bluuebunny/crossref_metadata_2025_split huggingface dataset:
Methodological considerations for a chronic neural interface with the cuneate nucleus of macaques
Authors: Suresh Aneesha K. , Winberry Jeremy E. , Versteeg Christopher , Chowdhury Raeed , Tomlinson Tucker , Rosenow Joshua M. , Miller Lee E. , Bensmaia Sliman J. 
Published: September 2017

While the response properties of neurons in the somatosensory nerves and anterior parietal cortex have been extensively studied, little is known about the encoding of tactile and proprioceptive information in the cuneate nucleus (CN) or external cuneate nucleus (ECN), the first recipients of upper limb somatosensory afferent signals. The major challenge in characterizing neural coding in CN/ECN has been to record from these tiny, difficult-to-access brain stem structures. Most previous investigations of CN response properties have been carried out in decerebrate or anesthetized animals, thereby eliminating the well-documented top-down signals from cortex, which likely exert a strong influence on CN responses. Seeking to fill this gap in our understanding of somatosensory processing, we describe an approach to chronically implanting arrays of electrodes in the upper limb representation in the brain stem in primates. First, we describe the topography of CN/ECN in rhesus macaques, including its somatotopic organization and the layout of its submodalities (touch and proprioception). Second, we describe the design of electrode arrays and the implantation strategy to obtain stable recordings. Third, we show sample responses of CN/ECN neurons in brain stem obtained from awake, behaving monkeys. With this method, we are in a position to characterize, for the first time, somatosensory representations in CN and ECN of primates. NEW & NOTEWORTHY In primates, the neural basis of touch and of our sense of limb posture and movements has been studied in the peripheral nerves and in somatosensory cortex, but coding in the cuneate and external cuneate nuclei, the first processing stage for these signals in the central nervous system, remains an enigma. We have developed a method to record from these nuclei, thereby paving the way to studying how sensory information from the limb is encoded there.
Surface electrodes record and label brain neurons in insects
Authors: Kostarakos Konstantinos , Hedwig Berthold 
Published: September 2017

We used suction electrodes to reliably record the activity of identified ascending auditory interneurons from the anterior surface of the brain in crickets. Electrodes were gently attached to the sheath covering the projection area of the ascending interneurons and the ringlike auditory neuropil in the protocerebrum. The specificity and selectivity of the recordings were determined by the precise electrode location, which could easily be changed without causing damage to the tissue. Different nonauditory fibers were recorded at other spots of the brain surface; stable recordings lasted for several hours. The same electrodes were used to deliver fluorescent tracers into the nervous system by means of electrophoresis. This allowed us to retrograde label the recorded auditory neurons and to reveal their cell body and dendritic structure in the first thoracic ganglion. By adjusting the amount of dye injected, we specifically stained the ringlike auditory neuropil in the brain, demonstrating the clusters of cell bodies contributing to it. Our data provide a proof that surface electrodes are a versatile tool to analyze neural processing in small brains of invertebrates. NEW & NOTEWORTHY We show that surface suction electrodes can be used to monitor the activity of auditory neurons in the cricket brain. They also allow delivering electrophoretically a fluorescent tracer to label the structure of the recorded neurons and the local neuropil to which the electrode was attached. This new extracellular recording and labeling technique is a versatile and useful method to explore neural processing in invertebrate sensory and motor systems.
The superior colliculus and the steering of saccades toward a moving visual target
Authors: Goffart Laurent , Cecala Aaron L. , Gandhi Neeraj J. 
Published: September 2017

Following the suggestion that a command encoding current target location feeds the oculomotor system during interceptive saccades, we tested the involvement of the deep superior colliculus (dSC). Extracellular activity of 52 saccade-related neurons was recorded in three monkeys while they generated saccades to targets that were static or moving along the preferred axis, away from (outward) or toward (inward) a fixated target with a constant speed (20°/s). Vertical and horizontal motions were tested when possible. Movement field (MF) parameters (boundaries, preferred vector, and firing rate) were estimated after spline fitting of the relation between the average firing rate during the motor burst and saccade amplitude. During radial target motions, the inner MF boundary shifted in the motion direction for some, but not all, neurons. Likewise, for some neurons, the lower boundaries were shifted upward during upward motions and the upper boundaries downward during downward motions. No consistent change was observed during horizontal motions. For some neurons, the preferred vectors were also shifted in the motion direction for outward, upward, and “toward the midline” target motions. The shifts of boundary and preferred vector were not correlated. The burst firing rate was consistently reduced during interceptive saccades. Our study demonstrates an involvement of dSC neurons in steering the interceptive saccade. When observed, the shifts of boundary in the direction of target motion correspond to commands related to past target locations. The absence of shift in the opposite direction implies that dSC activity does not issue predictive commands related to future target location. NEW & NOTEWORTHY The deep superior colliculus is involved in steering the saccade toward the current location of a moving target. During interceptive saccades, the active population consists of a continuum of cells ranging from neurons issuing commands related to past locations of the target to neurons issuing commands related to its current location. The motor burst of collicular neurons does not contain commands related to the future location of a moving target.
Antagonism of EG-VEGF Receptors as Targeted Therapy for Choriocarcinoma Progression In Vitro and In Vivo
Authors: Traboulsi Wael , Sergent Frédéric , Boufettal Houssine , Brouillet Sophie , Slim Rima , Hoffmann Pascale , Benlahfid Mohammed , Zhou Qun Y. , Balboni Gianfranco , Onnis Valentina , Bolze Pierre A. , Salomon Aude , Sauthier Philippe , Mallet François , Aboussaouira Touria , Feige Jean J. , Benharouga Mohamed , Alfaidy Nadia 
Published: September 2017

Abstract
Purpose: Choriocarcinoma (CC) is the most malignant gestational trophoblastic disease that often develops from complete hydatidiform moles (CHM). Neither the mechanism of CC development nor its progression is yet characterized. We recently identified endocrine gland–derived vascular endothelial growth factor (EG-VEGF) as a novel key placental growth factor that controls trophoblast proliferation and invasion. EG-VEGF acts via two receptors, PROKR1 and PROKR2. Here, we demonstrate that EG-VEGF receptors can be targeted for CC therapy.
Experimental Design: Three approaches were used: (i) a clinical investigation comparing circulating EG-VEGF in control (n = 20) and in distinctive CHM (n = 38) and CC (n = 9) cohorts, (ii) an in vitro study investigating EG-VEGF effects on the CC cell line JEG3, and (iii) an in vivo study including the development of a novel CC mouse model, through a direct injection of JEG3-luciferase into the placenta of gravid SCID-mice.
Results: Both placental and circulating EG-VEGF levels were increased in CHM and CC (×5) patients. EG-VEGF increased JEG3 proliferation, migration, and invasion in two-dimensional (2D) and three-dimensional (3D) culture systems. JEG3 injection in the placenta caused CC development with large metastases compared with their injection into the uterine horn. Treatment of the animal model with EG-VEGF receptor's antagonists significantly reduced tumor development and progression and preserved pregnancy. Antibody-array and immunohistological analyses further deciphered the mechanism of the antagonist's actions.
Conclusions: Our work describes a novel preclinical animal model of CC and presents evidence that EG-VEGF receptors can be targeted for CC therapy. This may provide safe and less toxic therapeutic options compared with the currently used multi-agent chemotherapies. Clin Cancer Res; 23(22); 7130–40. ©2017 AACR.
Targeting Prostate Cancer Subtype 1 by Forkhead Box M1 Pathway Inhibition
Authors: Ketola Kirsi , Munuganti Ravi S.N. , Davies Alastair , Nip Ka Mun , Bishop Jennifer L. , Zoubeidi Amina 
Published: September 2017

Abstract
Purpose: Prostate cancer was recently classified to three clinically relevant subtypes (PCS) demarcated by unique pathway activation and clinical aggressiveness. In this preclinical study, we investigated molecular targets and therapeutics for PCS1, the most aggressive and lethal subtype, with no treatment options available in the clinic.
Experimental Design: We utilized the PCS1 gene set and our model of enzalutamide (ENZR) castration-resistant prostate cancer (CRPC) to identify targetable pathways and inhibitors for PCS1. The findings were evaluated in vitro and in the ENZR CRPC xenograft model in vivo.
Results: The results revealed that ENZR CRPC cells are enriched with PCS1 signature and that Forkhead box M1 (FOXM1) pathway is the central driver of this subtype. Notably, we identified Monensin as a novel FOXM1-binding agent that selectively targets FOXM1 to reverse the PCS1 signature and its associated stem-like features and reduces the growth of ENZR CRPC cells and xenograft tumors.
Conclusions: Our preclinical data indicate FOXM1 pathway as a master regulator of PCS1 tumors, namely in ENZR CRPC, and targeting FOXM1 reduces cell growth and stemness in ENZR CRPC in vitro and in vivo. These preclinical results may guide clinical evaluation of targeting FOXM1 to eradicate highly aggressive and lethal PCS1 prostate cancer tumors. Clin Cancer Res; 23(22); 6923–33. ©2017 AACR.
Matrix Screen Identifies Synergistic Combination of PARP Inhibitors and Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors in Ewing Sarcoma
Authors: Heske Christine M. , Davis Mindy I. , Baumgart Joshua T. , Wilson Kelli , Gormally Michael V. , Chen Lu , Zhang Xiaohu , Ceribelli Michele , Duveau Damien Y. , Guha Rajarshi , Ferrer Marc , Arnaldez Fernanda I. , Ji Jiuping , Tran Huong-Lan , Zhang Yiping , Mendoza Arnulfo , Helman Lee J. , Thomas Craig J. 
Published: September 2017

Abstract
Purpose: Although many cancers are showing remarkable responses to targeted therapies, pediatric sarcomas, including Ewing sarcoma, remain recalcitrant. To broaden the therapeutic landscape, we explored the in vitro response of Ewing sarcoma cell lines against a large collection of investigational and approved drugs to identify candidate combinations.
Experimental Design: Drugs displaying activity as single agents were evaluated in combinatorial (matrix) format to identify highly active, synergistic drug combinations, and combinations were subsequently validated in multiple cell lines using various agents from each class. Comprehensive metabolomic and proteomic profiling was performed to better understand the mechanism underlying the synergy. Xenograft experiments were performed to determine efficacy and in vivo mechanism.
Results: Several promising candidates emerged, including the combination of small-molecule PARP and nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, a rational combination as NAMPTis block the rate-limiting enzyme in the production of nicotinamide adenine dinucleotide (NAD+), a necessary substrate of PARP. Mechanistic drivers of the synergistic cell killing phenotype of these combined drugs included depletion of NMN and NAD+, diminished PAR activity, increased DNA damage, and apoptosis. Combination PARPis and NAMPTis in vivo resulted in tumor regression, delayed disease progression, and increased survival.
Conclusions: These studies highlight the potential of these drugs as a possible therapeutic option in treating patients with Ewing sarcoma. Clin Cancer Res; 23(23); 7301–11. ©2017 AACR.
Circulating Cell-free DNA for Metastatic Cervical Cancer Detection, Genotyping, and Monitoring
Authors: Kang Zhigang , Stevanović Sanja , Hinrichs Christian S. , Cao Liang 
Published: September 2017

Abstract
Purpose: Circulating cell-free (ccf) human papillomavirus (HPV) DNA may serve as a unique tumor marker for HPV-associated malignancies, including cervical cancer. We developed a method to genotype and quantify circulating HPV DNA in patients with HPV16- or HPV18-positive metastatic cervical cancer for potential disease monitoring and treatment-related decision making.
Experimental Design: In this retrospective study, HPV ccfDNA was measured in serum samples from 19 metastatic cervical cancer patients by duplex digital droplet PCR (ddPCR). Nine patients had received tumor-infiltrating lymphocyte (TIL) immunotherapy. ccfDNA data were aligned with the tumor HPV genotype, drug treatment, and clinical outcome.
Results: In blinded tests, HPV ccfDNA was detected in 19 of 19 (100%) patients with HPV-positive metastatic cervical cancer but not in any of the 45 healthy blood donors. The HPV genotype harbored in the patients' tumors was correctly identified in 87 of 87 (100%) sequential patient serum samples from 9 patients who received TIL immunotherapy. In three patients who experienced objective cancer regression after TIL treatment, a transient HPV ccfDNA peak was detected 2–3 days after TIL infusion. Furthermore, persistent clearance of HPV ccfDNA was only observed in two patients who experienced complete response (CR) after TIL immunotherapy.
Conclusions: HPV ccfDNA represents a promising tumor marker for noninvasive HPV genotyping and may be used in selecting patients for HPV type–specific T-cell-based immunotherapies. It may also have value in detecting antitumor activity of therapeutic agents and in the long-term follow-up of cervical cancer patients in remission. Clin Cancer Res; 23(22); 6856–62. ©2017 AACR.
Heart Failure–Related Hyperphosphorylation in the Cardiac Troponin I C Terminus Has Divergent Effects on Cardiac Function In Vivo
Authors: Li Yuejin , Zhu Guangshuo , Paolocci Nazareno , Zhang Pingbo , Takahashi Cyrus , Okumus Nazli , Heravi Amir , Keceli Gizem , Ramirez-Correa Genaro , Kass David A. , Murphy Anne M. 
Published: September 2017

Background:
In human heart failure, Ser199 (equivalent to Ser200 in mouse) of cTnI (cardiac troponin I) is significantly hyperphosphorylated, and in vitro studies suggest that it enhances myofilament calcium sensitivity and alters calpain-mediated cTnI proteolysis. However, how its hyperphosphorylation affects cardiac function in vivo remains unknown.

Methods and Results:
To address the question, 2 transgenic mouse models were generated: a phospho-mimetic cTnIS200D and a phospho-silenced cTnIS200A, each driven by the cardiomyocyte-specific α-myosin heavy chain promoter. Cardiac structure assessed by echocardiography and histology was normal in both transgenic models compared with littermate controls (n=5). Baseline in vivo hemodynamics and isolated muscle studies showed that cTnIS200D significantly prolonged relaxation and lowered left ventricular peak filling rate, whereas ejection fraction and force development were normal (n=5). However, with increased heart rate or β-adrenergic stimulation, cTnIS200D mice had less enhanced ejection fraction or force development versus controls, whereas relaxation improved similarly to controls (n=5). By contrast, cTnIS200A was functionally normal both at baseline and under the physiological stresses. To test whether either mutation impacted cardiac response to ischemic stress, isolated hearts were subjected to ischemia/reperfusion. cTnIS200D were protected, recovering 88±8% of contractile function versus 35±15% in littermate controls and 28±8% in cTnIS200A (n=5). This was associated with less cTnI proteolysis in cTnIS200D hearts.

Conclusions:
Hyperphosphorylation of this serine in cTnI C terminus impacts heart function by depressing diastolic function at baseline and limiting systolic reserve under physiological stresses. However, paradoxically, it preserves heart function after ischemia/reperfusion injury, potentially by decreasing proteolysis of cTnI.
Impact of Worsened Metabolic Syndrome on the Risk of Dementia: A Nationwide Cohort Study
Authors: Fan Yen‐Chun , Chou Chia‐Chi , You San‐Lin , Sun Chien‐An , Chen Chien‐Jen , Bai Chyi‐Huey 
Published: September 2017

Background
The relationship of alteration of metabolic syndrome (MetS) with dementia remains unclear. The purpose of study was to evaluate the association between dynamic change in MetS status around a 5‐year period and dementia.

Methods and Results

The cohort study was conducted from the Taiwanese Survey on Prevalence of Hypertension, Hyperglycemia, and Hyperlipidemia in 2002, with follow‐up in 2007. The sample was subsequently linked to the National Health Insurance Research Database. Participants were divided into 3 groups: persistent MetS (MetS both in 2002 and 2007); nonpersistent MetS (MetS either in 2002 or 2007); and non‐MetS (MetS neither in 2002 nor 2007). Furthermore, the individuals with nonpersistent MetS were categorized as improved MetS (MetS in 2002 but not in 2007) and worsened MetS (MetS not in 2002 but in 2007). Each participant was tracked until the end of 2011 to identify the development of dementia. In total, 3458 participants aged 40 to 80 years were included. Up to 10 years and 31 741 person‐years of follow‐up, 76 patients developed dementia. Only a relationship was found between the nonpersistent MetS and dementia (adjusted hazard ratio=1.93; 95% confidence interval =1.17–3.19;
P
=0.010). Moreover, a significantly higher dementia risk was observed in patients with worsened MetS (adjusted
hazard ratio
=2.22; 95%
confidence interval
=1.32–3.72;
P
=0.003), but not those with persistent (
P
=0.752) or improved (
P
=0.829) MetS. Similar results were detected in participants aged ≥65 years.

Conclusions
Patients with worsened MetS had an increased dementia risk during the 10‐year follow‐up period in a population‐based sample.
Rural–urban differences in accessing mental health treatment in patients with psychosis
Authors: Thirthalli Jagadisha , Reddy K Shanivaram , Kare Manoranjitha , Das Soumitra , Gangadhar BN 
Published: September 2017

Background: Delay in accessing psychiatric treatment has considerable influence on the outcome of psychoses. Systematic studies examining the source of the delay are lacking in India. In this article, we examine rural–urban differences regarding delay in accessing psychiatric care in patients with psychosis, an issue which was hitherto not studied. Aims: To evaluate the rural–urban differences in treatment seeking among patients with psychosis. Methods: Patients with psychotic disorders who presented to the outpatient department of an academic psychiatric institute for the first time ( n = 551) were interviewed using a semi-structured interview tool to assess the date of onset of illness. Results: Families in urban areas had significantly higher level of education and greater income than their rural counterparts. However, there was no difference in urban and rural patients in the duration of untreated illness (DUI). There was no correlation between average years of education of the family members and DUI (spearman’s rho = −0.01; p = .77). Conclusions: Despite the proximity to psychiatric centers, better education and greater income, patients in urban areas do not access psychiatric care earlier than patients in rural areas. So, mere presence of services would not make patients access them early.
Traditional manual acupuncture combined with rehabilitation therapy for shoulder hand syndrome after stroke within the Chinese healthcare system: a systematic review and meta-analysis
Authors: Peng Le , Zhang Chao , Zhou Lan , Zuo Hong-Xia , He Xiao-Kuo , Niu Yu-Ming 
Published: September 2017

Objective: To investigate the effectiveness of traditional manual acupuncture combined with rehabilitation therapy versus rehabilitation therapy alone for shoulder hand syndrome after stroke. Data sources: PubMed, EMBASE, the Cochrane Library, Chinese Biomedicine Database, China National Knowledge Infrastructure, VIP Information Database, Wan Fang Database and reference lists of the eligible studies were searched up to July 2017 for relevant studies. Methods: Randomized controlled trials that compared the combined effects of traditional manual acupuncture and rehabilitation therapy to rehabilitation therapy alone for shoulder hand syndrome after stroke were included. Two reviewers independently screened the searched records, extracted the data and assessed risk of bias of the included studies. The treatment effect sizes were pooled in a meta-analysis using RevMan 5.3 software. Results: A total of 20 studies involving 1918 participants were included in this study. Compared to rehabilitation therapy alone, the combined therapy significantly reduced pain on the visual analogue scale and improved limb movement on the Fugl–Meyer Assessment scale and the performance of activities of daily living (ADL) on the Barthel Index scale or Modified Barthel Index scale. Of these, the visual analogue scale score changes were significantly higher (mean difference = 1.49, 95% confidence interval = 1.15–1.82, P < 0.00001) favoring the combined therapy after treatment, with severe heterogeneity ( I2 = 71%, P = 0.0005). Conclusion: Current evidence suggests that traditional manual acupuncture integrated with rehabilitation therapy is more effective in alleviating pain, improving limb movement and ADL. However, considering the relatively low quality of available evidence, further rigorously designed and large-scale randomized controlled trials are needed to confirm the results.
Falls in people with multiple sclerosis: experiences of 115 fall situations
Authors: Carling Anna , Forsberg Anette , Nilsagård Ylva 
Published: September 2017

Objectives: The aim was to describe falls and the perceived causes, experienced by people with multiple sclerosis shortly after falling. Design: A qualitative study using content analysis and quantitative data to illustrate where and why people report falls most commonly. Semi-structured telephone interviews were performed. Interviews were conducted shortly (0–10 days) after a fall. Subjects: In all, 67 informants who had reported at least one fall during the previous three-month period and who used a walking aid participated. Results: A total of 57 (85%) informants fell at least once during eight months resulting in 115 falls; 90 (78%) falls happened indoors, most commonly in the kitchen ( n = 20; 17%) or bathroom ( n = 16; 14%). Informants fell during everyday activities and walking aids had been used in more than a third of the reported falls. The falls were influenced of both intrinsic and extrinsic factors. Two categories emerged from the analysis: ‘activities when falling’ and ‘influencing factors’. The category contained three (basic activities of daily living, instrumental activities of daily living and leisure and work) and six (multiple sclerosis–related symptoms, fluctuating body symptoms, being distracted, losing body control, challenging surrounding and involvement of walking aid) subcategories, respectively. Conclusion: The majority of falls occurs indoors and in daily activities. Several factors interacted in fall situations and should be monitored and considered to reduce the gap between the person’s capacity and the environmental demands that cause fall risk. Fluctuation of bodily symptoms between and within a day is a variable not earlier targeted in multiple sclerosis fall risk research.