bluuebunny/crossref_metadata_2025_split huggingface dataset:
CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy
Authors: Aspit Liam , Levitas Aviva , Etzion Sharon , Krymko Hanna , Slanovic Leonel , Zarivach Raz , Etzion Yoram , Parvari Ruti 
Published: December 2018

BackgroundDilated cardiomyopathy (DCM) is a primary myocardial disease leading to contractile dysfunction, progressive heart failure and excessive risk of sudden cardiac death. Around half of DCM cases are idiopathic, and genetic factors seem to play an important role.AimWe investigated a possible genetic cause of DCM in two consanguineous children from a Bedouin family.Methods and resultsUsing exome sequencing and searching for rare homozygous variations, we identified a nucleotide change in the donor splice consensus sequence of exon 7 inCAP2as the causative mutation. Using patient-derived fibroblasts, we demonstrated that the mutation causes skipping of exons 6 and 7. The resulting protein is missing 64 amino acids in its N-CAP domain that should prevent its correct folding.CAP2protein level was markedly reduced without notable compensation by the homolog CAP1. However, β-actin mRNA was elevated as demonstrated by real-time qPCR. In agreement with the essential role of CAP2 in actin filament polymerization, we demonstrate that the mutation affects the kinetics of repolymerization of actin in patient fibroblasts.ConclusionsThis is the first report of a recessive deleterious mutation in CAP2 and its association with DCM in humans. The clinical phenotype recapitulates the damaging effects on the heart observed inCap2knockout mice including DCM and cardiac conduction disease, but not the other effects on growth, viability, wound healing and eye development. Our data underscore the importance of the proper kinetics of actin polymerization for normal function of the human heart.
The Speech Arm Vision Eyes (SAVE) scale predicts large vessel occlusion stroke as well as more complicated scales
Authors: Keenan Kevin J , Smith Wade S 
Published: December 2018

IntroductionThe Speech Arm Vision Eyes (SAVE) scale, a 4-item clinical scale emphasizing binary scoring and avoidance of nuanced examination distinctions, predicts LVOs with similar characteristics as more complex scales.MethodsReceiver operating characteristic analyses of the prospective STOPStroke study assessed the ability of the SAVE scale and other published scales to predict LVO. We identified scale thresholds with positive likelihood ratios with 95% confidence intervals of ≥5.0 or negative likelihood ratios with 95% confidence intervals of ≤0.5.Results735patients were studied. LVO prevalence was 33%. Area under the curve was 0.79 for SAVE, 0.82 for FAST-ED, 0.80 for mNIHSS and NIHSS, and lower for all other scales. SAVE=4, EMSA=6, mNIHSS≥10, NIHSS≥16, and RACE≥8 had positive likelihood ratios with 95% confidence intervals ≥5.0. SAVE≥2, CPSS≥2, C-STAT≥1, EMSA≥4, FAST-ED≥3, G-FAST≥3, mNIHSS≥6, NIHSS≥9, PASS≥1, RACE≥2, VAN=1, and 3I-SS≥1 had negative likelihood ratios with 95% confidence intervals ≤0.5.ConclusionsSAVE=4 performed similarly to more complex scales at predicting LVO. Other simplified scales did not have thresholds with positive likelihood ratios with 95% confidence intervals ≥5.0. Validation is need in a prehospital cohort of patients with suspected stroke.
Use of geosocial networking applications is independently associated with diagnosis of STI among men who have sex with men testing for STIs: findings from the cross-sectional MSM Internet Survey Ireland (MISI) 2015
Authors: O’Connor Lois , O'Donnell Kate , Barrett Peter , Hickson Ford Colin Ian , McCartney Daniel , Quinlan Mick , Barrasa Alicia , Fitzgerald Margaret , Igoe Derval 
Published: December 2018

ObjectivesMSM Internet Survey Ireland (MISI) 2015 was an anonymous, self-completed, cross-sectional internet survey assessing sexual behaviours and health needs among men who have sex with men (MSM) in Ireland. We explored factors associated with self-reported STI diagnosis among MSM who were sexually active and had an STI test in the previous year.MethodsWe compared the study population (n=1158; 37% of total population), with the sexually active MISI population not testing for STIs (n=1620; 52% of total population). Within the study population, we identified sociodemographics and sexual behaviours associated with self-reporting STI diagnosis. We used multivariable logistic regression to estimate adjusted odds ratios (aORs).ResultsThe sociodemographics, lifestyle and sexual behaviours of the study population differed significantly from the sexually active MISI population who did not test for STIs. Within the study population, 65% met a sexual partner via geosocial networking smartphone application (GSNa) and 21% self-reported an STI diagnosis in the previous year. On univariable analysis, factors associated with STI diagnosis included: older age, identifying as gay, HIV-positive status, increasing number of sexual partners in the previous year, condomless anal intercourse (CAI) with ≥2 non-steady partners and using GSNa to meet a new sexual partner in the previous year or most recent sexual partner. On multivariable analysis, STI diagnosis was associated with: being aged 25–39 years (aOR 1.8, 95% CI 1.04 to 3.15), CAI with ≥2 non-steady partners (aOR 2.8, 95% CI 1.84 to 4.34), total number of sexual partners (aOR 1.02, 95% CI 1.00 to 1.03) and using GSNa to meet a new sexual partner (aOR 1.95, 95% CI 1.12 to 3.39).ConclusionsSTI diagnosis among MSM testing for STIs is associated with GSNa use, as well as sexual behaviours. GSNas are key settings for STI prevention interventions, which should prioritise men with high numbers of sexual partners and those with multiple CAI partners.
Results from a cross-sectional sexual and reproductive health study among school girls in Tanzania: high prevalence of bacterial vaginosis
Authors: Francis Suzanna C , Holm Hansen Christian , Irani Julia , Andreasen Aura , Baisley Kathy , Jespers Vicky , Crucitti Tania , Changalucha John , Hayes Richard J , Nnko Soori , Watson-Jones Deborah , Buvé Anne 
Published: December 2018

ObjectivesBacterial vaginosis (BV) increases women’s susceptibility to sexually transmitted infections (STIs) and HIV and may partly explain the high incidence of STI/HIV among girls and young women in East and southern Africa. The objectives of this study were to investigate the association between BV and sexual debut, to investigate other potential risk factors of BV and to estimate associations between BV and STIs.MethodsSecondary school girls in Mwanza, aged 17 and 18 years, were invited to join a cross-sectional study. Consenting participants were interviewed and samples were obtained for STI and BV testing. Factors associated with prevalent BV were analysed using multivariable logistic regression. Y-chromosome was tested as a biomarker for unprotected penile-vaginal sex.ResultsOf the 386 girls who were enrolled, 163 (42%) reported having ever had penile-vaginal sex. Ninety-five (25%) girls had BV. The prevalence of BV was 33% and 19% among girls who reported or did not report having ever had penile-vaginal sex, respectively. BV was weakly associated with having ever had one sex partner (adjusted odds ratio (aOR) 1.59;95% CI 0.93 to 2.71) and strongly associated with two or more partners (aOR = 3.67; 95% CI 1.75 to 7.72), receptive oral sex (aOR 6.38; 95% CI 1.22 to 33.4) and having prevalent human papillomavirus infection (aOR = 1.73; 95% CI 1.02 to 2.95). Of the 223 girls who reported no penile-vaginal sex, 12 (5%) tested positive for an STI and 7 (3%) tested positive for Y-chromosome. Reclassifying these positive participants as having ever had sex did not change the key results.ConclusionsTanzanian girls attending school had a high prevalence of BV. Increasing number of sex partner was associated with BV; however, 19% of girls who reported no penile-vaginal sex had BV. This suggests that penile-vaginal sexual exposure may not be a prerequisite for BV. There was evidence of under-reporting of sexual debut.
Maternal history of miscarriages and measures of fertility in relation to childhood asthma
Authors: Magnus Maria Christine , Karlstad Øystein , Parr Christine Louise , Page Christian M , Nafstad Per , Magnus Per , London Stephanie J , Wilcox Allen J , Nystad Wenche , Håberg Siri Eldevik 
Published: December 2018

BackgroundIt remains unclear what underlies the greater risk of asthma reported among children conceived by assisted reproductive technologies (ART).ObjectiveOur aim was to clarify the role of parental subfertility and unmeasured confounding on the association between ART and childhood asthma, and to examine the possibility for common mechanisms underlying parental subfertility and miscarriages influencing asthma pathogenesis.MethodsWe used data from national Norwegian health registries (n=474 402) and the Norwegian Mother and Child Cohort Study (MoBa) (n=75 797). We used log-linear regression to estimate overall associations, and fixed-effects logistic regression to estimate associations within siblings.ResultsART offspring had greater asthma risk, the adjusted relative risk (aRR) was 1.20 (95% CI 1.09 to 1.32) in the registry-based cohort, and 1.42 (95% CI 1.14 to 1.76) in MoBa. The sibling analysis yielded similar associations, although the CI included the null value. The elevated asthma risk among ART offspring was attenuated when they were compared with spontaneously conceived offspring with time to conception >12 months, aRR 1.22 (95% CI 0.95 to 1.57). Asthma risk also increased with maternal history of early miscarriages (≤12 weeks), with an aRR of 1.07 (95% CI 1.03 to 1.11) for one, aRR 1.18 (95% CI 1.10 to 1.26) for two and aRR 1.24 (95% CI 1.12 to 1.37) for three or more.ConclusionOur findings indicate that both parental subfertility and characteristics related to the ART procedure itself might increase offspring asthma risk, although this needs to be confirmed in future studies, and further suggest that common mechanisms underlying parental subfertility and recurrent miscarriages might influence offspring asthma pathogenesis.
Democratizing Authority in the Built Environment
Authors: Andersen Michael P. , Kolb John , Chen Kaifei , Fierro Gabe , Culler David E. , Katz Randy 
Published: December 2018

Operating systems and applications in the built environment have relied upon central authorization and management mechanisms that restrict their scalability, especially with respect to administrative overhead. We propose a new set of primitives encompassing syndication, security, and service execution that unifies the management of applications and services across the built environment, while enabling participants to individually delegate privilege across multiple administrative domains with no loss of security or manageability. We show how to leverage a decentralized authorization syndication platform to extend the design of building operating systems beyond the single administrative domain of a building. The authorization system leveraged is based on blockchain smart contracts to permit decentralized and democratized delegation of authorization without central trust. Upon this, a publish/subscribe syndication tier and a containerized service execution environment are constructed. Combined, these mechanisms solve problems of delegation, federation, device protection and service execution that arise throughout the built environment. We leverage a high-fidelity city-scale emulation to verify the scalability of the authorization tier, and briefly describe a prototypical democratized operating system for the built environment using this foundation.
This is an extension of work presented in Ref. [3].
Ipsilateral finger representations in the sensorimotor cortex are driven by active movement processes, not passive sensory input
Authors: Berlot Eva , Prichard George , O’Reilly Jill , Ejaz Naveed , Diedrichsen Jörn 
Published: December 2018

Hand and finger movements are mostly controlled through crossed corticospinal projections from the contralateral hemisphere. During unimanual movements, activity in the contralateral hemisphere is increased while the ipsilateral hemisphere is suppressed below resting baseline. Despite this suppression, unimanual movements can be decoded from ipsilateral activity alone. This indicates that ipsilateral activity patterns represent parameters of ongoing movement, but the origin and functional relevance of these representations is unclear. In this study, we asked whether ipsilateral representations are caused by active movement or whether they are driven by sensory input. Participants alternated between performing single finger presses and having fingers passively stimulated while we recorded brain activity using high-field (7T) functional imaging. We contrasted active and passive finger representations in sensorimotor areas of ipsilateral and contralateral hemispheres. Finger representations in the contralateral hemisphere were equally strong under passive and active conditions, highlighting the importance of sensory information in feedback control. In contrast, ipsilateral finger representations in the sensorimotor cortex were stronger during active presses. Furthermore, the spatial distribution of finger representations differed between hemispheres: the contralateral hemisphere showed the strongest finger representations in Brodmann areas 3a and 3b, whereas the ipsilateral hemisphere exhibited stronger representations in premotor and parietal areas. Altogether, our results suggest that finger representations in the two hemispheres have different origins: contralateral representations are driven by both active movement and sensory stimulation, whereas ipsilateral representations are mainly engaged during active movement. NEW & NOTEWORTHY Movements of the human body are mostly controlled by contralateral cortical regions. The function of ipsilateral activity during movements remains elusive. Using high-field neuroimaging, we investigated how human contralateral and ipsilateral hemispheres represent active and passive finger presses. We found that representations in contralateral sensorimotor cortex are equally strong during both conditions. Ipsilateral representations were mostly present during active movement, suggesting that sensorimotor areas do not receive direct sensory input from the ipsilateral hand.
LTD at mossy fiber synapses onto stratum lucidum interneurons requires TrkB and retrograde endocannabinoid signaling
Authors: Pan Enhui , Zhao Zirun , McNamara James O. 
Published: December 2018

Hippocampal mossy fiber axons simultaneously activate CA3 pyramidal cells and stratum lucidum interneurons (SLINs), the latter providing feedforward inhibition to control CA3 pyramidal cell excitability. Filopodial extensions of giant boutons of mossy fibers provide excitatory synaptic input to the SLIN. These filopodia undergo extraordinary structural plasticity causally linked to execution of memory tasks, leading us to seek the mechanisms by which activity regulates these synapses. High-frequency stimulation of the mossy fibers induces long-term depression (LTD) of their calcium-permeable AMPA receptor synapses with SLINs; previous work localized the site of induction to be postsynaptic and the site of expression to be presynaptic. Yet, the underlying signaling events and the identity of the retrograde signal are incompletely understood. We used whole cell recordings of SLINs in hippocampal slices from wild-type and mutant mice to explore the mechanisms. Genetic and pharmacologic perturbations revealed a requirement for both the receptor tyrosine kinase TrkB and its agonist, brain-derived neurotrophic factor (BDNF), for induction of LTD. Inclusion of inhibitors of Trk receptor kinase and PLC in the patch pipette prevented LTD. Endocannabinoid receptor antagonists and genetic deletion of the CB1 receptor prevented LTD. We propose a model whereby release of BDNF from mossy fiber filopodia activates TrkB and PLCγ1 signaling postsynaptically within SLINs, triggering synthesis and release of an endocannabinoid that serves as a retrograde signal, culminating in reduced glutamate release. Insights into the signaling pathways by which activity modifies function of these synapses will facilitate an understanding of their contribution to the local circuit and behavioral consequences of hippocampal granule cell activity.NEW & NOTEWORTHY We investigated signaling mechanisms underlying plasticity of the hippocampal mossy fiber filopodial synapse with interneurons in stratum lucidum. High-frequency stimulation of the mossy fibers induces long-term depression of this synapse. Our findings are consistent with a model in which brain-derived neurotrophic factor released from filopodia activates TrkB of a stratum lucidum interneuron; the ensuing activation of PLCγ1 induces synthesis of an endocannabinoid, which provides a retrograde signal leading to reduced release of glutamate presynaptically.
Autologous Dendritic Cell-Cytokine Induced Killer Cell Immunotherapy Combined with S-1 Plus Cisplatin in Patients with Advanced Gastric Cancer: A Prospective Study
Authors: Qiao Guoliang , Wang Xiaoli , Zhou Lei , Zhou Xinna , Song Yuguang , Wang Shuo , Zhao Lei , Morse Michael A. , Hobeika Amy , Song Jin , Yi Xin , Xia Xuefeng , Ren Jun , Lyerly Herbert Kim 
Published: December 2018

AbstractPurpose:We have assessed the combination of DC–CIK with S-1 plus cisplatin chemotherapy in advanced gastric cancer (AGC) and the role of mutational analysis of circulating tumor DNA (ctDNA) and T-cell receptor (TCR) repertoire in predicting clinical outcomes.Patients and Methods:Consecutive patients (n = 63) with AGC were allocated to treatment with S-1 alone, S-1 plus cisplatin, DC–CIK combined with S-1 or DC–CIK combined with S-1 plus cisplatin. The primary endpoints were progression-free survival (PFS) and overall survival (OS) at 1 year; the secondary endpoints were disease control rate and analysis of ctDNA and TCR repertoire.Results:The DC–CIK infusions were well tolerated with no serious adverse events. The disease control rates (CR+PR+SD) were 5.6%, 33.3%, 47.1%, and 76.9% in the S-1 alone, the S-1 plus cisplatin, DC–CIK combined with S-1 and DC–CIK combined with the S-1 plus cisplatin groups, respectively (P = 0.001). After adjusting for competing risk factors, treatment with DC-CIK combined with S-1 plus cisplatin was confirmed to be an independent predictor of PFS and OS (P = 0.001). A decrease in the frequency and number of mutations in ctDNA was observed in 19 patients (63.3%) following the DC–CIK infusions. Decreased ctDNA mutational frequency and restored TCR repertoire were associated with improved PFS and OS (P = 0.001).Conclusions:DC–CIK combined with S-1 plus cisplatin provided a favorable PFS and OS in patients with AGC and the combination therapy was safe with tolerable toxicities. Clinical efficacy correlated with decreases in ctDNA mutational profiles and restored TCR repertoire.
A Phase II Study of Tumor-infiltrating Lymphocyte Therapy for Human Papillomavirus–associated Epithelial Cancers
Authors: Stevanović Sanja , Helman Sarah R. , Wunderlich John R. , Langhan Michelle M. , Doran Stacey L. , Kwong Mei Li M. , Somerville Robert P.T. , Klebanoff Christopher A. , Kammula Udai S. , Sherry Richard M. , Yang James C. , Rosenberg Steven A. , Hinrichs Christian S. 
Published: December 2018

Abstract

Purpose:
Cellular therapy is an emerging cancer treatment modality, but its application to epithelial cancers has been limited. This clinical trial evaluated tumor-infiltrating lymphocyte (TIL) therapy for the treatment of patients with metastatic human papillomavirus (HPV)-associated carcinomas.

Patients and Methods:
The trial was a phase II design with two cohorts, cervical cancers and noncervical cancers. Cell infusion was preceded by a lymphocyte-depleting conditioning regimen and followed by systemic high-dose aldesleukin.

Results:
Objective tumor responses occurred in 5 of 18 (28%) patients in the cervical cancer cohort and 2 of 11 (18%) patients in the noncervical cancer cohort. Two of the responses in cervical cancer were complete and are ongoing 67 and 53 months after treatment. Responses in the noncervical cancer cohort were in anal cancer and oropharyngeal cancer. The HPV reactivity of the infused T cells correlated with clinical response. Peripheral blood repopulation with HPV-reactive T cells also correlated with clinical response.

Conclusions:
These findings support the concept that cellular therapy can mediate the regression of epithelial cancers, and they suggest the importance of predictive biomarkers and novel treatment platforms for more effective therapies.
Discovery and Characterization of Recurrent, Targetable ALK Fusions in Leiomyosarcoma
Authors: Davis Lara E. , Nusser Kevin D. , Przybyl Joanna , Pittsenbarger Janét , Hofmann Nicolle E. , Varma Sushama , Vennam Sujay , Debiec-Rychter Maria , van de Rijn Matt , Davare Monika A. 
Published: December 2018

Abstract

Soft-tissue sarcomas such as leiomyosarcoma pose a clinical challenge because systemic treatment options show only modest therapeutic benefit. Discovery and validation of targetable vulnerabilities is essential. To discover putative kinase fusions, we analyzed existing transcriptomic data from leiomyosarcoma clinical samples. Potentially oncogenic ALK rearrangements were confirmed by application of multiple RNA-sequencing fusion detection algorithms and FISH. We functionally validated the oncogenic potential and targetability of discovered kinase fusions through biochemical, cell-based (Ba/F3, NIH3T3, and murine smooth muscle cell) and in vivo tumor modeling approaches. We identified ALK rearrangements in 9 of 377 (2.4%) patients with leiomyosarcoma, including a novel KANK2-ALK fusion and a recurrent ACTG2-ALK fusion. Functional characterization of the novel ALK fusion, KANK2-ALK, demonstrates it is a dominant oncogene in Ba/F3 or NIH3T3 model systems, and has tumorigenic potential when introduced into smooth muscle cells. Oral monotherapy with targeted ALK kinase inhibitor lorlatinib significantly inhibits tumor growth and prolongs survival in a murine model of KANK2-ALK leiomyosarcoma. These results provide the first functional validation of a targetable oncogenic kinase fusion as a driver in a subset of leiomyosarcomas. Overall, these findings suggest that some soft-tissue sarcomas may harbor previously unknown kinase gene translocations, and their discovery may propel new therapeutic strategies in this treatment-refractory cancer.

Implications:
A subset of leiomyosarcomas harbor previously unrecognized oncogenic ALK fusions that are highly responsive to ALK inhibitors and thus these data emphasize the importance of detailed genomic investigations of leiomyosarcoma tumors.