bluuebunny/crossref_metadata_2025 huggingface dataset:
Portrait of Italian Cardio-Oncology: Results of a Nationwide Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO) Survey
Authors: Canale Maria Laura , Turazza Fabio , Lestuzzi Chiara , Parrini Iris , Camerini Andrea , Russo Giulia , Colivicchi Furio , Gabrielli Domenico , Gulizia Michele Massimo , Oliva Stefano , Tarantini Luigi , Maurea Nicola , Rigacci Luigi , Petrolati Sandro , Casolo Giancarlo , Bisceglia Irma
Published: June 2021

Aims: Cardio-oncology has achieved a pivotal role in science, but real world data on its clinical impact are still limited.

Methods: A questionnaire was sent out to all cardio-oncology services across Italy (n = 120). The questionnaire was made up of 28 questions divided into four blocks: (A) general information on hospitals and service, (B) the inner organization of cardio-oncology and its relationships with out-of-hospital cardiologists and general practitioners, (C) educational needs and referral guidelines, and (D) activities/specific workload.

Results: Ninety-six out of 120 (80%) completed the questionnaire; 9.4% were cancer centers while 90.6% were general hospitals. A cardio-oncology team was present in 56% of the cancer centers and in 20% only of general hospitals, and a cardio-oncology pathway was active in 55% of cancer centers and in just 14% of the general hospitals. Relationships with out-of-hospital cardiologists and general practitioners were lacking. The guidelines of reference were ESC and ANMCO/AIOM. Patients receiving anthracycline chemotherapy underwent scheduled monitoring by means of echocardiography in 58% of cases. Routine use of cardiac damage biomarkers was overall low, ranging from 22 to 33% while the use of global longitudinal strain reached 44%.

Conclusions: Italian cardio-oncology showed a growing influence on clinical practice but still has room for improvement. Cardio-oncology teams are still scarce, and the application of dedicated paths is poor. The need for specific training has been highlighted.
Deep Graph Mapper: Seeing Graphs Through the Neural Lens
Authors: Bodnar Cristian , Cangea Cătălina , Liò Pietro
Published: June 2021

Graph summarization has received much attention lately, with various works tackling the challenge of defining pooling operators on data regions with arbitrary structures. These contrast the grid-like ones encountered in image inputs, where techniques such as max-pooling have been enough to show empirical success. In this work, we merge the Mapper algorithm with the expressive power of graph neural networks to produce topologically grounded graph summaries. We demonstrate the suitability of Mapper as a topological framework for graph pooling by proving that Mapper is a generalization of pooling methods based on soft cluster assignments. Building upon this, we show how easy it is to design novel pooling algorithms that obtain competitive results with other state-of-the-art methods. Additionally, we use our method to produce GNN-aided visualisations of attributed complex networks.
Challenges and Opportunities for in situ Maintenance of the Native Brazilian Cotton Gossypium mustelinum Miers
Authors: Barroso Paulo Augusto Vianna , Hoffmann Lúcia Vieira , da Costa Nataly Duarte Lopes
Published: June 2021

The native Brazilian cotton Gossypium mustelinum has never been planted. It is tetraploid and may cross with cultivated cotton. Endemic to Northeast Brazil, it was known only to grow in semi-arid areas, but expeditions in 2011, 2016, and 2018 localized plants in preservation areas on the coast of Northeast Brazil (in the States of Paraiba and Pernambuco), as predicted before by niche simulations. New climatic modeling shows that new populations can still be found in the Pernambuco semi-arid area, despite the lack of herbarium and germplasm bank information. Historical data show that the preserved populations are in regions where sympatry has not occurred in the last 47 years. Gene flow is unlikely to be a threat, and communication may foster significantly in in situ preservation.
Prognostic Value of MEG3 and Its Correlation With Immune Infiltrates in Gliomas
Authors: Xu Xiaoping , Zhong Zhenglan , Shao Yongxiang , Yi Yong
Published: June 2021

Accumulating evidence has revealed that dysregulated lncRNA expression contributes to the onset and progression of cancer. However, the mechanistic role of lncRNA in glioma progression and tumor immunology remains largely unknown. This study aimed to evaluate the significance of maternally expressed gene 3 (MEG3) in the prognosis of and its immune-related roles in gliomas. The expression levels of MEG3 were analyzed using Oncomine and TIMER database. As an important imprinted gene, the copy number variation (CNV) of MEG3 in both glioblastoma multiforme (GBM) and low-grade glioma (LGG) were analyzed using GSCALite database, whereas its prognostic significance was assessed using PrognoScan and GEPIA databases. The relationship between MEG3 and tumor-infiltrated immune cells was analyzed using TIMER. Results showed that MEG3 expression was lower in most of the human cancer tissues than in the normal tissues. We also found that heterozygous deletion of MEG3 occurred more frequent than heterozygous amplification in gliomas, and mRNA expression of MEG3 was significantly positively correlated with its CNV in both the GBM and LGG group. Survival analysis showed that the CNV level of MEG3 had significant correlation with overall survival (OS) and progression-free survival (PFS) compared with wild type in LGG. Lower MEG3 expression was related with poor prognosis. Further analysis showed that in GBM, MEG3 expression level was significantly positively correlated with that of infiltrating CD8+ T cells and significantly negatively correlated with that of infiltrating dendritic cells. In LGG, MEG3 expression level was significantly negatively correlated with levels of infiltrating B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. Univariate Cox survival analysis demonstrated that only the level of infiltrating dendritic cells significantly affected the survival time of patients with GBM, while all six types of immune cells had a significant effect on the survival time of patients with LGG. Furthermore, MEG3 expression showed strong correlations with multiple immune markers in gliomas, especially in LGG. The current findings suggest that MEG3 expression might serve as a possible prognostic marker and potential immunotherapeutic target for gliomas.
Upregulated Expression of Profilin1 on Dendritic Cells in Patients With Severe Aplastic Anemia
Authors: Yu Hong , Zhao Yang , Pan Xiaofeng , Liu Chunyan , Fu Rong
Published: June 2021

Severe aplastic anemia (SAA) is a life-threatening form of bone marrow failure that is associated with very high mortality. Dendritic cells (DCs) are antigen presenting cells (APCs) with powerful movement ability, which is an important factor affecting immune function. The expression of profilin1 (Pfn1) plays an important role in the regulation of cell movement ability. We detected the expression of Pfn1 mRNA in the bone marrow (BM) myeloid dendritic cells (mDCs) from patients with SAA using RT-PCR. Next, we examined Pfn1 expression on mDCs using flow cytometry (FCM). We also assessed the relationship between Pfn1 expression and cytokine levels. Our data showed increased Pfn1 mRNA expression in patients with SAA. The expression of Pfn1 in BM mDCs increased in SAA patients. The expression of Pfn1 on mDCs and cytokines (TNF-α and IFN-γ) were positively correlated in the serum of untreated patients with SAA. Taken together, we found that the expression of Pfn1 on mDCs of SAA patients increased, which may affect the function of mDCs. Profilin 1 may be involved in the immunopathogenesis of SAA.
NKG2D Enhances Double-Negative T Cell Regulation of B Cells
Authors: Hu Shi-hua , Zhang Long-hui , Gao Jie , Guo Jing-heng , Xun Xiao-dong , Xiang Xiao , Cheng Qian , Li Zhao , Zhu Ji-ye
Published: June 2021

Numerous studies reported a small subpopulation of TCRαβ+CD4-CD8- (double-negative) T cells that exert regulatory functions in the peripheral lymphocyte population. However, the origin of these double-negative T (DNT) cells is controversial. Some researchers reported that DNT cells originated from the thymus, and others argued that these cells are derived from peripheral immune induction. We report a possible mechanism for the induction of nonregulatory CD4+ T cells to become regulatory double-negative T (iDNT) cells in vitro. We found that immature bone marrow dendritic cells (CD86+MHC-II- DCs), rather than mature DCs (CD86+MHC-II+), induced high levels of iDNT cells. The addition of an anti-MHC-II antibody to the CD86+MHC-II+ DC group significantly increased induction. These iDNT cells promoted B cell apoptosis and inhibited B cell proliferation and plasma cell formation. A subgroup of iDNT cells expressed NKG2D. Compared to NKG2D- iDNT cells, NKG2D+ iDNT cells released more granzyme B to enhance B cell regulation. This enhancement may function via NKG2D ligands expressed on B cells following lipopolysaccharide stimulation. These results demonstrate that MHC-II impedes induction, and iDNT cells may be MHC independent. NKG2D expression on iDNT cells enhanced the regulatory function of these cells. Our findings elucidate one possible mechanism of the induction of peripheral immune tolerance and provide a potential treatment for chronic allograft rejection in the future.
NLRP3 Regulates IL-4 Expression in TOX+ CD4+ T Cells of Cutaneous T Cell Lymphoma to Potentially Promote Disease Progression
Authors: Huanosta-Murillo Enrique , Alcántara-Hernández Marcela , Hernández-Rico Brenda , Victoria-Acosta Georgina , Miranda-Cruz Patricia , Domínguez-Gómez María Antonieta , Jurado-Santacruz Fermín , Patiño-López Genaro , Pérez-Koldenkova Vadim , Palma-Guzmán Alam , Licona-Limón Paula , Fuentes-Pananá Ezequiel M. , Lemini-López Alicia , Bonifaz Laura C.
Published: June 2021

In cutaneous T cell lymphoma (CTCL), a dominant Th2 profile associated with disease progression has been proposed. Moreover, although the production and regulation of IL-4 expression during the early stages of the disease may have important implications in later stages, these processes are poorly understood. Here, we demonstrate the presence of TOX+ CD4+ T cells that produce IL-4+ in early-stage skin lesions of CTCL patients and reveal a complex mechanism by which the NLRP3 receptor promotes a Th2 response by controlling IL-4 production. Unassembled NLRP3 is able to translocate to the nucleus of malignant CD4+ T cells, where it binds to the human il-4 promoter. Accordingly, IL-4 expression is decreased by knocking down and increased by promoting the nuclear localization of NLRP3. We describe a positive feedback loop in which IL-4 inhibits NLRP3 inflammasome assembly, thereby further increasing its production. IL-4 induced a potentially malignant phenotype measured based on TOX expression and proliferation. This mechanism of IL-4 regulation mediated by NLRP3 is amplified in late-stage CTCL associated with disease progression. These results indicate that NLRP3 might be a key regulator of IL-4 expression in TOX+ CD4+ T cells of CTCL patients and that this mechanism might have important implications in the progression of the disease.
Means, Motive, and Opportunity: Do Non-Islet-Reactive Infiltrating T Cells Contribute to Autoimmunity in Type 1 Diabetes?
Authors: Rodriguez-Calvo Teresa , Christoffersson Gustaf , Bender Christine , von Herrath Matthias G. , Mallone Roberto , Kent Sally C. , James Eddie A.
Published: June 2021

In human type 1 diabetes and animal models of the disease, a diverse assortment of immune cells infiltrates the pancreatic islets. CD8+T cells are well represented within infiltrates and HLA multimer staining of pancreas sections provides clear evidence that islet epitope reactive T cells are present within autoimmune lesions. Thesebona fideeffectors have been a key research focus because these cells represent an intellectually attractive culprit for β cell destruction. However, T cell receptors are highly diverse in human insulitis. This suggests correspondingly broad antigen specificity, which includes a majority of T cells for which there is no evidence of islet-specific reactivity. The presence of “non-cognate” T cells in insulitis raises suspicion that their role could be beyond that of an innocent bystander. In this perspective, we consider the potential pathogenic contribution of non-islet-reactive T cells. Our intellectual framework will be that of a criminal investigation. Having arraigned islet-specific CD8+T cells for the murder of pancreatic β cells, we then turn our attention to the non-target immune cells present in human insulitis and consider the possible regulatory, benign, or effector roles that they may play in disease. Considering available evidence, we overview the case that can be made that non-islet-reactive infiltrating T cells should be suspected as co-conspirators or accessories to the crime and suggest some possible routes forward for reaching a better understanding of their role in disease.
In Vivo Sustained Release of Peptide Vaccine Mediated by Dendritic Mesoporous Silica Nanocarriers
Authors: An Weiteng , Defaus Sira , Andreu David , Rivera-Gil Pilar
Published: June 2021

Mesoporous silica nanoparticles have drawn increasing attention as promising candidates in vaccine delivery. Previous studies evaluating silica-based vaccine delivery systems concentrated largely on macromolecular antigens, such as inactivated whole viruses. In this study, we synthesized dendritic mesoporous silica nanoparticles (DMSNs), and we evaluated their effectiveness as delivery platforms for peptide-based subunit vaccines. We encapsulated and tested in vivo an earlier reported foot-and-mouth disease virus (FMDV) peptide vaccine (B2T). The B2T@DMSNs formulation contained the peptide vaccine and the DMSNs without further need of other compounds neither adjuvants nor emulsions. We measured in vitro a sustained release up to 930 h. B2T@DMSNs-57 and B2T@DMSNs-156 released 23.7% (135 µg) and 22.8% (132 µg) of the total B2T. The formation of a corona of serum proteins around the DMSNs increased the B2T release up to 61% (348 µg/mg) and 80% (464 µg/mg) for B2T@DMSNs-57 and B2T@DMSNs-156. In vitro results point out to a longer sustained release, assisted by the formation of a protein corona around DMSNs, compared to the reference formulation (i.e., B2T emulsified in Montanide). We further confirmed in vivo immunogenicity of B2T@DMSNs in a particle size-dependent manner. Since B2T@DMSNs elicited specific immune responses in mice with high IgG production like the reference B2T@Montanide™, self-adjuvant properties of the DMSNs could be ascribed. Our results display DMSNs as efficacious nanocarriers for peptide-based vaccine administration.
The Safety and Immunogenicity of the mRNA-BNT162b2 SARS-CoV-2 Vaccine in Hemodialysis Patients
Authors: Zitt Emanuel , Davidovic Tamara , Schimpf Judith , Abbassi-Nik Armin , Mutschlechner Beatrix , Ulmer Hanno , Benda Magdalena A. , Sprenger-Mähr Hannelore , Winder Thomas , Lhotta Karl
Published: June 2021

Background

Hemodialysis patients are at high risk for severe COVID-19. SARS-CoV-2 vaccination related safety and immunogenicity data in these patients are rare.

Methods

In this observational study SARS-CoV-2-seronegative hemodialysis patients were vaccinated with two doses of the Pfizer/BioNTech mRNA-BNT162b2 vaccine (COMIRNATY® 30 µg) and followed for 90 days. Local and systemic side effects were assessed at every dialysis session during the first post-vaccination week after the first and second vaccine dose. Immunogenicity was determined four weeks after vaccination by quantifying anti-SARS-CoV-2 spike protein IgG antibodies (LIAISON® SARS-CoV-2-TrimericS IgG chemiluminescent immunoassay) expressed in binding activity units per milliliter (BAU/mL) adapted to the WHO International standard.

Results

Fifty patients (32% women, 68% men) with a mean (SD) age of 67.6 (14.8) years were included. Mild local reactions occurred in 38% after the first injection, and in 29.2% with mild, in 2.1% with moderate and in 2.1% with severe degree after the second injection. Systemic reactive events occurred less often, with diarrhea (4% mild, 4% moderate) and fatigue (8% mild) being the most frequent ones. After the first injection 42% of the patients developed a positive response using the assay specific cut-off value of 33.8 binding activity units per milliliter (BAU/mL) with a median (Q1, Q3) anti-SARS-CoV-2 spike IgG concentration of 20.0 (11.7, 51.0) BAU/mL. After the second injection the percentage of seropositive patients increased to 97.9% with an anti-SARS-CoV-2 spike IgG concentration of 1075 (290.8, 1735) BAU/mL. Higher age and immunosuppression were associated with lower, calcitriol treatment and prior seroconversion to hepatitis B vaccination with significantly higher antibody concentration.

Conclusions

The mRNA-BNT162b2 SARS-CoV-2 vaccine appears to be safe and well-tolerated and shows a high immunogenicity in hemodialysis patients.
Declining Levels of Neutralizing Antibodies Against SARS-CoV-2 in Convalescent COVID-19 Patients One Year Post Symptom Onset
Authors: Xiang Tiandan , Liang Boyun , Fang Yaohui , Lu Sihong , Li Sumeng , Wang Hua , Li Huadong , Yang Xiaoli , Shen Shu , Zhu Bin , Wang Baoju , Wu Jun , Liu Jia , Lu Mengji , Yang Dongliang , Dittmer Ulf , Trilling Mirko , Deng Fei , Zheng Xin
Published: June 2021

Major advances have been made in understanding the dynamics of humoral immunity briefly after the acute coronavirus disease 2019 (COVID-19). However, knowledge concerning long-term kinetics of antibody responses in convalescent patients is limited. During a one-year period post symptom onset, we longitudinally collected 162 samples from 76 patients and quantified IgM and IgG antibodies recognizing the nucleocapsid (N) protein or the receptor binding domain (RBD) of the spike protein (S). After one year, approximately 90% of recovered patients still had detectable SARS-CoV-2-specific IgG antibodies recognizing N and RBD-S. Intriguingly, neutralizing activity was only detectable in ~43% of patients. When neutralization tests against the E484K-mutated variant of concern (VOC) B.1.351 (initially identified in South Africa) were performed among patients who neutralize the original virus, the capacity to neutralize was even further diminished to 22.6% of donors. Despite declining N- and S-specific IgG titers, a considerable fraction of recovered patients had detectable neutralizing activity one year after infection. However, neutralizing capacities, in particular against an E484K-mutated VOC were only detectable in a minority of patients one year after symptomatic COVID-19. Our findings shed light on the kinetics of long-term immune responses after natural SARS-CoV-2 infection and argue for vaccinations of individuals who experienced a natural infection to protect against emerging VOC.
Fat and Happy: Profiling Mosquito Fat Body Lipid Storage and Composition Post-blood Meal
Authors: Pinch Matthew , Mitra Soumi , Rodriguez Stacy D. , Li Yiyi , Kandel Yashoda , Dungan Barry , Holguin F. Omar , Attardo Geoffrey M. , Hansen Immo A.
Published: June 2021

The fat body is considered the insect analog of vertebrate liver and fat tissue. In mosquitoes, a blood meal triggers a series of processes in the fat body that culminate in vitellogenesis, the process of yolk formation. Lipids are stored in the fat body in specialized organelles called lipid droplets that change in size depending on the nutritional and metabolic status of the insect. We surveyed lipid droplets in female Aedes aegypti fat body during a reproductive cycle using confocal microscopy and analyzed the dynamic changes in the fat body lipidome during this process using LC/MS. We found that lipid droplets underwent dynamic changes in volume after the mosquito took a blood meal. The lipid composition found in the fat body is quite complex with 117 distinct lipids that fall into 19 classes and sublcasses. Our results demonstrate that the lipid composition of the fat body is complex as most lipid classes underwent significant changes over the course of the vitellogenic cycle. This study lays the foundation for identifying unknown biochemical pathways active in the mosquito fat body, that are high-value targets for the development of novel mosquito control strategies.
Cetacean Research and Citizen Science in Kenya
Authors: Mwango’mbe Michael Gilbert , Spilsbury Jane , Trott Steve , Nyunja Judith , Wambiji Nina , Collins Tim , Gomes Inês , Pérez-Jorge Sergi
Published: June 2021

In 2011, several non-governmental and government agencies established the Kenya Marine Mammal Network (KMMN) to provide a platform for the consistent collection of data on marine mammals along the Kenyan coast, identify areas of importance and engage marine users and the general public in marine mammal conservation. Prior to the KMMN, relatively little was known about marine mammals in Kenya, limiting conservation strategies. The KMMN collects data nationwide through dedicated surveys, opportunistic sightings and participative citizen science, currently involving more than 100 contributors. This paper reviews data on sightings and strandings for small cetaceans in Kenya collated by the KMMN. From 2011 to 2019, 792 records of 11 species of small cetaceans were documented. The most frequently reported inshore species were the Indo-Pacific bottlenose dolphin and Indian Ocean humpback dolphin. Offshore species, included killer whales, short-finned pilot whale and long-snouted spinner dolphin. Indo-Pacific bottlenose dolphins, long-snouted spinner dolphins, striped dolphins and Risso’s dolphins were recorded through stranding reports. The efforts of the KMMN were disseminated through international meetings (International Whaling Commission, World Marine Mammal Conference), national status reports, outreach and social media. Data has also supported the identification of three IUCN Important Marine Mammal Areas and one Area of Interest in Kenya. Further research is needed to improve estimates of cetacean abundance and distribution, particularly in unstudied coastal areas, and to assess the extent of anthropogenic threats associated with fisheries, coastal and port development, seismic exercises and unregulated tourism. The expansion of the network should benefit from the participation of remote coastal fishing communities, government research agencies, tourism and seismic operations, among others. The KMMN demonstrated the value of dedicated and citizen science data to enhance marine mammal conservation strategies to boost awareness and eco-tourism and to bring the public and science closer together, promoting research and effective conservation efforts.
Derivation and Validation of a Nomogram for Predicting 90-Day Survival in Patients With HBV-Related Acute-on-Chronic Liver Failure
Authors: Chen Jun-feng , Weng Wei-zhen , Huang Miao , Peng Xiao-hua , He Jian-rong , Zhang Jing , Xiong Jing , Zhang Shao-quan , Cao Hui-juan , Gao Bin , Lin Deng-na , Gao Juan , Gao Zhi-liang , Lin Bing-liang
Published: June 2021

Background: Conventional prognostic models do not fully reflect the severity of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). This study aimed to establish an effective and convenient nomogram for patients with HBV-related ACLF.

Methods: A nomogram was developed based on a retrospective cohort of 1,353 patients treated at the Third Affiliated Hospital of Sun Yat-sen University from January 2010 to June 2016. The predictive accuracy and discriminatory ability of the nomogram were determined by a concordance index (C-index) and calibration curve, and were compared with current scoring systems. The results were validated using an independent retrospective cohort of 669 patients consecutively treated at the same institution from July 2016 to March 2018. This study is registered at ClinicalTrials.gov (NCT03992898).

Results: Multivariable analysis of the derivation cohort found that independent predictors of 90-day survival were age, white blood cell (WBC) count, hemoglobin (Hb), aspartate aminotransferase (AST), total bilirubin (TBil), international normalized ratio, serum creatinine (Cr), alpha fetoprotein (AFP), serum sodium (Na), hepatic encephalopathy (HE), pre-existing chronic liver disease(PreLD), and HBV DNA load. All factors were included in the nomogram. The nomogram calibration curve for the probability of 90-day survival indicated that nomogram-based predictions were in good agreement with actual observations. The C-index of the nomogram was 0.790, which was statistically significantly greater than those for the current scoring systems in the derivation cohort (P < 0.001). The results were confirmed in the validation cohort.

Conclusions: The proposed nomogram is more accurate in predicting the 90-day survival of patients with HBV-related ACLF than current commonly used methods.
Low Acyl Gellan as an Excipient to Improve the Sprayability and Mucoadhesion of Iota Carrageenan in a Nasal Spray to Prevent Infection With SARS-CoV-2
Authors: Robinson Thomas E. , Moakes Richard J. A. , Grover Liam M.
Published: June 2021

The COVID-19 global pandemic, as well as the widespread persistence of influenza and the common cold, create the need for new medical devices such as nasal sprays to prevent viral infection and transmission. Carrageenan, a sulfated polysaccharide, has a broad, non-pharmacological antiviral capacity, however it performs poorly in two key areas; spray coverage and mucoadhesion. Therefore gellan, another polysaccharide, was investigated as an excipient to improve these properties. It was found that viscoelastic relaxation time was the key predictor of spray coverage, and by reducing this value from 2.5 to 0.25 s, a mix of gellan and carrageenan gave more than four times the coverage of carrageenan alone (p < 0.0001). Gellan also demonstrated enhanced adhesion to a mucus analog that increased significantly with time (p < 0.0001), suggesting the development of specific gellan–mucin interactions. This property was conferred to carrageenan on mixing the two polymers. Together, this data suggests that gellan is a promising excipient to improve both sprayability and mucoadhesion of carrageenan for use in antiviral nasal sprays.
Genomic Analysis of the Endophytic Stenotrophomonas Strain 169 Reveals Features Related to Plant-Growth Promotion and Stress Tolerance
Authors: Ulrich Kristina , Kube Michael , Becker Regina , Schneck Volker , Ulrich Andreas
Published: June 2021

Plant-associated Stenotrophomonas isolates have great potential for plant growth promotion, especially under stress conditions, due to their ability to promote tolerance to abiotic stresses such as salinity or drought. The endophytic strain Stenotrophomonas sp. 169, isolated from a field-grown poplar, increased the growth of inoculated in vitro plants, with a particular effect on root development, and was able to stimulate the rooting of poplar cuttings in the greenhouse. The strain produced high amounts of the plant growth-stimulating hormone auxin under in vitro conditions. The comparison of the 16S rRNA gene sequences and the phylogenetic analysis of the core genomes showed a close relationship to Stenotrophomonas chelatiphaga and a clear separation from Stenotrophomonas maltophilia. Whole genome sequence analysis revealed functional genes potentially associated with attachment and plant colonization, growth promotion, and stress protection. In detail, an extensive set of genes for twitching motility, chemotaxis, flagella biosynthesis, and the ability to form biofilms, which are connected with host plant colonization, could be identified in the genome of strain 169. The production of indole-3-acetic acid and the presence of genes for auxin biosynthesis pathways and the spermidine pathway could explain the ability to promote plant growth. Furthermore, the genome contained genes encoding for features related to the production of different osmoprotective molecules and enzymes mediating the regulation of stress tolerance and the ability of bacteria to quickly adapt to changing environments. Overall, the results of physiological tests and genome analysis demonstrated the capability of endophytic strain 169 to promote plant growth. In contrast to related species, strain 169 can be considered non-pathogenic and suitable for biotechnology applications.
Calcineurin Participation in Hebbian and Homeostatic Plasticity Associated With Extinction
Authors: Reyes-García Salma E. , Escobar Martha L.
Published: June 2021

In nature, animals need to adapt to constant changes in their environment. Learning and memory are cognitive capabilities that allow this to happen. Extinction, the reduction of a certain behavior or learning previously established, refers to a very particular and interesting type of learning that has been the basis of a series of therapies to diminish non-adaptive behaviors. In recent years, the exploration of the cellular and molecular mechanisms underlying this type of learning has received increasing attention. Hebbian plasticity (the activity-dependent modification of the strength or efficacy of synaptic transmission), and homeostatic plasticity (the homeostatic regulation of plasticity) constitute processes intimately associated with memory formation and maintenance. Particularly, long-term depression (LTD) has been proposed as the underlying mechanism of extinction, while the protein phosphatase calcineurin (CaN) has been widely related to both the extinction process and LTD. In this review, we focus on the available evidence that sustains CaN modulation of LTD and its association with extinction. Beyond the classic view, we also examine the interconnection among extinction, Hebbian and homeostatic plasticity, as well as emergent evidence of the participation of kinases and long-term potentiation (LTP) on extinction learning, highlighting the importance of the balance between kinases and phosphatases in the expression of extinction. Finally, we also integrate data that shows the association between extinction and less-studied phenomena, such as synaptic silencing and engram formation that open new perspectives in the field.
Ketogenic Diet Therapy for the Treatment of Post-encephalitic and Autoimmune-Associated Epilepsies
Authors: Husari Khalil S. , Cervenka Mackenzie C.
Published: June 2021

Introduction: Acute Encephalitis is associated with a high risk of acute symptomatic seizures, status epilepticus, and remote symptomatic epilepsy. Ketogenic diet therapies (KDT) have been established as a feasible and safe adjunctive management of refractory- and super-refractory status epilepticus. However, the role of KDT in the chronic management of Post-encephalitic epilepsy (PE) and autoimmune-associated epilepsy (AE) is unknown. This study aims to investigate the use of KDT in patients with PE and AE.

Methods: A retrospective single-center case series examining adult patients with PE and AE treated with the modified Atkins diet (MAD), a KDT commonly used by adults with drug-resistant epilepsy.

Results: Ten patients with PE and AE who were treated with adjunctive MAD were included. Four patients had either confirmed or presumed viral encephalitis, five patients had seronegative AE, and one patient had GAD65 AE. The median latency between starting MAD and onset of encephalitis was 6 years (IQR: 1–10). The median duration of MAD was 10 months (IQR: 3.75–36). Three patients (30%) became seizure-free, one patient (10%) achieved 90% seizure freedom, and three patients (30%) achieved a 50–75% reduction in their baseline seizure frequency, while three patients (30%) had no significant benefit. Overall, seven patients (70%) achieved ≥50% seizure reduction.

Conclusion: In addition to its established role in the treatment of RSE, KDT may be a safe and feasible option for the treatment of chronic PE and AE, particularly in those with prior history of SE. Prospective studies are warranted to explore the efficacy of KDT in management of patients with PE and AE.
Early Effects of Passive Leg-Raising Test, Fluid Challenge, and Norepinephrine on Cerebral Autoregulation and Oxygenation in COVID-19 Critically Ill Patients
Authors: Robba Chiara , Messina Antonio , Battaglini Denise , Ball Lorenzo , Brunetti Iole , Bassetti Matteo , Giacobbe Daniele R. , Vena Antonio , Patroniti Nicolo' , Cecconi Maurizio , Matta Basil F. , Liu Xiuyun , Rocco Patricia R. M. , Czosnyka Marek , Pelosi Paolo
Published: June 2021

Background: Coronavirus disease 2019 (COVID-19) patients are at high risk of neurological complications consequent to several factors including persistent hypotension. There is a paucity of data on the effects of therapeutic interventions designed to optimize systemic hemodynamics on cerebral autoregulation (CA) in this group of patients.

Methods: Single-center, observational prospective study conducted at San Martino Policlinico Hospital, Genoa, Italy, from October 1 to December 15, 2020. Mechanically ventilated COVID-19 patients, who had at least one episode of hypotension and received a passive leg raising (PLR) test, were included. They were then treated with fluid challenge (FC) and/or norepinephrine (NE), according to patients' clinical conditions, at different moments. The primary outcome was to assess the early effects of PLR test and of FC and NE [when clinically indicated to maintain adequate mean arterial pressure (MAP)] on CA (CA index) measured by transcranial Doppler (TCD). Secondary outcomes were to evaluate the effects of PLR test, FC, and NE on systemic hemodynamic variables, cerebral oxygenation (rSo2), and non-invasive intracranial pressure (nICP).

Results: Twenty-three patients were included and underwent PLR test. Of these, 22 patients received FC and 14 were treated with NE. The median age was 62 years (interquartile range = 57–68.5 years), and 78% were male. PLR test led to a low CA index [58% (44–76.3%)]. FC and NE administration resulted in a CA index of 90.8% (74.2–100%) and 100% (100–100%), respectively. After PLR test, nICP based on pulsatility index and nICP based on flow velocity diastolic formula was increased [18.6 (17.7–19.6) vs. 19.3 (18.2–19.8) mm Hg, p = 0.009, and 12.9 (8.5–18) vs. 15 (10.5–19.7) mm Hg, p = 0.001, respectively]. PLR test, FC, and NE resulted in a significant increase in MAP and rSo2.

Conclusions: In mechanically ventilated severe COVID-19 patients, PLR test adversely affects CA. An individualized strategy aimed at assessing both the hemodynamic and cerebral needs is warranted in patients at high risk of neurological complications.
Research on the Glial–Lymphatic System and Its Relationship With Alzheimer’s Disease
Authors: Ding Danhua , Wang Xinyu , Li Qianqian , Li Lanjun , Wu Jun
Published: June 2021

Metabolic waste clearance is essential to maintain body homeostasis, in which the lymphatic system plays a vital role. Conversely, in recent years, studies have identified the glial–lymphatic system in the brain, which primarily comprises the inflow of fluid along the para-arterial space. Aquaporin-4 mediates the convection of interstitial fluid in the brain and outflow along the paravenous space. β-Amyloid deposition is a characteristic pathological change in Alzheimer’s disease, and some studies have found that the glial–lymphatic system plays an important role in its clearance. Thus, the glial–lymphatic system may influence Alzheimer’s disease severity and outcome; therefore, this review summarizes the current and available research on the glial–lymphatic system and Alzheimer’s disease.
Tumor Immune Microenvironment Components and Checkpoint Molecules in Anaplastic Variant of Diffuse Large B-Cell Lymphoma
Authors: Xu Tianqi , Chai Jia , Wang Kaijing , Jia Qingge , Liu Yixiong , Wang Yingmei , Xu Junpeng , Yu Kangjie , Zhao Danhui , Ma Jing , Fan Linni , Yan Qingguo , Guo Shuangping , Chen Gang , Chen Qiongrong , Xiao Hualiang , Liu Fang , Qi Chubo , Liang Rong , Li Mingyang , Wang Zhe
Published: June 2021

Background

Anaplastic diffuse large B-cell lymphoma(A-DLBCL) is a rare morphological subtype characterized by the presence of polygonal, bizarre-shaped tumor cells. Our previous research found that A-DLBCL displays many genetic alterations and biological features that differ greatly from those of ordinary DLBCL. However, the status of tumor immune microenvironment components and checkpoint molecules in A-DLBCL remains unclear.

Methods

Thirty A-DLBCL patients were enrolled to study tumor immune microenvironment components and checkpoint molecules and their associations with clinicopathological features and prognosis.

Results

Patients with A-DLBCL presented higher expression of PD-L1 (40%vs10%, P=0.004) than patients with ordinary DLBCL. FISH analysis showed that extra copies of PD-L1 were more frequent in A-DLBCL cases than in ordinary DLBCL cases (23.3%vs4.0%, P=0.001). The numbers of PD-1+TILs (tumor infiltrating lymphocytes) and CD8+T cells were significantly lower in A-DLBCL versus ordinary DLBCL. In contrast, the numbers of GATA3+Th2 cells, FOXP3+Tregs and CD33+myeloid-derived suppressor cells (MDSCs) were significantly higher in A-DLBCL than in ordinary DLBCL. The associations between clinicopathological features and tumor immune microenvironment cell frequency were analyzed in A-DLBCL patients. Briefly, the number of PD-1+TILs was lower and the number of CD33+MDSCs was higher in patients with mutatedTP53compared to those with wild-typeTP53. The number of FOXP3+Tregs was much lower in patients with a noncomplete response (CR) to chemotherapy than in those with a complete response. The number of CD8+T cells showed a decreasing trend in patients with high International Prognostic Index (IPI) scores and in those with concurrent MYC and BCL2 and/or BCL6 abnormalities. Univariate survival analysis showed that patients with PD-L1+, mPD-L1+(PD-L1+nonmalignant stromal cells) or mPD-L1+status had a significantly poorer overall survival (OS) than those with PD-L1-status. An increase in the number of CD3+T cells, FOXP3+Treg cells and T-bet+Th1 cells was significantly associated with prolonged OS in patients with A-DLBCL.

Conclusion

Our study suggests that A-DLBCL displays a distinct pattern of tumor immune microenvironment components and checkpoint molecules that distinguish it from ordinary DLBCL. The analysis of tumor immune microenvironment components and checkpoint molecules could help in predicting the prognosis of A-DLBCL patients and determining therapeutic strategies targeting the tumor immune microenvironment.
Current Triple-Negative Breast Cancer Subtypes: Dissecting the Most Aggressive Form of Breast Cancer
Authors: Ensenyat-Mendez Miquel , Llinàs-Arias Pere , Orozco Javier I. J. , Íñiguez-Muñoz Sandra , Salomon Matthew P. , Sesé Borja , DiNome Maggie L. , Marzese Diego M.
Published: June 2021

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease defined by the absence of estrogen receptor (ER) and progesterone receptor (PR) expression, and human epidermal growth factor receptor 2 (HER2) overexpression that lacks targeted treatments, leading to dismal clinical outcomes. Thus, better stratification systems that reflect intrinsic and clinically useful differences between TNBC tumors will sharpen the treatment approaches and improve clinical outcomes. The lack of a rational classification system for TNBC also impacts current and emerging therapeutic alternatives. In the past years, several new methodologies to stratify TNBC have arisen thanks to the implementation of microarray technology, high-throughput sequencing, and bioinformatic methods, exponentially increasing the amount of genomic, epigenomic, transcriptomic, and proteomic information available. Thus, new TNBC subtypes are being characterized with the promise to advance the treatment of this challenging disease. However, the diverse nature of the molecular data, the poor integration between the various methods, and the lack of cost-effective methods for systematic classification have hampered the widespread implementation of these promising developments. However, the advent of artificial intelligence applied to translational oncology promises to bring light into definitive TNBC subtypes. This review provides a comprehensive summary of the available classification strategies. It includes evaluating the overlap between the molecular, immunohistochemical, and clinical characteristics between these approaches and a perspective about the increasing applications of artificial intelligence to identify definitive and clinically relevant TNBC subtypes.
Inflammatory Environment Promotes the Adhesion of Tumor Cells to Brain Microvascular Endothelial Cells
Authors: Wang Ke , Dong Shuang , Higazy Doaa , Jin Lijing , Zou Qingcui , Chen Haowei , Inayat Aakif , Hu Sheng , Cui Min
Published: June 2021

Cancer patients usually suffer from unfavorable prognosis, particularly with the occurrence of brain metastasis of lung cancer. The key incident of brain metastasis initiation is crossing of blood-brain barrier (BBB) by cancer cells. Although preventing brain metastasis is a principal goal of cancer therapy, the cellular mechanisms and molecular regulators controlling the transmigration of cancer cells into the brain are still not clearly illustrated. We analyzed the mRNA expression profiles of metastatic brain tissues and TNF-α treated cancer cells to understand the changes in adhesion molecule expression during the tumor phase. To imitate the tumor microenvironment, an in vitro model was developed and the low or high metastatic potential lung tumor cells (A549 or H358) were cultured with the human brain microvascular endothelial cells (hBMECs) under TNF-α treatment. The analysis of online database indicated an altered expression for adhesion molecules and enrichment of their associated signaling pathways. TNF-α treatment activated hBMECs via up-regulating several adhesion molecules, including ICAM1, CD112, CD47, and JAM-C. Meanwhile, TNF-α induced an increased expression of adhesion molecule ligands such as ALCAM and CD6 in both A549 and H358. Moreover, the expression of adhesion molecules and the ligands were also increased both in A549- or H358-hBMECs mixed culture system, which promoted tumor cells adhesion to endothelial cells. These results suggested that the enhanced interaction between tumor cells and brain microvascular endothelium might facilitate the incidence of metastatic brain tumors and further offer a better comprehension of brain metastasis prevention and treatment.
Gastric Cancer Stem Cells: A Glimpse on Metabolic Reprogramming
Authors: Addeo Martina , Di Paola Giuseppina , Verma Henu Kumar , Laurino Simona , Russi Sabino , Zoppoli Pietro , Falco Geppino , Mazzone Pellegrino
Published: June 2021

Gastric cancer (GC) is one of the most widespread causes of cancer-related death worldwide. Recently, emerging implied that gastric cancer stem cells (GCSCs) play an important role in the initiation and progression of GC. This subpopulation comprises cells with several features, such as self-renewal capability, high proliferating rate, and ability to modify their metabolic program, which allow them to resist current anticancer therapies. Metabolic pathway intermediates play a pivotal role in regulating cell differentiation both in tumorigenesis and during normal development. Thus, the dysregulation of both anabolic and catabolic pathways constitutes a significant opportunity to target GCSCs in order to eradicate the tumor progression. In this review, we discuss the current knowledge about metabolic phenotype that supports GCSC proliferation and we overview the compounds that selectively target metabolic intermediates of CSCs that can be used as a strategy in cancer therapy.
Effect of Vertebral Fracture on Auxological Profiles of Children Undergoing Acute Lymphoblastic Leukemia Treatment
Authors: Ahn Moon Bae , Kim Seongkoo , Cho Won Kyoung , Lee Jae Wook , Jung Min Ho , Chung Nack-Gyun , Cho Bin , Suh Byung-Kyu
Published: June 2021

Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, and children with ALL often experience skeletal morbidity such as vertebral fractures (VF) during and after ALL treatment. Among various treatment-associated factors that affect growth pattern, the presence of VF might trigger growth impairment.

Objective: This study aimed to investigate the overall VF incidence following childhood ALL treatment and examined the association of VF with growth.

Methods: Children diagnosed with ALL whose treatment was completed between 2 and 15 years of age and who were screened with lateral thoracolumbar spine radiographs were enrolled. Clinical data, including anthropometric parameters were obtained at leukemia diagnosis (LD), treatment completion (TC), and 12 months following TC while VF assessment were obtained at TC and 12 months following TC.

Results: In total, 155 children were included, and height status was decreased, whereas weight and BMI status were increased throughout three observational points. VF incidence at TC was 18.7%. Height status were lower in children with VF at LD, TC, and 12 months following TC, while a greater height decline was observed during the treatment period. Age and height status at LD and average glucocorticoid (GC) dose were associated VF incidence at TC. The presence of VF was a significant risk factor of height decline during the treatment period.

Conclusion: A substantial number of children experienced VF following ALL treatment completion, and the presence of VF might adversely affect auxological status in children. VF detection by routine surveillance throughout childhood ALL treatment is recommended to try to prevent compromised growth.
The Role and Mechanism of Histone Deacetylases in Acute Kidney Injury
Authors: Zhou Xun , Chen Hui , Shi Yingfeng , Ma Xiaoyan , Zhuang Shougang , Liu Na
Published: June 2021

Acute kidney injury (AKI) is a common clinical complication with an incidence of up to 8–18% in hospitalized patients. AKI is also a complication of COVID-19 patients and is associated with an increased risk of death. In recent years, numerous studies have suggested that epigenetic regulation is critically involved in the pathophysiological process and prognosis of AKI. Histone acetylation, one of the epigenetic regulations, is negatively regulated by histone deacetylases (HDACs). Increasing evidence indicates that HDACs play an important role in the pathophysiological development of AKI by regulation of apoptosis, inflammation, oxidative stress, fibrosis, cell survival, autophagy, ATP production, and mitochondrial biogenesis (MB). In this review, we summarize and discuss the role and mechanism of HDACs in the pathogenesis of AKI.
A Detector for Premature Atrial and Ventricular Complexes
Authors: García-Isla Guadalupe , Mainardi Luca , Corino Valentina D. A.
Published: June 2021

The relationship between premature atrial complexes (PACs) and atrial fibrillation (AF), stroke and myocardium degradation is unclear. Current PAC detectors are beat classifiers that attain low sensitivity on PAC detection. The lack of a proper PAC detector hinders the study of the implications of this event and its monitoring. In this work a PAC and ventricular detector is presented. Two PhysioNet open-source databases were used: the long-term ST database (LTSTDB) and the supraventricular arrhythmia database (SVDB). A combination of heart rate variability (HRV) and morphological features were used to classify beats. Morphological features were extracted from the ECG as well as on the 4th scale of the discrete wavelet transform (DWT). After feature selection, a random forest algorithm was trained for a binary classification of PAC (S) vs. others and for a multi-labels classification to discriminate between normal (N), S and ventricular (V) beats. The algorithm was tested in a 10-fold cross-validation following a patient-wise train-test division (i.e., no beats belonging to the same patient were included both in the test and train set). The resultant median sensitivity, specificity and positive predictive value (PPV) were 99.29, 99.54, and 100% for (N), 95.83, 99.39, and 35.68% for (S), 100, 99.90, and 79.63% for (V). The proposed method attains a greater PAC and ventricular beat sensitivity and PPV than the state-of-the-art classifiers.