bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial
Authors: Duerinck Johnny , Schwarze Julia Katharina , Awada Gil , Tijtgat Jens , Vaeyens Freya , Bertels Cleo , Geens Wietse , Klein Samuel , Seynaeve Laura , Cras Louise , D’Haene Nicky , Michotte Alex , Caljon Ben , Salmon Isabelle , Bruneau Michaël , Kockx Mark , Van Dooren Sonia , Vanbinst Anne-Marie , Everaert Hendrik , Forsyth Ramses , Neyns Bart 
Published: June 2021

BackgroundPatients with recurrent glioblastoma (rGB) have a poor prognosis with a median overall survival (OS) of 30–39 weeks in prospective clinical trials. Intravenous administration of programmed cell death protein 1 and cytotoxic T-lymphocyte-associated antigen 4 inhibitors has low activity in patients with rGB. In this phase I clinical trial, intracerebral (IC) administration of ipilimumab (IPI) and nivolumab (NIVO) in combination with intravenous administration of NIVO was investigated.MethodsWithin 24 hours following the intravenous administration of a fixed dose (10 mg) of NIVO, patients underwent a maximal safe resection, followed by injection of IPI (10 mg; cohort-1), or IPI (5 mg) plus NIVO (10 mg; cohort-2) in the brain tissue lining the resection cavity. Intravenous administration of NIVO (10 mg) was repeated every 2 weeks (max. five administrations). Next generation sequencing and RNA gene expression profiling was performed on resected tumor tissue.ResultsTwenty-seven patients were enrolled (cohort-1: n=3; cohort-2: n=24). All patients underwent maximal safe resection and planned IC administrations and preoperative NIVO. Thirteen patients (cohort-1: n=3; cohort-2: n=10) received all five postoperative intravenous doses of NIVO. In cohort-2, 14 patients received a median of 3 (range 1–4) intravenous doses. Subacute postoperative neurological deterioration (n=2) was reversible on steroid treatment; no other central nervous system toxicity was observed. Immune-related adverse events were infrequent and mild. GB recurrence was diagnosed in 26 patients (median progression-free survival (PFS) is 11.7 weeks (range 2–152)); 21 patients have died due to progression. Median OS is 38 weeks (95% CI: 27 to 49) with a 6-month, 1-year, and 2-year OS-rate of, respectively, 74.1% (95% CI: 57 to 90), 40.7% (95% CI: 22 to 59), and 27% (95% CI: 9 to 44). OS compares favorable against a historical cohort (descriptive Log-Rank p>0.003). No significant difference was found with respect to PFS (descriptive Log-Rank test p>0.05). A higher tumor mRNA expression level of B7-H3 was associated with a significantly worse survival (multivariate Cox logistic regression, p>0.029).ConclusionIC administration of NIVO and IPI following maximal safe resection of rGB was feasible, safe, and associated with encouraging OS.Trial registrationNCT03233152.
Theoretical predictions of structural electronic and optical properties of vanadium ferrite
Authors: Bushra Munir H. , Afaq A. , Bakar Abu , ul Aarifeen Najm , Ullah Farid , Fatima Rida , Asif Muhammad 
Published: June 2021

The structural properties of Vanadium Ferrite VFe2O4 are reported for temperature range 0–1000 K using Density Functional Theory. A comparative study with the available experimental and theoretical data in the literature is also presented. Effects of temperature on lattice constant, volume and bulk modulus are deduced that with the increase in temperature, bulk modulus decreases and lattice constant slightly increases. This proves that the material VFe2O4 remains in the same cubic phase for temperature range 0–1000 K. In addition, the optical response is observed with six optical constants like absorption, reflectivity, eloss, dielectric functions, refraction and optical conductivity. Band structures and electronic density of states are also computed by using TB-mBJ potential. We hope that our findings would provide a help to experimentalists in fabricating VFe2O4 for temperature-sensitive optical devices.
ATR Inhibition Induces CDK1–SPOP Signaling and Enhances Anti–PD-L1 Cytotoxicity in Prostate Cancer
Authors: Tang Zhe , Pilié Patrick G. , Geng Chuandong , Manyam Ganiraju C. , Yang Guang , Park Sanghee , Wang Daoqi , Peng Shan , Wu Cheng , Peng Guang , Yap Timothy A. , Corn Paul G. , Broom Bradley M. , Thompson Timothy C. 
Published: June 2021

Abstract

Purpose:
Despite significant benefit for other cancer subtypes, immune checkpoint blockade (ICB) therapy has not yet been shown to significantly improve outcomes for men with castration-resistant prostate cancer (CRPC). Prior data have shown that DNA damage response (DDR) deficiency, via genetic alteration and/or pharmacologic induction using DDR inhibitors (DDRi), may improve ICB response in solid tumors in part due to induction of mitotic catastrophe and innate immune activation. Discerning the underlying mechanisms of this DDRi–ICB interaction in a prostate cancer–specific manner is vital to guide novel clinical trials and provide durable clinical responses for men with CRPC.

Experimental Design:
We treated prostate cancer cell lines with potent, specific inhibitors of ATR kinase, as well as with PARP inhibitor, olaparib. We performed analyses of cGAS–STING and DDR signaling in treated cells, and treated a syngeneic androgen-indifferent, prostate cancer model with combined ATR inhibition and anti–programmed death ligand 1 (anti–PD-L1), and performed single-cell RNA sequencing analysis in treated tumors.

Results:
ATR inhibitor (ATRi; BAY1895433) directly repressed ATR–CHK1 signaling, activated CDK1–SPOP axis, leading to destabilization of PD-L1 protein. These effects of ATRi are distinct from those of olaparib, and resulted in a cGAS–STING-initiated, IFN-β–mediated, autocrine, apoptotic response in CRPC. The combination of ATRi with anti–PD-L1 therapy resulted in robust innate immune activation and a synergistic, T-cell–dependent therapeutic response in our syngeneic mouse model.

Conclusions:
This work provides a molecular mechanistic rationale for combining ATR-targeted agents with immune checkpoint blockade for patients with CRPC. Multiple early-phase clinical trials of this combination are underway.
ptFVa (
Pseudonaja Textilis
Venom-Derived Factor Va) Retains Structural Integrity Following Proteolysis by Activated Protein C
Authors: Schreuder Mark , Liu Xiaosong , Cheung Ka Lei , Reitsma Pieter H. , Nicolaes Gerry A.F. , Bos Mettine H.A. 
Published: June 2021

Objective:

The Australian snake venom ptFV (
Pseudonaja textilis
venom-derived factor V) variant retains cofactor function despite APC (activated protein C)-dependent proteolysis. Here, we aimed to unravel the mechanistic principles by determining the role of the absent Arg306 cleavage site that is required for the inactivation of FVa (mammalian factor Va).

Approach and Results:
Our findings show that in contrast to human FVa, APC-catalyzed proteolysis of ptFVa at Arg306 and Lys507 does not abrogate ptFVa cofactor function. Remarkably, the structural integrity of APC-proteolyzed ptFVa is maintained indicating that stable noncovalent interactions prevent A2-domain dissociation. Using Molecular Dynamics simulations, we uncovered key regions located in the A1 and A2 domain that may be at the basis of this remarkable characteristic.

Conclusions:
Taken together, we report a completely novel role for uniquely adapted regions in ptFVa that prevent A2 domain dissociation. As such, these results challenge our current understanding by which strict regulatory mechanisms control FVa activity.
Pravastatin Versus Placebo in Pregnancies at High Risk of Term Preeclampsia
Authors: Döbert Moritz , Varouxaki Anna Nektaria , Mu An Chi , Syngelaki Argyro , Ciobanu Anca , Akolekar Ranjit , De Paco Matallana Catalina , Cicero Simona , Greco Elena , Singh Mandeep , Janga Deepa , del Mar Gil Maria , Jani Jacques C. , Bartha José Luis , Maclagan Kate , Wright David , Nicolaides Kypros H. 
Published: June 2021

Background:
Effective screening for term preeclampsia is provided by a combination of maternal factors with measurements of mean arterial pressure, serum placental growth factor, and serum soluble fms-like tyrosine kinase-1 at 35 to 37 weeks of gestation, with a detection rate of ≈75% at a screen-positive rate of 10%. However, there is no known intervention to reduce the incidence of the disease.

Methods:
In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1120 women with singleton pregnancies at high risk of term preeclampsia to receive pravastatin at a dose of 20 mg/d or placebo from 35 to 37 weeks of gestation until delivery or 41 weeks. The primary outcome was delivery with preeclampsia at any time after randomization. The analysis was performed according to intention to treat.

Results:

A total of 29 women withdrew consent during the trial. Preeclampsia occurred in 14.6% (80 of 548) of participants in the pravastatin group and in 13.6% (74 of 543) in the placebo group. Allowing for the effect of risk at the time of screening and participating center, the mixed-effects Cox regression showed no evidence of an effect of pravastatin (hazard ratio for statin/placebo, 1.08 [95% CI, 0.78–1.49];
P
=0.65). There was no evidence of interaction between the effect of pravastatin, estimated risk of preeclampsia, pregnancy history, adherence, and aspirin treatment. There was no significant between-group difference in the incidence of any secondary outcomes, including gestational hypertension, stillbirth, abruption, delivery of small for gestational age neonates, neonatal death, or neonatal morbidity. There was no significant between-group difference in the treatment effects on serum placental growth factor and soluble fms-like tyrosine kinase-1 concentrations 1 and 3 weeks after randomization. Adherence was good, with reported intake of ≥80% of the required number of tablets in 89% of participants. There were no significant between-group differences in neonatal adverse outcomes or other adverse events.

Conclusions:
Pravastatin in women at high risk of term preeclampsia did not reduce the incidence of delivery with preeclampsia.

Registration:

URL:
https://www.isrctn.com
; Unique identifier ISRCTN16123934.
Frequency-Dependent Estimation of Effective Spatial Degrees of Freedom
Authors: Kunz Torben , Laepple Thomas 
Published: June 2021

AbstractClimate variability occurs over wide ranges of spatial and temporal scales. It exhibits a complex spatial covariance structure, which depends on geographic location (e.g., tropics vs extratropics) and also consists of a superposition of (i) components with gradually decaying positive correlation functions and (ii) teleconnections that often involve anticorrelations. In addition, there are indications that the spatial covariance structure depends on frequency. Thus, a comprehensive assessment of the spatiotemporal covariance structure of climate variability would require an extensive set of statistical diagnostics. Therefore, it is often desirable to characterize the covariance structure by a simple summarizing metric that is easy to compute from datasets. Such summarizing metrics are useful, for example, in the context of comparisons between climate models or between models and observations. Here we introduce a frequency-dependent version of a simple measure of the effective spatial degrees of freedom. The measure is based on the temporal variance of the global average of some climate variable, and its novel aspect consists in its frequency dependence. We also provide a clear geometric interpretation of the measure. Its easy applicability is demonstrated using near-surface temperature and precipitation fields obtained from a paleoclimate model simulation. This application reveals a distinct scaling behavior of the spatial degrees of freedom as a function of frequency, ranging from monthly to millennial scales.
Impact of Temperature on Physical and Mental Health: Evidence from China
Authors: Yang Zhiming , Yang Bo , Liu Pengfei , Zhang Yunquan , Yuan Xiao-Chen 
Published: June 2021

AbstractClimate may significantly affect human society. Few studies have focused on the temperature impact on residents’ health, especially mental health status. This paper uses 98 423 observations in China to study the relationship between temperature and health, based on the China Family Panel Studies survey during 2010–16. We analyze the health effects of extreme hot and cold weather and compare the effects under different social demographic factors including gender, age, and income. We find that temperature and health status exhibit a nonlinear relationship. Women and low-income households are more likely to be impacted by extreme cold, whereas men, the elderly, and high-income households are more sensitive to extreme heat. Our results highlight the potential effects of extreme temperatures on physical and mental health and provide implications for future policy decisions to protect human health under a changing climate.
Autophagy receptors as viral targets
Authors: Ylä-Anttila Päivi 
Published: June 2021

AbstractActivation of autophagy is part of the innate immune response during viral infections. Autophagy involves the sequestration of endogenous or foreign components from the cytosol within double-membraned vesicles and the delivery of their content to the lysosomes for degradation. As part of innate immune responses, this autophagic elimination of foreign components is selective and requires specialized cargo receptors that function as links between a tagged foreign component and the autophagic machinery. Pathogens have evolved ways to evade their autophagic degradation to promote their replication, and recent research has shown autophagic receptors to be an important and perhaps previously overlooked target of viral autophagy inhibition. This is a brief summary of the recent progress in knowledge of virus-host interaction in the context of autophagy receptors.
Effects of chiropractic spinal manipulation on laser-evoked pain and brain activity
Authors: Provencher Benjamin , Northon Stéphane , Gevers Montoro Carlos , O’Shaughnessy Julie , Piché Mathieu 
Published: June 2021

AbstractThe aim of this study was to examine the mechanisms underlying hypoalgesia induced by spinal manipulation (SM). Eighty-two healthy volunteers were assigned to one of the four intervention groups: no intervention, SM at T4 (homosegmental to pain), SM at T8 (heterosegmental to pain) or light mechanical stimulus at T4 (placebo). Eighty laser stimuli were applied on back skin at T4 to evoke pain and brain activity related to Aδ- and C-fibers activation. The intervention was performed after 40 stimuli. Laser pain was decreased by SM at T4 (p = 0.028) but not T8 (p = 0.13), compared with placebo. However, brain activity related to Aδ-fibers activation was not significantly modulated (all p > 0.05), while C-fiber activity could not be measured reliably. This indicates that SM produces segmental hypoalgesia through inhibition of nociceptive processes that are independent of Aδ fibers. It remains to be clarified whether the effect is mediated by the inhibition of C-fiber activity.
mLoc-mRNA: predicting multiple sub-cellular localization of mRNAs using random forest algorithm coupled with feature selection via elastic net
Authors: Meher Prabina Kumar , Rai Anil , Rao Atmakuri Ramakrishna 
Published: June 2021

AbstractBackgroundLocalization of messenger RNAs (mRNAs) plays a crucial role in the growth and development of cells. Particularly, it plays a major role in regulating spatio-temporal gene expression. The in situ hybridization is a promising experimental technique used to determine the localization of mRNAs but it is costly and laborious. It is also a known fact that a single mRNA can be present in more than one location, whereas the existing computational tools are capable of predicting only a single location for such mRNAs. Thus, the development of high-end computational tool is required for reliable and timely prediction of multiple subcellular locations of mRNAs. Hence, we develop the present computational model to predict the multiple localizations of mRNAs.ResultsThe mRNA sequences from 9 different localizations were considered. Each sequence was first transformed to a numeric feature vector of size 5460, based on thek-mer features of sizes 1–6. Out of 5460 k-mer features, 1812 important features were selected by the Elastic Net statistical model. The Random Forest supervised learning algorithm was then employed for predicting the localizations with the selected features. Five-fold cross-validation accuracies of 70.87, 68.32, 68.36, 68.79, 96.46, 73.44, 70.94, 97.42 and 71.77% were obtained for the cytoplasm, cytosol, endoplasmic reticulum, exosome, mitochondrion, nucleus, pseudopodium, posterior and ribosome respectively. With an independent test set, accuracies of 65.33, 73.37, 75.86, 72.99, 94.26, 70.91, 65.53, 93.60 and 73.45% were obtained for the respective localizations. The developed approach also achieved higher accuracies than the existing localization prediction tools.ConclusionsThis study presents a novel computational tool for predicting the multiple localization of mRNAs. Based on the proposed approach, an online prediction server “mLoc-mRNA” is accessible athttp://cabgrid.res.in:8080/mlocmrna/. The developed approach is believed to supplement the existing tools and techniques for the localization prediction of mRNAs.
VISPR-online: a web-based interactive tool to visualize CRISPR screening experiments
Authors: Cui Yingbo , Wang Zihang , Köster Johannes , Liao Xiangke , Peng Shaoliang , Tang Tao , Huang Chun , Yang Canqun 
Published: June 2021

Abstract
Background
VISPR is an interactive visualization and analysis framework for CRISPR screening experiments. However, it only supports the output of MAGeCK, and requires installation and manual configuration. Furthermore, VISPR is designed to run on a single computer, and data sharing between collaborators is challenging.

Results
To make the tool easily accessible to the community, we present VISPR-online, a web-based general application allowing users to visualize, explore, and share CRISPR screening data online with a few simple steps. VISPR-online provides an exploration of screening results and visualization of read count changes. Apart from MAGeCK, VISPR-online supports two more popular CRISPR screening analysis tools: BAGEL and JACKS. It provides an interactive environment for exploring gene essentiality, viewing guide RNA (gRNA) locations, and allowing users to resume and share screening results.

Conclusions
VISPR-online allows users to visualize, explore and share CRISPR screening data online. It is freely available at http://vispr-online.weililab.org, while the source code is available at https://github.com/lemoncyb/VISPR-online.
PEPC of sugarcane regulated glutathione S-transferase and altered carbon–nitrogen metabolism under different N source concentrations in Oryza sativa
Authors: Lian Ling , Lin Yuelong , Wei Yidong , He Wei , Cai Qiuhua , Huang Wei , Zheng Yanmei , Xu Huibin , Wang Fuxiang , Zhu Yongsheng , Luo Xi , Xie Huaan , Zhang Jianfu 
Published: June 2021

Abstract
Background
Phosphoenolpyruvate carboxylase (PEPC) plays an important role in the primary metabolism of higher plants. Several studies have revealed the critical importance of PEPC in the interaction of carbon and nitrogen metabolism. However, the function mechanism of PEPC in nitrogen metabolism is unclear and needs further investigation.

Results
This study indicates that transgenic rice expressing the sugarcane C4-PEPC gene displayed shorter primary roots and fewer crown roots at the seedling stage. However, total nitrogen content was significantly higher in transgenic rice than in wild type (WT) plants. Proteomic analysis revealed that there were more differentially expressed proteins (DEPs) responding to nitrogen changes in transgenic rice. In particular, the most enriched pathway “glutathione (GSH) metabolism”, which mainly contains GSH S-transferase (GST), was identified in transgenic rice. The expression of endogenous PEPC, GST and several genes involved in the TCA cycle, glycolysis and nitrogen assimilation changed in transgenic rice. Correspondingly, the activity of enzymes including GST, citrate synthase, 6-phosphofructokinase, pyruvate kinase and ferredoxin-dependent glutamate synthase significantly changed. In addition, the levels of organic acids in the TCA cycle and carbohydrates including sucrose, starch and soluble sugar altered in transgenic rice under different nitrogen source concentrations. GSH that the substrate of GST and its components including glutamic acid, cysteine and glycine accumulated in transgenic rice. Moreover, the levels of phytohormones including indoleacetic acid (IAA), zeatin (ZT) and isopentenyladenosine (2ip) were lower in the roots of transgenic rice under total nutrients. Taken together, the phenotype, physiological and biochemical characteristics of transgenic rice expressing C4-PEPC were different from WT under different nitrogen levels.

Conclusions
Our results revealed the possibility that PEPC affects nitrogen metabolism through regulating GST, which provide a new direction and concepts for the further study of the PEPC functional mechanism in nitrogen metabolism.
Assessing the accuracy of ultrasound measurements of tracheal diameter: an in vitro experimental study
Authors: Ye Ran , Cai Feifei , Guo Chengnan , Zhang Xiaocheng , Yan Dan , Chen Chengshui , Chen Bin 
Published: June 2021

Abstract
Background
Recent studies indicate that ultrasound can detect changes in tracheal diameter during endotracheal tube (ETT) cuff inflation. We sought to assess the accuracy of ultrasound measurement of tracheal diameter, and to determine the relationship between tracheal wall pressure (TWP), cuff inflation volume (CIV), and the degree of tracheal deformation.

Methods
Our study comprised two parts: the first included 45 porcine tracheas, the second 41 porcine tracheas. Each trachea was intubated with a cuffed ETT, which was connected to an injector and the manometer via a three-way tap. The cuff was inflated and the cuff pressure recorded before and after intubation. The tracheal diameter was measured using ultrasound. This included three separate measurements: outer transverse diameter (OTD), internal transverse diameter (ITD), and anterior tracheal wall thicknesses (ATWT). A precision electronic Vernier caliper was also used to measure tracheal diameter. We calculated TWP and the percentage change of tracheal diameter. The Bland–Altman method, linear regression, and locally weighted regression (LOESS) were used to analyze the data.

Results
There were strong correlation and agreement for OTD (r = 0.97, P < 0.001) and ITD (r = 0.90, P < 0.001) as measured by ultrasound and by precision electronic Vernier caliper, but a poor correlation for ATWT (r = 0.58, P < 0.001). There was a strong correlation between the percentage change of OTD (OTD%, r = 0.75, P < 0.001) and CIV, the percentage change of ITD (ITD%, r = 0.77, P < 0.001) and CIV, TWP (r = 0.75, P < 0.001) and CIV. And a strong correlation was also found between TWP and OTD% (r = 0.84, P < 0.001), TWP and ITD% (r = 0.84, P < 0.001).

Conclusions
Use of ultrasound to measure OTD and ITD is accurate, but is less accurate for ATWT. There is a close correlation between OTD%, ITD%, CIV and TWP.