bluuebunny/crossref_metadata_2025_split huggingface dataset:
TELEmedicine for EPIlepsy Care (TELE-EPIC): protocol of a randomised, open controlled non-inferiority clinical trial
Authors: Licchetta Laura , Trivisano Marina , Baldin Elisa , Mohamed Susan , Raschi Emanuel , Mostacci Barbara , Zenesini Corrado , Contin Manuela , Vigevano Federico , Bisulli Francesca , Tinuper Paolo , Vignatelli Luca 
Published: December 2021

IntroductionEpilepsy is a chronic condition requiring consistent follow-up aimed at seizure control, and monitoring of anti-seizure medication (ASM) levels and side effects. Telemedicine (TM) offers invaluable support to patient follow-up, guaranteeing the prompt availability of a team of experts for persons with epilepsy (PWE) widely distributed across the country. Although many health institutions have endorsed the use of TM, robust data on effectiveness, safety and costs of TM applied to epilepsy are lacking. TELEmedicine for EPIlepsy Care (TELE-EPIC) will evaluate the effectiveness of video consultation (VC) via TM compared with usual care (UC) for the monitoring of PWE (TELE-EPIC_RCT). Moreover, TELE-EPIC will apply an innovative Volumetric Absorptive Microsampling (VAMS) device for quantitation of ASM through finger prick blood sampling as an alternative to venipuncture sampling (TELE-EPIC_VAMS).Methods and analysisTELE-EPIC_RCT is a multicentre, open, pragmatic two-arm randomised controlled trial prospectively including adult and paediatric outpatients with established diagnosis of epilepsy consecutively attending the Epilepsy Centres of Bologna and Rome, respectively. The primary outcome is the non-inferiority of VC on seizure control compared with UC after an 18-month follow-up. Secondary outcomes are adherence to treatment, ASM-related adverse events, quality of life, mood disorders, patient and caregiver satisfaction, safety and costs. TELE-EPIC_VAMS is a cross-validation study for blood ASM quantitation through a novel, VAMS-based device, comparing (1) VAMS versus plasma samples (reference standard method); and (2) nurse-collected versus self-collected blood by VAMS device.Ethics and disseminationThe study has been approved by the local ethics committee (349-2019-SPER-AUSLBO). Complete information about the state of project, relevant events and results will be regularly updated on the project’s webpage on ClinicalTrials.gov. The project’s results and data on the potential impact of TM in epilepsy will be disseminated on social media. A closeout meeting will be convened for the communication and dissemination of the project, highlighting its main achievements and impacts.Trial registration numberNCT04496310
Childhood strokes in China describing clinical characteristics, risk factors and performance indicators: a case-series study
Authors: Deng Yaxian , Liu Gaifen , Zhang Guitao , Xu Juanyu , Yao Chunmei , Wang Lei , Zhao Chengsong , Wang Yongjun 
Published: December 2021

AimTo investigate clinical characteristics, risk factors (RFs), neurologic deficits and medical care provided in children who had a stroke in China.MethodsWe conducted a retrospective case-series study using the medical records of children aged 1 month to 18 years with arterial ischaemic stroke (AIS) or haemorrhagic stroke (HS) (with the entry codes I60, I61, I62, I63 (ICD-10)), who were admitted to different hospitals in Beijing, between January 2018 and December 2018. We obtained the following information from the charts: demographic characteristics, clinical presentations, RFs for paediatric stroke, laboratory examination, neuroimaging records and neurologic sequelae.ResultsWe identified 312 first admissions for stroke (172 AIS and 140 HS). The mean age at onset was 8.6±3.9 years for patients who had an AIS and 8 (5–13) years for patients who had an HS. There were more males than females in both groups (AIS: 59.88% vs 40.12%; HS: 52.14% vs 47.86%). A known aetiology was identified in 92.44% and 86.43% of patients who had an AIS and HS, respectively. The leading cause of AIS was cerebrovascular diseases including moyamoya (68.6%), while that for HS was arteriovenous malformation (51.43%). The most common initial clinical presentation was hemiplegia (86.05%) in patients who had an AIS and headache (67.86%) in patients who had an HS. The use of healthcare, including acute treatment (antithrombotic in 17.44%, anticoagulant in 5.23%) and secondary prevention (antithrombotic in 6.39%, anticoagulant in 1.16%), varied and was significantly lower among patients who had an AIS. The most common complications were epilepsy (22.09%) and pneumonia (4.65%) in patients who had an AIS and epilepsy (17.14%) and hydrocephalus (12.14%) in patients who had an HS. Neurological deficits occurred in 62.8% of patients who had an AIS and 72.86% of patients who had an HS.ConclusionCerebral arteriopathy was a major RF for both AIS and HS in children living in China. Large epidemiological studies are required to identify RFs to prevent stroke as well as appropriate interventions.
Diverse and changing use of the Salish Sea by Pacific salmon, trout, and char
Authors: Quinn Thomas P. , Losee James P. 
Published: December 2021

Each year, juveniles of eight salmonid species enter the Salish Sea — the inland marine waters between northwestern Washington, USA, and British Columbia, Canada. These species vary in the proportions remaining there and migrating to feed in the Pacific Ocean. Such differential migration affects their growth rates and exposure to habitat alteration, predators, fisheries, and contaminants. We review these diverse migration patterns and present data from Puget Sound illustrating the variation in downstream migration timing, residency in the Salish Sea, and upriver return timing. Recreational catch records indicate that proportionally fewer remain in the Salish Sea than in past decades for several species, and the declines began after peaks in the late 1970s – early 1980s. These declines resist easy explanation because the factors controlling residency are poorly understood, and the Salish Sea has changed over the past decades. Regardless of the cause, the diversity of migration patterns is important to the ecology of the salmon and trout species and to the humans and other members of the Salish Sea community with which they interact.
Revisiting dynamics of interacting quintessence
Authors: Pérez Patrocinio , Nucamendi Ulises , De Arcia Roberto 
Published: December 2021

AbstractWe apply the tools of the dynamical system theory in order to revisit and uncover the structure of a nongravitational interaction between pressureless dark matter and dark energy described by a scalar field $$\phi $$
ϕ
. For a coupling function $$Q = -(\alpha d\rho _m/dt + \beta d\rho _\phi /dt )$$

Q
=
-
(
α
d

ρ
m

/
d
t
+
β
d

ρ
ϕ

/
d
t
)

, where t is the cosmic time, we have found that it can be rewritten in the form $$Q = 3H (\alpha \rho _m + \beta (d\phi /dt)^2 )/(1-\alpha +\beta )$$

Q
=
3
H
(
α

ρ
m

+
β

(
d
ϕ
/
d
t
)

2

)
/

(
1
-
α
+
β
)

, so that its dependence on the dark matter density and on the kinetic term of the scalar field is linear and proportional to the Hubble parameter. We analyze the scenarios $$\alpha =0$$

α
=
0

, $$\alpha = \beta $$

α
=
β

and $$\alpha = -\beta $$

α
=
-
β

, separately and in order to describe the cosmological evolution we have calculated various observables. A notable result of this work is that, unlike for the noninteracting scalar field with exponential potential where five critical points appear, in the case studied here, with the exception of the matter dominated solution, the remaining singular points are transformed into scaling solutions enriching the phase space. It is shown that for $$\alpha \ne 0$$

α
≠
0

, a separatrix arises modifying prominently the structure of the phase space. This represents a novel feature no mentioned before in the literature.
MULTI-SCALE MECHANICAL BEHAVIOR ANALYSIS ON FLUID–SOLID COUPLING FOR OSTEONS IN VARIOUS GRAVITATIONAL FIELDS
Authors: ZHANG HAO , LIU HAI-YING , ZHANG CHUN-QIU , LIU ZHEN-ZHONG , WANG WEI 
Published: December 2021

Background: Compact bone mainly consists of cylindrical osteon structures. In microgravity, the change in the mechanical microenvironment of osteocytes might be the root cause of astronauts’ bone loss during space flights. Methods: A multi-scale three-dimensional (3D) fluid–solid coupling finite element model of osteons with a two-stage pore structure was developed using COMSOL software based on the natural structure of osteocytes. Gradients in gravitational fields of [Formula: see text]1, 0, 1, 2.5, and 3.7[Formula: see text]g were used to investigate the changes in the mechanical microenvironment on osteocyte structure. The difference in arteriole pulsating pressure and static compression stress caused by each gravity gradient was investigated. Results: The mechanical response of osteocytes increased with the value of g, compared with the Earth’s gravitational field. For instance, the fluid pressure of osteocytes and the von Mises stress of bone matrix near lacunae decreased by 31.3% and 99.9%, respectively, in microgravity. Under static loading, only about 16.7% of osteocytes in microgravity and 58.3% of osteocytes in the Earth’s gravitational field could reach the fluid shear stress threshold of biological reactions in cell culture experiments. Compared with the Earth’s gravitational field, the pressure gradient inside osteocytes severely decreased in microgravity. Conclusion: The mechanical microenvironment of osteocytes in microgravity might cause significant changes in the mechanical microenvironment of osteocytes, which may lead to disuse osteoporosis in astronauts.
Validation of Genetic Markers Associated with Survival in Colorectal Cancer Patients Treated with Oxaliplatin-Based Chemotherapy
Authors: Park Hanla A. , Seibold Petra , Edelmann Dominic , Benner Axel , Canzian Federico , Alwers Elizabeth , Jansen Lina , Schneider Martin , Hoffmeister Michael , Brenner Hermann , Chang-Claude Jenny 
Published: December 2021

Abstract

Background:
Associations between candidate genetic variants and treatment outcomes of oxaliplatin, a drug commonly used for colorectal cancer patients, have been reported but not robustly established. This study aimed to validate previously reported prognostic and predictive genetic markers for oxaliplatin treatment outcomes and evaluate additional putative functional variants.

Methods:
Fifty-three SNPs were selected based on previous reports (40 SNPs) or putative function in candidate genes (13 SNPs). We used data from 1,502 patients with stage II–IV colorectal cancer who received primary adjuvant chemotherapy, 37% of whom received oxaliplatin treatment. Multivariable Cox proportional hazards models for overall survival and progression-free survival were applied separately in stage II–III and stage IV patients. For predictive SNPs, differential outcomes according to the type of chemotherapy (oxaliplatin-based vs. others) were evaluated using an interaction term. For prognostic SNPs, the association was assessed solely in patients with oxaliplatin-based treatment.

Results:
Twelve SNPs were predictive and/or prognostic at P &lt; 0.05 with differential survival based on the type of treatment, in patients with stage II–III (GSTM5-rs11807, ERCC2-rs13181, ERCC2-rs1799793, ERCC5-rs2016073, XPC-rs2228000, P2RX7-rs208294, HMGB1-rs1360485) and in patients with stage IV (GSTM5-rs11807, MNAT1-rs3783819, MNAT1-rs4151330, CXCR1-rs2234671, VEGFA-rs833061, P2RX7-rs2234671). In addition, five novel putative functional SNPs were identified to be predictive (ATP8B3-rs7250872, P2RX7-rs2230911, RPA1-rs5030755, MGMT-rs12917, P2RX7-rs2227963).

Conclusions:
Some SNPs yielded prognostic and/or predictive associations significant at P &lt; 0.05, however, none of the associations remained significant after correction for multiple testing.

Impact:
We did not robustly confirm previously reported SNPs despite some suggestive findings but identified further potential predictive SNPs, which warrant further investigation in well-powered studies.
Associations of Oral Contraceptives with Mammographic Breast Density in Premenopausal Women
Authors: Yaghjyan Lusine , Smotherman Carmen , Heine John , Colditz Graham A. , Rosner Bernard , Tamimi Rulla M. 
Published: December 2021

Abstract

Background:
We investigated the associations of oral contraceptives (OC) with percent breast density (PD), absolute dense area (DA), nondense area (NDA), and a novel image intensity variation (V) measure in premenopausal women.

Methods:
This study included 1,233 controls from a nested case–control study within Nurses' Health Study II cohort. Information on OCs was collected in 1989 and updated biennially. OC use was defined from the questionnaire closest to the mammogram date. PD, DA, and NDA were measured from digitized film mammograms using a computer-assisted thresholding technique; the V measure was obtained with a previously developed algorithm measuring the SD of pixel values in the eroded breast region. Generalized linear regression was used to assess associations between OCs and density measures (square root–transformed PD, DA, and NDA, and –untransformed V).

Results:
OC use was not associated with PD [current vs. never: β = −0.06; 95% confidence interval (CI), −0.37–0.24; past vs. never: β = 0.10; 95% CI, −0.09–0.29], DA (current vs. never: β = −0.20; 95% CI −0.59–0.18; past vs. never: β = 0.13; 95% CI, −0.12–0.39), and NDA (current vs. never: β = −0.19; 95% CI, −0.56–0.18; past vs. never: β = −0.01; 95% CI, −0.28–0.25). Women with younger age at initiation had significantly greater V-measure (&lt;20 years vs. never: β = 26.88; 95% CI, 3.18–50.58; 20–24 years vs. never: β = 20.23; 95% CI, −4.24–44.71; 25–29 years vs. never: β = 2.61; 95% CI −29.00–34.23; ≥30 years vs. never: β = 0.28; 95% CI, −34.16–34.72, Ptrend = 0.03).

Conclusions:
Our findings suggest that an earlier age at first OC use was associated with significantly greater V.

Impact:
These findings could guide decisions about the age for OC initiation.
DNA Methylation in Peripheral Blood: Providing Novel Biomarkers of Exposure and Immunity to Examine Cancer Risk
Authors: Michaud Dominique S. , Kelsey Karl T. 
Published: December 2021

Abstract
DNA methylation is an epigenetic phenomenon that can alter and control gene expression. Because methylation plays a key role in cell differentiation, methylation markers have been identified that are unique to a given cell type; these markers are stable and can be measured in tissue or whole blood. The article by Katzke and colleagues, published in this issue, uses methylation markers to estimate proportions of immune cell subtypes in peripheral blood samples that were collected prior to diagnosis, thus allowing them to directly examine associations with pancreatic cancer risk. Given that immune-cell counts cannot be measured from archived blood, and that retrospective case–control studies rely on blood that is collected after cancer diagnosis, few studies have been able to examine the role of the systemic immune response in cancer risk. Measurement of DNA methylation in peripheral blood, primarily through development of whole-genome approaches, has also opened new doors to examining cancer etiology.
See related article by Katzke et al., p. 2179
Modulation of the Human Pancreatic Ductal Adenocarcinoma Immune Microenvironment by Stereotactic Body Radiotherapy
Authors: Mills Bradley N. , Qiu Haoming , Drage Michael G. , Chen Chunmo , Mathew Jocelyn S. , Garrett-Larsen Jesse , Ye Jian , Uccello Taylor P. , Murphy Joseph D. , Belt Brian A. , Lord Edith M. , Katz Alan W. , Linehan David C. , Gerber Scott A. 
Published: December 2021

Abstract

Purpose:
Stereotactic body radiotherapy (SBRT) is an emerging treatment modality for pancreatic ductal adenocarcinoma (PDAC), which can effectively prime cytotoxic T cells by inducing immunogenic tumor cell death in preclinical models. SBRT effects on human PDAC have yet to be thoroughly investigated; therefore, this study aimed to characterize immunomodulation in the human PDAC tumor microenvironment following therapy.

Experimental Design:
Tumor samples were obtained from patients with resectable PDAC. Radiotherapy was delivered a median of 7 days prior to surgical resection, and sections were analyzed by multiplex IHC (mIHC), RNA sequencing, and T-cell receptor sequencing (TCR-seq).

Results:
Analysis of SBRT-treated tumor tissue indicated reduced tumor cell density and increased immunogenic cell death relative to untreated controls. Radiotherapy promoted collagen deposition; however, vasculature was unaffected and spatial analyses lacked evidence of T-cell sequestration. Conversely, SBRT resulted in fewer tertiary lymphoid structures and failed to lessen or reprogram abundant immune suppressor populations. Higher percentages of PD-1+ T cells were observed following SBRT, and a subset of tumors displayed more clonal T-cell repertoires.

Conclusions:
These findings suggest that SBRT augmentation of antitumor immunogenicity may be dampened by an overabundance of refractory immunosuppressive populations, and support the continued development of SBRT/immunotherapy combination for human PDAC.
Safety, Activity, and Long-term Outcomes of Pomalidomide in the Treatment of Kaposi Sarcoma among Individuals with or without HIV Infection
Authors: Ramaswami Ramya , Polizzotto Mark N. , Lurain Kathryn , Wyvill Kathleen M. , Widell Anaida , George Jomy , Goncalves Priscila , Steinberg Seth M. , Whitby Denise , Uldrick Thomas S. , Yarchoan Robert 
Published: December 2021

AbstractPurpose:Kaposi sarcoma (KS) is caused by Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). KS, which develops most frequently among people with HIV, is generally treated with chemotherapy, but these drugs have acute and cumulative toxicities. We previously described initial results of a trial of pomalidomide, an oral immunomodulatory derivative of thalidomide, in patients with KS. Here, we present results on the full cohort and survival outcomes.Patients and Methods:Participants with KS with or without HIV were treated with pomalidomide 5 mg once daily for 21 days per 28-day cycle with aspirin 81 mg daily for thromboprophylaxis. Participants with HIV received antiretroviral therapy. Response was defined by modified version of the AIDS Clinical Trial Group KS criteria. We evaluated tumor responses (including participants who had a second course), adverse events, progression-free survival (PFS), and long-term outcomes.Results:Twenty-eight participants were enrolled. Eighteen (64%) were HIV positive and 21 (75%) had advanced (T1) disease. The overall response rate was 71%: 95% confidence interval (CI) 51%–87%. Twelve of 18 HIV-positive (67%; 95% CI, 41–87%) and 8 of 10 HIV-negative participants (80%; 95% CI, 44%–97%) had a response. Two of 4 participants who received a second course of pomalidomide had a partial response. The median PFS was 10.2 months (95% CI: 7.6–15.7 months). Grade 3 neutropenia was noted among 50% of participants. In the follow-up period, 3 participants with HIV had other KSHV-associated diseases.Conclusions:Pomalidomide is a safe and active chemotherapy-sparing agent for the treatment of KS among individuals with or without HIV.
Abstract IACICR01: Perspective on bivalent degraders
Authors: Ciulli Alessio 
Published: December 2021

Abstract
Bivalent degrader molecules (also known as PROTACs) recruit proteins to E3 ligases for targeted protein degradation. Formation of a ternary complex between the PROTAC, the E3 and the target leads to the tagging of the target protein by ubiquitination, and subsequent proteasomal degradation.
Over the past 6 years, PROTACs have witnessed significant development and exponential rise in interest and adoption across academia and the biopharma industry, enabled by the discoveries of high-quality, drug-like small-molecule ligands for the E3 ligases cereblon (CRBN) and von Hippel-Lindau (VHL). They are today firmly established both as chemical tools to study biology and as next-generation medicine, with a first wave of PROTAC molecules advancing in clinical trials against cancer and other diseases. Degrading rather than inhibiting a target protein offers a novel modality of chemical intervention, and advantages such as more efficacious drug response at lower doses, and enhanced target selectivity, with potentially reduced side effects and disease resistance.
This lecture will offer a perspective on this rapidly evolving field, from deepened understanding of how PROTACs work, to current trends in their development, including recent expansion beyond bivalency, and an outlook on future directions.
Citation Format: Alessio Ciulli. Perspective on bivalent degraders [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr IACICR01.
Abstract LBA005: Detection of KRAS amplification on extrachromosomal DNA (ecDNA) upon acquired resistance to KRASG12C inhibitors
Authors: Hansen Ryan J , Horton Steven , Wiese Julie , Bibay BellJohn , Mora-Blanco E.Lorena , Nguyen Nam-Phuong , Engstrom Lars D , Briere David M , Calinisan Andres , Olson Peter , Awad Mark M , Aguirre Andrew J , Christiansen Jason , Hassig Christian , Kasibhatla Shailaja 
Published: December 2021

Abstract
The recent discovery and clinical validation of KRAS inhibitors (KRASi) has ushered in a new therapeutic approach to directly address the previously undruggable mutant KRAS-driven cancers. Unfortunately, as with other oncogene-directed therapies, acquired resistance to KRASi has been observed that is partially attributed to secondary mutations in KRAS and/or mutations or fusions in other mitogen-activated protein kinase (MAPK) signaling genes. Emerging evidence suggests that amplification of oncogenes on acentric extrachromosomal DNA (ecDNA) might constitute an important mechanism of rapid resistance to receptor tyrosine kinase (RTK) and MAPK targeting therapies. Therefore, we investigated whether resistance to KRASi monotherapy is mediated through an ecDNA mechanism. We previously noted focal gene amplification of KRAS and MET in recurrent tumors isolated from patients treated with the selective KRASG12C inhibitor, adagrasib. Analysis of next-generation sequencing (NGS) data from a patient tumor revealed evidence of circular DNA structures encompassing the KRAS locus. Consistent with this finding, interphase FISH analysis indicated the presence of KRAS amplifications on ecDNA in this adagrasib-treated patient tumor. To further interrogate this biology, we examined a genetically modified CT26 murine tumor model harboring KRASG12C alteration. Analogous to the clinical observations, both adagrasib as well as the recently approved KRASi sotorasib, induced transient tumor regressions that subsequently resumed growth following several weeks of continuous therapy. Strikingly, whole-genome sequencing data from isolated recurrent tumors revealed focal amplification of KRASG12C and metaphase FISH confirmed high levels of KRASG12C on ecDNA as compared to vehicle-treated samples. Further mechanistic studies are underway. Collectively, these observations implicate ecDNA as an important mediator of resistance to KRASi monotherapy and reinforce the critical need for novel therapeutic strategies to address ecDNA oncogene amplification-driven cancers.
Citation Format: Ryan J Hansen, Steven Horton, Julie Wiese, BellJohn Bibay, E.Lorena Mora-Blanco, Nam-Phuong Nguyen, Lars D Engstrom, David M Briere, Andres Calinisan, Peter Olson, Mark M Awad, Andrew J Aguirre, Jason Christiansen, Christian Hassig, Shailaja Kasibhatla. Detection of KRAS amplification on extrachromosomal DNA (ecDNA) upon acquired resistance to KRASG12C inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA005.