bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cancer immunotherapy with PI3K and PD-1 dual-blockade via optimal modulation of T cell activation signal
Authors: Isoyama Sho , Mori Shigeyuki , Sugiyama Daisuke , Kojima Yasuhiro , Tada Yasuko , Shitara Kohei , Hinohara Kunihiko , Dan Shingo , Nishikawa Hiroyoshi 
Published: August 2021

BackgroundImmune checkpoint blockade (ICB) induces durable clinical responses in patients with various types of cancer. However, its limited clinical efficacy requires the development of better approaches. In addition to immune checkpoint molecules, tumor-infiltrating immunosuppressive cells including regulatory T cells (Tregs) play crucial roles in the immune suppressive tumor microenvironment. While phosphatidylinositol 3-kinase (PI3K) inhibition as a Treg-targeted treatment has been implicated in animal models, its effects on human Tregs and on the potential impairment of effector T cells are required to be clarified for successful cancer immunotherapy.MethodsThe impact of a selective-PI3K inhibitor ZSTK474 with or without anti-programmed cell death 1 (PD-1) monoclonal antibody on Tregs and CD8+T cells were examined with in vivo animal models and in vitro experiments with antigen specific and non-specific fashions using peripheral blood from healthy individuals and cancer patients. Phenotypes and functions of Tregs and effector T cells were examined with comprehensive gene and protein expression assays.ResultsImproved antitumor effects by the PI3K inhibitor in combination with ICB, particularly PD-1 blockade, were observed in mice and humans. Although administration of the PI3K inhibitor at higher doses impaired activation of CD8+T cells as well as Tregs, the optimization (doses and timing) of this combination treatment selectively decreased intratumoral Tregs, resulting in increased tumor antigen-specific CD8+T cells in the treated mice. Moreover, on the administration of the PI3K inhibitor with the optimal dose for selectively deleting Tregs, PI3K signaling was inhibited not only in Tregs but also in activated CD8+T cells, leading to the enhanced generation of tumor antigen-specific memory CD8+T cells which contributed to durable antitumor immunity. These opposing outcomes between Tregs and CD8+T cells were attributed to the high degree of dependence on T cell signaling in the former but not in the latter.ConclusionsPI3K inhibitor in the combination with ICB with the optimized protocol fine-tuned T cell activation signaling for antitumor immunity via decreasing Tregs and optimizing memory CD8+T cell responses, illustrating a promising combination therapy.
Clinical and molecular parameters associated to pneumonitis development in non-small-cell lung cancer patients receiving chemoimmunotherapy from NADIM trial
Authors: Sierra-Rodero Belén , Cruz-Bermúdez Alberto , Nadal Ernest , Garitaonaindía Yago , Insa Amelia , Mosquera Joaquín , Casal-Rubio Joaquín , Dómine Manuel , Majem Margarita , Rodriguez-Abreu Delvys , Martinez-Marti Alex , De Castro Carpeño Javier , Cobo Manuel , López Vivanco Guillermo , Del Barco Edel , Bernabé Caro Reyes , Viñolas Nuria , Barneto Aranda Isidoro , Viteri Santiago , Massuti Bartomeu , Laza-Briviesca Raquel , Casarrubios Marta , García-Grande Aránzazu , Romero Atocha , Franco Fernando , Provencio Mariano 
Published: August 2021

BackgroundPneumonitis (Pn) is one of the main immune-related adverse effects, having a special importance in lung cancer, since they share affected tissue. Despite its clinical relevance, Pn development remains an unpredictable treatment adverse effect, whose mechanisms are mainly unknown, being even more obscure when it is associated to chemoimmunotherapy.MethodsIn order to identify parameters associated to treatment related Pn, we analyzed clinical variables and molecular parameters from 46 patients with potentially resectable stage IIIA non-small-cell lung cancer treated with neoadjuvant chemoimmunotherapy included in the NADIM clinical trial (NCT03081689). Pn was defined as clinical or radiographic evidence of lung inflammation without alternative diagnoses, from treatment initiation to 180 days.ResultsAmong 46 patients, 12 developed Pn (26.1%). Sex, age, smoking status, packs-year, histological subtype, clinical or pathological response, progression-free survival, overall survival and number of nivolumab cycles, were not associated to Pn development. Regarding molecular parameters at diagnosis, Pn development was not associated to programmed death ligand 1, TPS, T cell receptor repertoire parameters, or tumor mutational burden. However, patients who developed Pn had statistically significant lower blood median levels of platelet to monocyte ratio (p=0.012) and teratocarcinoma-derived growth factor 1 (p=0.013; area under the curve (AUC) 0.801), but higher median percentages of natural killers (NKs) (p=0.019; AUC 0.786), monocytes (p=0.017; AUC 0.791), MSP (p=0.006; AUC 0.838), PARN (p=0.017; AUC 0.790), and E-Cadherin (p=0.022; AUC 0.788). In addition, the immune scenario of Pn after neoadjuvant treatment involves: high levels of neutrophils and NK cells, but low levels of B and T cells in peripheral blood; increased clonality of intratumoral T cells; and elevated plasma levels of several growth factors (EGF, HGF, VEGF, ANG-1, PDGF, NGF, and NT4) and inflammatory cytokines (MIF, CCL16, neutrophil gelatinase-associated lipocalin, BMP-4, and u-PAR).ConclusionsAlthough statistically underpowered, our results shed light on the possible mechanisms behind Pn development, involving innate and adaptative immunity, and open the possibility to predict patients at high risk. If confirmed, this may allow the personalization of both, the surveillance strategy and the therapeutic approaches to manage Pn in patients receiving chemoimmunotherapy.
Baseline Cognitive Impairment in Patients With Asymptomatic Carotid Stenosis in the CREST-2 Trial
Authors: Lazar Ronald M. , Wadley Virginia G. , Myers Terina , Jones Michael R. , Heck Donald V. , Clark Wayne M. , Marshall Randolph S. , Howard Virginia J. , Voeks Jenifer H. , Manly Jennifer J. , Moy Claudia S. , Chaturvedi Seemant , Meschia James F. , Lal Brajesh K. , Brott Thomas G. , Howard George 
Published: August 2021

Background and Purpose:
Studies of carotid artery disease have suggested that high-grade stenosis can affect cognition, even without stroke. The presence and degree of cognitive impairment in such patients have not been reported and compared with a demographically matched population-based cohort.

Methods:

We studied cognition in 1000 consecutive CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) patients, a treatment trial for asymptomatic carotid disease. Cognitive assessment was after randomization but before assigned treatment. The cognitive battery was developed in the general population REGARDS Study (Reasons for Geographic and Racial Differences in Stroke), involving Word List Learning Sum, Word List Recall, and Word List fluency for animal names and the letter F. The carotid stenosis patients were >45 years old with ≥70% asymptomatic carotid stenosis and no history of prevalent stroke. The distribution of cognitive performance for the patients was standardized, accounting for age, race, and education using performance from REGARDS, and after further adjustment for hypertension, diabetes, dyslipidemia, and smoking. Using the Wald Test, we tabulated the proportion of
Z
scores less than the anticipated deviate for the population-based cohort for representative percentiles.

Results:

There were 786 baseline assessments. Mean age was 70 years, 58% men, and 52% right-sided stenosis. The overall
Z
score for patients was significantly below expected for higher percentiles (
P
<0.0001 for 50th, 75th, and 95th percentiles) and marginally below expected for the 25th percentile (
P
=0.015). Lower performance was attributed largely to Word List Recall (
P
<0.0001 for all percentiles) and for Word List Learning (50th, 75th, and 95th percentiles below expected,
P
≤0.01). The scores for left versus right carotid disease were similar.

Conclusions:
Baseline cognition of patients with severe carotid stenosis showed below normal cognition compared to the population-based cohort, controlling for demographic and cardiovascular risk factors. This cohort represents the largest group to date to demonstrate that poorer cognition, especially memory, in this disease.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT02089217.
Serious Adverse Events and Their Impact on Functional Outcome in Acute Ischemic Stroke in the WAKE-UP Trial
Authors: Lettow Iris , Jensen Märit , Schlemm Eckhard , Boutitie Florent , Quandt Fanny , Cheng Bastian , Ebinger Martin , Endres Matthias , Fiebach Jochen B. , Thijs Vincent , Lemmens Robin , Muir Keith W. , Nighoghossian Norbert , Pedraza Salvador , Simonsen Claus Z. , Gerloff Christian , Thomalla Götz ,   on behalf of the WAKE-UP Investigators
Published: August 2021

Background and Purpose:
During the first days and weeks after an acute ischemic stroke, patients are prone to complications that can influence further treatment, recovery, and functional outcome. In clinical trials, severe complications are recorded as serious adverse events (SAE). We analyzed the effect of SAE on functional outcome and predictors of SAE in the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke).

Methods:
We performed a post hoc analysis of WAKE-UP, a multicenter, randomized, placebo-controlled clinical trial of magnetic resonance imaging-guided intravenous thrombolysis with alteplase in patients with acute ischemic stroke and unknown time of onset. Functional outcome was assessed by the modified Rankin Scale 90 days after the stroke. SAE were reported to a central safety desk and recorded and categorized by organ system using Medical Dictionary for Regulatory Activities terminology. We used logistic regression analysis to determine the effect of SAE on functional outcome and linear multiple regression analysis to identify baseline predictors of SAE.

Results:

Among 503 patients randomized, 199 SAE were reported for n=110 (22%) patients. Of those patients who did suffer a SAE, 20 (10%) had a fatal outcome. Patients suffering from at least one SAE had a lower odds of reaching a favorable outcome (modified Rankin Scale score of 0–1) at 90 days (adjusted odds ratio, 0.36 [95% CI, 0.21–0.61],
P
<0.001). Higher age (
P
=0.04) and male sex (
P
=0.01) were predictors for the occurrence of SAE.

Conclusions:
SAEs were observed in about one in 5 patients, were more frequent in elderly and male patients and were associated with worse functional outcome. These results may help to assess the risk of SAE in future stroke trials and create awareness for severe complications after stroke in clinical practice.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01525290. URL:
https://eudract.ema.europa.eu
; Unique identifier: 2011-005906-32.
CircRNAs and their regulatory roles in cancers
Authors: Tao Mei , Zheng Ming , Xu Yanhua , Ma Shuo , Zhang Weiwei , Ju Shaoqing 
Published: August 2021

AbstractCircular RNAs (circRNAs), a novel type of non-coding RNAs (ncRNAs), have a covalently closed circular structure resulting from pre-mRNA back splicing via spliceosome and ribozymes. They can be classified differently in accordance with different criteria. As circRNAs are abundant, conserved, and stable, they can be used as diagnostic markers in various diseases and targets to develop new therapies. There are various functions of circRNAs, including sponge for miR/proteins, role of scaffolds, templates for translation, and regulators of mRNA translation and stability. Without m7G cap and poly-A tail, circRNAs can still be degraded in several ways, including RNase L, Ago-dependent, and Ago-independent degradation. Increasing evidence indicates that circRNAs can be modified by N-6 methylation (m6A) in many aspects such as biogenesis, nuclear export, translation, and degradation. In addition, they have been proved to play a regulatory role in the progression of various cancers. Recently, methods of detecting circRNAs with high sensitivity and specificity have also been reported. This review presents a detailed overview of circRNAs regarding biogenesis, biomarker, functions, degradation, and dynamic modification as well as their regulatory roles in various cancers. It’s particularly summarized in detail in the biogenesis of circRNAs, regulation of circRNAs by m6A modification and mechanisms by which circRNAs affect tumor progression respectively. Moreover, existing circRNA detection methods and their characteristics are also mentioned.
Small airway function in Finnish COVID-19 survivors
Authors: Lindahl Anna , Reijula Jere , Malmberg Leo Pekka , Aro Miia , Vasankari Tuula , Mäkelä Mika Juhani 
Published: August 2021

AbstractFollow-up studies of COVID-19 patients have found lung function impairment up to six months after initial infection, but small airway function has not previously been studied. Patients (n = 20) hospitalised for a severe SARS-CoV-2 infection underwent spirometry, impulse oscillometry, and multiple measurements of alveolar nitric oxide three to six months after acute infection. None of the patients had small airway obstruction, nor increased nitric oxide concentration in the alveolar level. None of the patients had a reduced FEV1/FVC or significant bronchodilator responses in IOS or spirometry. In conclusion, we found no evidence of inflammation or dysfunction in the small airways.
Metal-based nanoparticles, sensors, and their multifaceted application in food packaging
Authors: Kumar Antul , Choudhary Anuj , Kaur Harmanjot , Mehta Sahil , Husen Azamal 
Published: August 2021

AbstractDue to the global rise of the human population, one of the top-most challenges for poor and developing nations is to use the food produces safely and sustainably. In this regard, the storage of surplus food (and derived products) without loss of freshness, nutrient stability, shelf life, and their parallel efficient utilization will surely boost the food production sector. One of the best technologies that have emerged within the last twenty years with applications in the packaging of food and industrial materials is the use of green mode-based synthesized nanoparticles (NPs). These NPs are stable, advantageous as well as eco-friendly. Over the several years, numerous publications have confirmed that these NPs exert antibacterial, antioxidant, and antifungal activity against a plethora of pathogens. The storage in metal-based NPs (M-NPs) does not hamper the food properties and packaging efficiency. Additionally, these M-NPs help in the improvement of properties including freshness indicators, mechanical properties, antibacterial and water vapor permeability during food packaging. As a result, the nano-technological application facilitates a simple, alternate, interactive as well as reliable technology. It even provides positive feedback to food industries and packaging markets. Taken together, the current review paper is an attempt to highlight the M-NPs for prominent applications of antimicrobial properties, nanosensors, and food packaging of food items. Additionally, some comparative reports associated with M-NPs mechanism of action, risks, toxicity, and overall future perspectives have also been made.
Global gene expression and chromatin accessibility of the peripheral nervous system in animal models of persistent pain
Authors: Stephens Kimberly E. , Zhou Weiqiang , Renfro Zachary , Ji Zhicheng , Ji Hongkai , Guan Yun , Taverna Sean D. 
Published: August 2021

Abstract
Background
Efforts to understand genetic variability involved in an individual’s susceptibility to chronic pain support a role for upstream regulation by epigenetic mechanisms.

Methods
To examine the transcriptomic and epigenetic basis of chronic pain that resides in the peripheral nervous system, we used RNA-seq and ATAC-seq of the rat dorsal root ganglion (DRG) to identify novel molecular pathways associated with pain hypersensitivity in two well-studied persistent pain models induced by chronic constriction injury (CCI) of the sciatic nerve and intra-plantar injection of complete Freund’s adjuvant (CFA) in rats.

Results
Our RNA-seq studies identify a variety of biological process related to synapse organization, membrane potential, transmembrane transport, and ion binding. Interestingly, genes that encode transcriptional regulators were disproportionately downregulated in both models. Our ATAC-seq data provide a comprehensive map of chromatin accessibility changes in the DRG. A total of 1123 regions showed changes in chromatin accessibility in one or both models when compared to the naïve and 31 shared differentially accessible regions (DAR)s. Functional annotation of the DARs identified disparate molecular functions enriched for each pain model which suggests that chromatin structure may be altered differently following sciatic nerve injury and hind paw inflammation. Motif analysis identified 17 DNA sequences known to bind transcription factors in the CCI DARs and 33 in the CFA DARs. Two motifs were significantly enriched in both models.

Conclusions
Our improved understanding of the changes in chromatin accessibility that occur in chronic pain states may identify regulatory genomic elements that play essential roles in modulating gene expression in the DRG.
Inflammatory resolution and vascular barrier restoration after retinal ischemia reperfusion injury
Authors: Abcouwer Steven F. , Shanmugam Sumathi , Muthusamy Arivalagan , Lin Cheng-mao , Kong Dejuan , Hager Heather , Liu Xuwen , Antonetti David A. 
Published: August 2021

Abstract
Background
Several retinal pathologies exhibit both inflammation and breakdown of the inner blood-retinal barrier (iBRB) resulting in vascular permeability, suggesting that treatments that trigger resolution of inflammation may also promote iBRB restoration.

Methods
Using the mouse retinal ischemia-reperfusion (IR) injury model, we followed the time course of neurodegeneration, inflammation, and iBRB disruption and repair to examine the relationship between resolution of inflammation and iBRB restoration and to determine if minocycline, a tetracycline derivative shown to reverse microglial activation, can hasten these processes.

Results
A 90-min ischemic insult followed by reperfusion in the retina induced cell apoptosis and inner retina thinning that progressed for approximately 2 weeks. IR increased vascular permeability within hours, which resolved between 3 and 4 weeks after injury. Increased vascular permeability coincided with alteration and loss of endothelial cell tight junction (TJ) protein content and disorganization of TJ protein complexes. Shunting of blood flow away from leaky vessels and dropout of leaky capillaries were eliminated as possible mechanisms for restoring the iBRB. Repletion of TJ protein contents occurred within 2 days after injury, long before restoration of the iBRB. In contrast, the eventual re-organization of TJ complexes at the cell border coincided with restoration of the barrier. A robust inflammatory response was evident a 1 day after IR and progressed to resolution over the 4-week time course. The inflammatory response included a rapid and transient infiltration of granulocytes and Ly6C+ classical inflammatory monocytes, a slow accumulation of Ly6Cneg monocyte/macrophages, and activation, proliferation, and mobilization of resident microglia. Extravasation of the majority of CD45+ leukocytes occurred from the superficial plexus. The presence of monocyte/macrophages and increased numbers of microglia were sustained until the iBRB was eventually restored. Intervention with minocycline to reverse microglial activation at 1 week after injury promoted early restoration of the iBRB coinciding with decreased expression of mRNAs for the microglial M1 markers TNF-α, IL-1β, and Ptgs2 (Cox-2) and increased expression of secreted serine protease inhibitor Serpina3n mRNA.

Conclusions
These results suggest that iBRB restoration occurs as TJ complexes are reorganized and that resolution of inflammation and restoration of the iBRB following retinal IR injury are functionally linked.
Experiences and perception towards reproductive health education among secondary school teachers in South India
Authors: Joseph Nitin , Mahato Vaibhav , Pandey Akhil , Mishra Shikha , Prakash Garima , Gandhi Rishika 
Published: August 2021

Abstract
Background
Reproductive health education (RHE) is an important component of school curricula. It helps students in the decision-making process regarding several issues concerning reproductive health. However delivering RHE at schools is a difficult task for the teachers.

Methods
This study was conducted to assess the experiences and perceptions towards reproductive health education (RHE) among 236 secondary school teachers in January 2019. Data were collected using a self-administered questionnaire.

Results
Only 21 (8.9%) were trained in RHE. Majority [179 (75.8%)] identified cultural barriers as the major challenge involved in its implementation. 95 (40.3%) teachers felt that the provision of sexual education as a part of RHE will promote pre-marital sexual activity among the students. Of the total, 185 (78.4%) had average while 51 (21.6%) participants had a good perception towards RHE. It was taught in only 3 (16.7%) out of the 18 schools surveyed. Only 11 (4.7%) participants felt that the availability of teaching aids to conduct RHE classes at their schools was adequate. Hardly 14 (5.9%) teachers had taken RHE classes for students. Among the rest, 135 (60.8%) expressed their willingness to take RHE classes with appropriate training. In multi variable analysis, participants aged ≤ 40 years (p = 0.031), those belonging to nuclear families (p = 0.013), and those who had taken classes in RHE (p = 0.037) had significantly good perception level towards RHE.

Conclusions
Teachers therefore need to be trained and given more opportunities to take RHE sessions which will help improve their perception towards RHE. Schools need to be better equipped with resources and various perceived barriers need to be overcome before RHE can be successfully implemented.
Serum biochemistry and haematology in wild and captive bearded seals (Erignathus barbatus) from Svalbard, Norway
Authors: Tryland Morten , Lydersen Christian , Kovacs Kit Maureen , Rafter Espen , Thoresen Stein Istre 
Published: August 2021

Abstract
Background
Health assessment of seals in captivity include haematology and serum biochemistry measurements. Because such parameters differ between species, it is crucial to have species-specific reference values for the interpretation of clinical samples. Furthermore, differences in nutrition and environment, life cycles as well as seasonal/annual cycles and varying physiological conditions can potentially affect serum chemistry and haematology parameters. Blood samples from four captive adult bearded seals (initially caught as pups in Svalbard, Norway, now held at Polaria, an Arctic experience centre in Tromsø, Norway) collected over a 16-month period were analysed for haematology (n = 22) and serum chemistry (n = 25) parameters. Serum chemistry analyses were also conducted on blood samples from 74 wild bearded seals (1995–2007) collected from Svalbard, Norway.

Results
We found higher activity of creatine kinase (CK) and higher concentrations of cortisol in the wild animals when compared to the captive seals, probably reflecting the physical restraint and concomitant stress induced during sampling. For the captive bearded seals, we did not find marked differences in haematology or serum chemistry parameters throughout the different seasons of sampling.

Conclusions
This study presents haematology and serum chemistry reference values for captive and wild bearded seals. Comparing physiological parameters for captive seals with wild seals indicated that having wild-caught bearded seals under the conditions offered at Polaria for several years did not markedly affect physiological parameters of the animals, and that training may have helped to alleviate stress associated with blood sampling and veterinary inspection.