosphorylation of NF-κB/p65 in astrocytes without toxic effect on astrocytes.ConclusionCollectively, these results demonstrate that intrathecally administered FTY720 attenuates mechanical allodynia in the chronic stage of the CRPS mouse model.
Tobacco manufacturer lobbying to undercut minimum price laws: an analysis of internal industry documents
Authors: Apollonio Dorie E , Glantz Stanton 
Published: January 2020

BackgroundIncreasing the price of tobacco products has the potential to reduce tobacco consumption. As other forms of promotion have been increasingly restricted over time, tobacco manufacturers have relied more on trade discounts. Minimum price laws that prevented the use of manufacturer promotions were once common; however in most US jurisdictions these discounts are now legally protected.MethodsWe collected tobacco industry documents, state legislation and court cases between 1987 and 2016 to review tobacco manufacturer strategies to change minimum price laws in the USA.ResultsBeginning in 2000, tobacco manufacturers lobbied to amend minimum price legislation after state regulators indicated that manufacturer promotions were illegal under existing laws. Companies viewed changing these laws as critical to maintaining tobacco sales, and after the initiation of an industry lobbying campaign, at least 20 states changed the way they calculated tobacco prices.ConclusionsModifying existing minimum price laws so that manufacturer discounts are no longer protected, and implementing new minimum price policies with comparable scope, would likely increase prices and reduce tobacco use.
BCJ numerators from differential operator of multidimensional residue
Authors: Chen Gang , Wang Tianheng 
Published: January 2020

AbstractIn previous works, we devised a differential operator for evaluating typical integrals appearing in the Cachazo–He–Yuan (CHY) forms and in this paper we further streamline this method. We observe that at tree level, the number of free parameters controlling the differential operator depends solely on the number of external lines, after solving the constraints arising from the scattering equations. This allows us to construct a reduction matrix that relates the parameters of a higher-order differential operator to those of a lower-order one. The reduction matrix is theory-independent and can be obtained by solving a set of explicitly given linear conditions. The repeated application of such reduction matrices eventually transforms a given tree-level CHY-like integral to a prepared form. We also provide analytic expressions for the parameters associated with any such prepared form at tree level. We finally give a compact expression for the multidimensional residue for any CHY-like integral in terms of the reduction matrices. We adopt a dual basis projector which leads to the CHY-like representation for the non-local Bern–Carrasco–Johansson (BCJ) numerators at tree level in Yang–Mills theory. These BCJ numerators are efficiently computed by the improved method involving the reduction matrix.
PIV
Authors: Miri Pardis , Flory Robert , Uusberg Andero , Culbertson Heather , Harvey Richard H. , Kelman Agata , Peper Davis Erik , Gross James J. , Isbister Katherine , Marzullo Keith 
Published: January 2020

We describe the design and evaluation of PIV, a personalizable and inconspicuous vibrotactile breathing pacer. Given the prevalence and adverse impact of anxiety and anxiety disorders, our goal is to develop a technology that helps people regulate their anxiety through paced breathing.
We examined two previously unstudied questions: What is an effective vibrotactile pattern for paced breathing, and where should the tactors be placed on the body to make the pacer most effective? We designed a series of personalized vibrotactile pacing patterns, and evaluated them on three body sites, in terms of self-reported and psychophysiological measures including skin conductance and breath wave parameters.
The results show that personalization plays an important role in PIV’s pattern and placement design choices. We concluded that the choice of frequency based, strong-exhale-phased patterns and abdomen placement are appropriate for future studies.
Self-motion trajectories can facilitate orientation-based figure-ground segregation
Authors: Dutta Arkadeb , Lev-Ari Tidhar , Barzilay Ouriel , Mairon Rotem , Wolf Alon , Ben-Shahar Ohad , Gutfreund Yoram 
Published: January 2020

Segregation of objects from the background is a basic and essential property of the visual system. We studied the neural detection of objects defined by orientation difference from background in barn owls ( Tyto alba). We presented wide-field displays of densely packed stripes with a dominant orientation. Visual objects were created by orienting a circular patch differently from the background. In head-fixed conditions, neurons in both tecto- and thalamofugal visual pathways (optic tectum and visual Wulst) were weakly responsive to these objects in their receptive fields. However, notably, in freely viewing conditions, barn owls occasionally perform peculiar side-to-side head motions (peering) when scanning the environment. In the second part of the study we thus recorded the neural response from head-fixed owls while the visual displays replicated the peering conditions; i.e., the displays (objects and backgrounds) were shifted along trajectories that induced a retinal motion identical to sampled peering motions during viewing of a static object. These conditions induced dramatic neural responses to the objects, in the very same neurons that where unresponsive to the objects in static displays. By reverting to circular motions of the display, we show that the pattern of the neural response is mostly shaped by the orientation of the background relative to motion and not the orientation of the object. Thus our findings provide evidence that peering and/or other self-motions can facilitate orientation-based figure-ground segregation through interaction with inhibition from the surround.NEW & NOTEWORTHY Animals frequently move their sensory organs and thereby create motion cues that can enhance object segregation from background. We address a special example of such active sensing, in barn owls. When scanning the environment, barn owls occasionally perform small-amplitude side-to-side head movements called peering. We show that the visual outcome of such peering movements elicit neural detection of objects that are rotated from the dominant orientation of the background scene and which are otherwise mostly undetected. These results suggest a novel role for self-motions in sensing objects that break the regular orientation of elements in the scene.
Single-unit activity in marmoset posterior parietal cortex in a gap saccade task
Authors: Ma Liya , Selvanayagam Janahan , Ghahremani Maryam , Hayrynen Lauren K. , Johnston Kevin D. , Everling Stefan 
Published: January 2020

Abnormal saccadic eye movements can serve as biomarkers for patients with several neuropsychiatric disorders. The common marmoset ( Callithrix jacchus) is becoming increasingly popular as a nonhuman primate model to investigate the cortical mechanisms of saccadic control. Recently, our group demonstrated that microstimulation in the posterior parietal cortex (PPC) of marmosets elicits contralateral saccades. Here we recorded single-unit activity in the PPC of the same two marmosets using chronic microelectrode arrays while the monkeys performed a saccadic task with gap trials (target onset lagged fixation point offset by 200 ms) interleaved with step trials (fixation point disappeared when the peripheral target appeared). Both marmosets showed a gap effect, shorter saccadic reaction times (SRTs) in gap vs. step trials. On average, stronger gap-period responses across the entire neuronal population preceded shorter SRTs on trials with contralateral targets although this correlation was stronger among the 15% “gap neurons,” which responded significantly during the gap. We also found 39% “target neurons” with significant saccadic target-related responses, which were stronger in gap trials and correlated with the SRTs better than the remaining neurons. Compared with saccades with relatively long SRTs, short-SRT saccades were preceded by both stronger gap-related and target-related responses in all PPC neurons, regardless of whether such response reached significance. Our findings suggest that the PPC in the marmoset contains an area that is involved in the modulation of saccadic preparation.NEW & NOTEWORTHY As a primate model in systems neuroscience, the marmoset is a great complement to the macaque monkey because of its unique advantages. To identify oculomotor networks in the marmoset, we recorded from the marmoset posterior parietal cortex during a saccadic task and found single-unit activities consistent with a role in saccadic modulation. This finding supports the marmoset as a valuable model for studying oculomotor control.
The MEK5–ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer
Authors: Cristea Sandra , Coles Garry L. , Hornburg Daniel , Gershkovitz Maya , Arand Julia , Cao Siqi , Sen Triparna , Williamson Stuart C. , Kim Jun W. , Drainas Alexandros P. , He Andrew , Cam Laurent Le , Byers Lauren Averett , Snyder Michael P. , Contrepois Kévin , Sage Julien 
Published: January 2020

Abstract

Small-cell lung cancer (SCLC) is an aggressive form of lung cancer with dismal survival rates. While kinases often play key roles driving tumorigenesis, there are strikingly few kinases known to promote the development of SCLC. Here, we investigated the contribution of the MAPK module MEK5–ERK5 to SCLC growth. MEK5 and ERK5 were required for optimal survival and expansion of SCLC cell lines in vitro and in vivo. Transcriptomics analyses identified a role for the MEK5–ERK5 axis in the metabolism of SCLC cells, including lipid metabolism. In-depth lipidomics analyses showed that loss of MEK5/ERK5 perturbs several lipid metabolism pathways, including the mevalonate pathway that controls cholesterol synthesis. Notably, depletion of MEK5/ERK5 sensitized SCLC cells to pharmacologic inhibition of the mevalonate pathway by statins. These data identify a new MEK5–ERK5–lipid metabolism axis that promotes the growth of SCLC.

Significance:
This study is the first to investigate MEK5 and ERK5 in SCLC, linking the activity of these two kinases to the control of cell survival and lipid metabolism.
Decitabine and Vorinostat with Chemotherapy in Relapsed Pediatric Acute Lymphoblastic Leukemia: A TACL Pilot Study
Authors: Burke Michael J. , Kostadinov Rumen , Sposto Richard , Gore Lia , Kelley Shannon M. , Rabik Cara , Trepel Jane B. , Lee Min-Jung , Yuno Akira , Lee Sunmin , Bhojwani Deepa , Jeha Sima , Chang Bill H. , Sulis Maria Luisa , Hermiston Michelle L. , Gaynon Paul , Huynh Van , Verma Anupam , Gardner Rebecca , Heym Kenneth M. , Dennis Robyn M. , Ziegler David S. , Laetsch Theodore W. , Oesterheld Javier E. , Dubois Steven G. , Pollard Jessica A. , Glade-Bender Julia , Cooper Todd M. , Kaplan Joel A. , Farooqi Midhat S. , Yoo Byunggil , Guest Erin , Wayne Alan S. , Brown Patrick A. 
Published: January 2020

Abstract

Purpose:
Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of drug resistance is a potential solution.

Patients and Methods:
We report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone, and PEG-asparaginase for pediatric patients with relapsed or refractory B-cell ALL (B-ALL). Twenty-three patients, median age 12 years (range, 1–21) were treated in this trial.

Results:
The most common grade 3–4 toxicities included hypokalemia (65%), anemia (78%), febrile neutropenia (57%), hypophosphatemia (43%), leukopenia (61%), hyperbilirubinemia (39%), thrombocytopenia (87%), neutropenia (91%), and hypocalcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia (n = 1); seizure, somnolence, and delirium (n = 1); and pneumonitis, hypoxia, and hyperbilirubinemia (n = 1). Infectious complications were common with 17 of 23 (74%) subjects experiencing grade ≥3 infections including invasive fungal infections in 35% (8/23). Nine subjects (39%) achieved a complete response (CR + CR without platelet recovery + CR without neutrophil recovery) and five had stable disease (22%). Nine (39%) subjects were not evaluable for response, primarily due to treatment-related toxicities. Correlative pharmacodynamics demonstrated potent in vivo modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects.

Conclusions:
Despite encouraging response rates and pharmacodynamics, the combination of decitabine and vorinostat on this intensive chemotherapy backbone was determined not feasible in B-ALL due to the high incidence of significant infectious toxicities. This study is registered at http://www.clinicaltrials.gov as NCT01483690.
First-in-Human Phase I Study of ABBV-838, an Antibody–Drug Conjugate Targeting SLAMF7/CS1 in Patients with Relapsed and Refractory Multiple Myeloma
Authors: Vij Ravi , Nath Rajneesh , Afar Daniel E.H. , Mateos María-Victoria , Berdeja Jesús G. , Raab Marc S. , Guenther Andreas , Martínez-López Joaquín , Jakubowiak Andrzej J. , Leleu Xavier , Weisel Katja , Wong Shekman , Gulbranson Scott , Sheridan James P. , Reddy Anita , Paiva Bruno , Singhal Anil , San-Miguel Jesús F. , Moreau Philippe 
Published: January 2020

Abstract

Purpose:
ABBV-838 is an antibody–drug conjugate targeting a unique epitope of CD2 subset 1, a cell-surface glycoprotein expressed on multiple myeloma cells. This phase I/Ib first-in-human, dose-escalation study (trial registration ID: NCT02462525) evaluated the safety, pharmacokinetics, and preliminary activity of ABBV-838 in patients with relapsed and refractory multiple myeloma (RRMM).

Patients and Methods:
Eligible patients (≥18 years) received ABBV-838 (3+3 design) intravenously starting from 0.6 mg/kg up to 6.0 mg/kg for 3-week dosing intervals (Q3W). Patients could continue ABBV-838 for up to 24 months. Assessment of alternate dosing intervals (Q1W and Q2W) was conducted in parallel.

Results:
As of March 2017, 75 patients received at least one dose of ABBV-838. The most common any-grade treatment-emergent adverse events (TEAE) were neutropenia and anemia (28.0% each), fatigue (26.7%), and nausea (25.3%). Grade 3/4/5 TEAEs were reported in 73.3% of patients across all treatment groups; most common were neutropenia (20.0%), anemia (18.7%), and leukopenia (13.3%). Grade 3/4/5 ABBV-838–related TEAEs were reported by 40.0% of patients across all treatment groups. Overall, 4.0% of patients experienced TEAEs leading to death, none ABBV-838 related. The MTD was not reached; the selected recommended dose for the expansion cohort was 5.0 mg/kg Q3W. Pharmacokinetic analysis showed that exposure was approximately dose proportional. The overall response rate was 10.7%; very good partial responses and partial responses were achieved by 2 (2.7%) and 6 (8.0%) patients, respectively.

Conclusions:
These results demonstrate that ABBV-838 is safe and well-tolerated in patients with RRMM with a very limited efficacy.
CDKN1B Deletions are Associated with Metastasis in African American Men with Clinically Localized, Surgically Treated Prostate Cancer
Authors: Faisal Farzana A. , Murali Sanjana , Kaur Harsimar , Vidotto Thiago , Guedes Liana B. , Salles Daniela Correia , Kothari Vishal , Tosoian Jeffrey J. , Han Sumin , Hovelson Daniel H. , Hu Kevin , Spratt Daniel E. , Baras Alexander S. , Tomlins Scott A. , Schaeffer Edward M. , Lotan Tamara L. 
Published: January 2020

Abstract

Purpose:
The potential biological determinants of aggressive prostate cancer in African American (AA) men are unknown. Here we characterize prostate cancer genomic alterations in the largest cohort to date of AA men with clinical follow-up for metastasis, with the aim to elucidate the key molecular drivers associated with poor prognosis in this population.

Experimental Design:
Targeted sequencing was retrospectively performed on 205 prostate tumors from AA men treated with radical prostatectomy (RP) to examine somatic genomic alterations and percent of the genome with copy-number alterations (PGA). Cox proportional hazards analyses assessed the association of genomic alterations with risk of metastasis.

Results:
At RP, 71% (145/205) of patients had grade group ≥3 disease, and 49% (99/202) were non–organ confined. The median PGA was 3.7% (IQR = 0.9%–9.4%) and differed by pathologic grade (P &lt; 0.001) and stage (P = 0.02). Median follow-up was 5 years. AA men with the highest quartile of PGA had increased risks of metastasis (multivariable: HR = 13.45; 95% CI, 2.55–70.86; P = 0.002). The most common somatic mutations were SPOP (11.2%), FOXA1 (8.3%), and TP53 (3.9%). The most common loci altered at the copy number level were CDKN1B (6.3%), CHD1 (4.4%), and PTEN (3.4%). TP53 mutations and deep deletions in CDKN1B were associated with increased risks of metastasis on multivariable analyses (TP53: HR = 9.5; 95% CI, 2.2–40.6; P = 0.002; CDKN1B: HR = 6.7; 95% CI, 1.3–35.2; P = 0.026).

Conclusions:
Overall, PGA, somatic TP53 mutations, and a novel finding of deep deletions in CDKN1B were associated with poor prognosis in AA men. These findings require confirmation in additional AA cohorts.
Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial
Authors: Graillon Thomas , Sanson Marc , Campello Chantal , Idbaih Ahmed , Peyre Matthieu , Peyrière Hadrien , Basset Noémie , Autran Didier , Roche Catherine , Kalamarides Michel , Roche Pierre-Hugues , Fuentes Stéphane , Tabouret Emeline , Barrie Maryline , Cohen Anita , Honoré Stéphane , Boucekine Mohamed , Baumstarck Karine , Figarella-Branger Dominique , Barlier Anne , Dufour Henry , Chinot Olivier Louis 
Published: January 2020

Abstract

Purpose:
Aggressive meningiomas that progress after surgery/radiotherapy represent an unmet medical need. Strong and constant expression of SSTR2A receptors and activation of the Pi3K/Akt/mTOR pathway have been demonstrated in meningiomas. The combination of everolimus, an mTOR inhibitor, and octreotide, a somatostatin agonist, has shown additive antitumor effect in vitro. The phase II CEVOREM trial investigated the efficacy of this combination on recurrent meningiomas.

Patients and Methods:
Patients with documented recurrent tumor progression ineligible for further surgery/radiotherapy were eligible to receive octreotide (30 mg/d, day 1) and everolimus (10 mg/d, days 1–28). The primary endpoint was the 6-month progression-free survival rate (PFS6). The secondary endpoints were overall survival, response rate, tumor growth rate according to central review, and safety.

Results:
A total of 20 patients were enrolled, including 2 with World Health Organization (WHO) grade I tumors, 10 with WHO grade II tumors, and 8 with WHO grade III tumors; furthermore, 4 patients harbored NF2 germline mutation. The overall PFS6 was 55% [95% confidence interval (CI), 31.3%–73.5%], and overall 6- and 12-month survival rates were 90% (95% CI, 65.6%–97.4%) and 75% (95% CI, 50.0%–88.7%), respectively. A major decrease (&gt;50%) was observed in the growth rate at 3 months in 78% of tumors. The median tumor growth rate decreased from 16.6%/3 months before inclusion to 0.02%/3 months at 3 months (P &lt; 0.0002) and 0.48%/3 months at 6 months after treatment (P &lt; 0.0003).

Conclusions:
The combination of everolimus and octreotide was associated with clinical and radiological activity in aggressive meningiomas and warrants further studies. Decrease in the tumor volume growth rate should be considered a complementary and sensitive endpoint to select potentially effective drugs for recurrent meningiomas.
Preclinical Activity of JNJ-7957, a Novel BCMA×CD3 Bispecific Antibody for the Treatment of Multiple Myeloma, Is Potentiated by Daratumumab
Authors: Frerichs Kristine A. , Broekmans Marloes E.C. , Marin Soto Jhon A. , van Kessel Berris , Heymans Martijn W. , Holthof Lisa C. , Verkleij Christie P.M. , Boominathan Rengasamy , Vaidya Bhavesh , Sendecki Jocelyn , Axel Amy , Gaudet Francois , Pillarisetti Kodandaram , Zweegman Sonja , Adams Homer C. , Mutis Tuna , van de Donk Niels W.C.J. 
Published: January 2020

Abstract

Purpose:
Multiple myeloma (MM) patients with disease refractory to all available drugs have a poor outcome, indicating the need for new agents with novel mechanisms of action.

Experimental Design:
We evaluated the anti-MM activity of the fully human BCMA×CD3 bispecific antibody JNJ-7957 in cell lines and bone marrow (BM) samples. The impact of several tumor- and host-related factors on sensitivity to JNJ-7957 therapy was also evaluated.

Results:
We show that JNJ-7957 has potent activity against 4 MM cell lines, against tumor cells in 48 of 49 BM samples obtained from MM patients, and in 5 of 6 BM samples obtained from primary plasma cell leukemia patients. JNJ-7957 activity was significantly enhanced in patients with prior daratumumab treatment, which was partially due to enhanced killing capacity of daratumumab-exposed effector cells. BCMA expression did not affect activity of JNJ-7957. High T-cell frequencies and high effector:target ratios were associated with improved JNJ-7957–mediated lysis of MM cells. The PD-1/PD-L1 axis had a modest negative impact on JNJ-7957 activity against tumor cells from daratumumab-naïve MM patients. Soluble BCMA impaired the ability of JNJ-7957 to kill MM cells, although higher concentrations were able to overcome this negative effect.

Conclusions:
JNJ-7957 effectively kills MM cells ex vivo, including those from heavily pretreated MM patients, whereby several components of the immunosuppressive BM microenvironment had only modest effects on its killing capacity. Our findings support the ongoing trial with JNJ-7957 as single agent and provide the preclinical rationale for evaluating JNJ-7957 in combination with daratumumab in MM.