bluuebunny/crossref_metadata_2025 huggingface dataset:
PET and CT Image Fusion of Lung Cancer With Siamese Pyramid Fusion Network
Authors: Xiao Ning , Yang Wanting , Qiang Yan , Zhao Juanjuan , Hao Rui , Lian Jianhong , Li Shuo
Published: March 2022

Background

The fusion of PET metabolic images and CT anatomical images can simultaneously display the metabolic activity and anatomical position, which plays an indispensable role in the staging diagnosis and accurate positioning of lung cancer.

Methods

In order to improve the information of PET-CT fusion image, this article proposes a PET-CT fusion method via Siamese Pyramid Fusion Network (SPFN). In this method, feature pyramid transformation is introduced to the siamese convolution neural network to extract multi-scale information of the image. In the design of the objective function, this article considers the nature of image fusion problem, utilizes the image structure similarity as the objective function and introduces L1 regularization to improve the quality of the image.

Results

The effectiveness of the proposed method is verified by more than 700 pairs of PET-CT images and elaborate experimental design. The visual fidelity after fusion reaches 0.350, the information entropy reaches 0.076.

Conclusion

The quantitative and qualitative results proved that the proposed PET-CT fusion method has some advantages. In addition, the results show that PET-CT fusion image can improve the ability of staging diagnosis compared with single modal image.
Rapid Identification of Mycobacterium tuberculosis Complex Using Mass Spectrometry: A Proof of Concept
Authors: Robinne Simon , Saad Jamal , Morsli Madjid , Hamidou Zelika Harouna , Tazerart Fatah , Drancourt Michel , Baron Sophie Alexandra
Published: March 2022

Mycobacteria that form the Mycobacterium tuberculosis complex are responsible for deadly tuberculosis in animals and patients. Identification of these pathogens at the species level is of primary importance for treatment and source tracing and currently relies on DNA analysis, including whole genome sequencing (WGS), which requires a whole day. In this study, we report the unprecedented discrimination of M. tuberculosis complex species using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS), with WGS as the comparative reference standard. In the first step, optimized peptide extraction applied to 36 isolates otherwise identified in five of the 11 M. tuberculosis complex variants by WGS yielded 139 MALDI-TOF spectra, which were used to identify biomarkers of interest that facilitate differentiation between variants. In a second step, 70/80 (88%) other isolates were correctly classified by an algorithm based on specific peaks. This study is the first to report a MALDI-TOF-MS method for discriminating M. tuberculosis complex mycobacteria that is easily implemented in clinical microbiology laboratories.
Targeting Multidrug Resistance With Antimicrobial Peptide-Decorated Nanoparticles and Polymers
Authors: Maleki Dizaj Solmaz , Salatin Sara , Khezri Khadijeh , Lee Jyh-Yeuan , Lotfipour Farzaneh
Published: March 2022

As a category of small peptides frequently found in nature, antimicrobial peptides (AMPs) constitute a major part of the innate immune system of various organisms. Antimicrobial peptides feature various inhibitory effects against fungi, bacteria, viruses, and parasites. Due to the increasing concerns of antibiotic resistance among microorganisms, development of antimicrobial peptides is an emerging tool as a favorable applicability prospect in food, medicine, aquaculture, animal husbandry, and agriculture. This review presents the latest research progress made in the field of antimicrobial peptides, such as their mechanism of action, classification, application status, design techniques, and a review on decoration of nanoparticles and polymers with AMPs that are used in treating multidrug resistance. Lastly, we will highlight recent progress in antiviral peptides to treat emerging viral diseases (e.g., anti-coronavirus peptides) and discuss the outlook of AMP applications.
Observation of the Gut Microbiota Profile in BALB/c Mice Induced by Plasmodium yoelii 17XL Infection
Authors: Guan Wei , Song Xiaonan , Yang Shuguo , Zhu Huiyin , Li Fang , Li Jian
Published: March 2022

Rodent malaria caused by Plasmodium yoelii 17XL (Py 17XL) is an ideal animal model for human malaria studies. Although the gut microbiota plays an important role in the occurrence and development of infectious diseases, the gut microbiota associated with Py 17XL infection remains unclear. In the current study, the gut microbiota composition of infected BALB/c mice was surveyed. Mouse fecal samples were collected at 0, 2, 5 days post-infection (dpi), and the gut microbiota was characterized by 16S rRNA sequencing. Operational taxonomic units (OTUs) were 634 ± 26 on average. Firmicutes and Bacteroidetes were typically predominant in the gut microbiota composition at the phylum level. Compared with the Ctrl, Firmicutes was significantly decreased after infection, while Bacteroidetes was notably increased. The most dominant family was Lactobacillaceae in all samples. The alpha diversity index showed that compared with that of the Ctrl, the observed OTU number was decreased at 2 dpi and then slightly increased at 5 dpi. LEfSe analysis revealed several bacterial taxa were notably related to Py-infected mice at the phylogenetic level. Several bacterial genera, such as Lactobacillus, were overrepresented in the Py-infected fecal microbiota at 2 dpi, while Muribaculaceae was overrepresented at 5 dpi. Moreover, Alistipes and Helicobacter were overrepresented at 5 dpi compared with 2 dpi. The results indicated Py infection could alter the gut microbiota composition of mice. Besides, biomarkers could serve as direct targets to elucidate their roles in the progression and pathogenesis of malaria and provide insights into studies of antimalarial drugs and malaria vaccines.
Pan-Genome Analysis of Laribacter hongkongensis: Virulence Gene Profiles, Carbohydrate-Active Enzyme Prediction, and Antimicrobial Resistance Characterization
Authors: Yuan Pei-Bo , Zhan Yi , Zhu Jia-Hui , Ling Jia-Hui , Chen En-Zhong , Liu Wan-Ting , Wang Lin-Jing , Zhong Yu-Xia , Chen Ding-Qiang
Published: March 2022

Laribacter hongkongensis is a new emerging foodborne pathogen that causes community-acquired gastroenteritis and traveler’s diarrhea. However, the genetic features of L. hongkongensis have not yet been properly understood. A total of 45 aquatic animal-associated L. hongkongensis strains isolated from intestinal specimens of frogs and grass carps were subjected to whole-genome sequencing (WGS), along with the genome data of 4 reported human clinical strains, the analysis of virulence genes, carbohydrate-active enzymes, and antimicrobial resistance (AMR) determinants were carried out for comprehensively understanding of this new foodborne pathogen. Human clinical strains were genetically more related to some strains from frogs inferred from phylogenetic trees. The distribution of virulence genes and carbohydrate-active enzymes exhibited different patterns among strains of different sources, reflecting their adaption to different host environments and indicating different potentials to infect humans. Thirty-two AMR genes were detected, susceptibility to 18 clinical used antibiotics including aminoglycoside, chloramphenicol, trimethoprim, and sulfa was checked to evaluate the availability of clinical medicines. Resistance to Rifampicin, Cefazolin, ceftazidime, Ampicillin, and ceftriaxone is prevalent in most strains, resistance to tetracycline, trimethoprim-sulfamethoxazole, ciprofloxacin, and levofloxacin are aggregated in nearly half of frog-derived strains, suggesting that drug resistance of frog-derived strains is more serious, and clinical treatment for L. hongkongensis infection should be more cautious.
High Resolution 31P Field Cycling NMR Reveals Unsuspected Features of Enzyme-Substrate-Cofactor Dynamics
Authors: Roberts Mary F. , Hedstrom Lizbeth
Published: March 2022

The dynamic interactions of enzymes and substrates underpins catalysis, yet few techniques can interrogate the dynamics of protein-bound ligands. Here we describe the use of field cycling NMR relaxometry to measure the dynamics of enzyme-bound substrates and cofactors in catalytically competent complexes of GMP reductase. These studies reveal new binding modes unanticipated by x-ray crystal structures and reaction-specific dynamic networks. Importantly, this work demonstrates that distal interactions not usually considered part of the reaction coordinate can play an active role in catalysis. The commercialization of shuttling apparatus will make field cycling relaxometry more accessible and expand its use to additional nuclei, promising more intriguing findings to come.
Effects of Remotely Supervised Physical Activity on Health Profile in Frail Older Adults: A Randomized Controlled Trial Protocol
Authors: Zhang Xin , Li Jinwei , Sui Xin , Xu Linqi , Zhu Lanyu , Pang Yue , Yu Tianzhuo , Lian Xiaoqian , Yu Tianyue , Li Yuewei , Xu Haiyan , Li Feng
Published: March 2022

Background

Frailty is considered a major public health challenge of the 21st century, characterized by the decline of multiform body functions. Physical activity may be the most effective intervention to delay frailty. This study aims to verify the effect of remotely supervised physical activity on health profile in community-dwelling frail older adults.

Design

This is a multicenter, three-blind, two-arm, and cohort randomized controlled study.

Methods

The intelligent exercise rehabilitation management system (IERMS) is an integrated digital platform that involves evaluation, guidance, monitoring, and feedback. A total of 120 participants aged ≥ 65 years and diagnosed as frailty on the FRAIL scale will be recruited and randomly divided into two groups. Group 1 will receive a 12-week IERMS-based intervention, and Group 2 will receive the usual care. Data will be collected at baseline, 12 and 24 weeks. The primary outcome is the physical function, and secondary outcomes include gait parameters, psychology, and cognition measurements. Analyses will be performed using DSS statistics, version 25. P < 0.05 will be considered statistically significant.

Conclusion

We believe that intervention plays a positive role in delaying the frailty. If our program is effective, we will provide a viable means to promote healthy aging in primary healthcare.

Trial registration number

ChiCTR2100052286; Pre-results.
Proteomics Challenges for the Assessment of Synuclein Proteoforms as Clinical Biomarkers in Parkinson’s Disease
Authors: Pons Marie-Laure , Loftus Neil , Vialaret Jerome , Moreau Stephane , Lehmann Sylvain , Hirtz Christophe
Published: March 2022

Parkinson’s disease is a complex neurodegenerative disorder resulting in a multifaceted clinical presentation which includes bradykinesia combined with either rest tremor, rigidity, or both, as well as many non-motor symptoms. The motor features of the disorder are associated with the pathological form of alpha synuclein aggregates and fibrils in Lewy bodies and loss of dopaminergic neurons in the substantia nigra. Parkinson’s disease is increasingly considered as a group of underlying disorders with unique genetic, biological, and molecular abnormalities that are likely to respond differentially to a given therapeutic approach. For this reason, it is clinically challenging to treat and at present, no therapy can slow down or arrest the progression of Parkinson’s disease. There is a clear unmet clinical need to develop reliable diagnostic and prognostic biomarkers. When disease-modifying treatments become available, prognostic biomarkers are required to support a definitive diagnosis and clinical intervention during the long prodromal period as no clinical implications or symptoms are observed. Robust diagnostic biomarkers would also be useful to monitor treatment response. Potential biomarkers for the sporadic form of Parkinson’s disease have mostly included synuclein species (monomer, oligomer, phosphorylated, Lewy Body enriched fraction and isoforms). In this review, we consider the analysis of synuclein and its proteoforms in biological samples using proteomics techniques (immunoassay and mass spectrometry) applied to neurodegenerative disease research.
Comparison of the Anti-inflammatory Properties of Two Nicotinic Acetylcholine Receptor Ligands, Phosphocholine and pCF3-diEPP
Authors: Richter Katrin , Papke Roger L. , Stokes Clare , Roy Danika C. , Espinosa Eduardo S. , Wolf Philipp M. K. , Hecker Andreas , Liese Juliane , Singh Vijay K. , Padberg Winfried , Schlüter Klaus-Dieter , Rohde Marius , McIntosh J. Michael , Morley Barbara J. , Horenstein Nicole A. , Grau Veronika , Simard Alain R.
Published: March 2022

Activation of nicotinic acetylcholine receptors (nAChRs) expressed by innate immune cells can attenuate pro-inflammatory responses. Silent nAChR agonists, which down-modulate inflammation but have little or no ionotropic activity, are of outstanding clinical interest for the prevention and therapy of numerous inflammatory diseases. Here, we compare two silent nAChR agonists, phosphocholine, which is known to interact with nAChR subunits α7, α9, and α10, and pCF3-N,N-diethyl-N′-phenyl-piperazine (pCF3-diEPP), a previously identified α7 nAChR silent agonist, regarding their anti-inflammatory properties and their effects on ionotropic nAChR functions. The lipopolysaccharide (LPS)-induced release of interleukin (IL)-6 by primary murine macrophages was inhibited by pCF3-diEPP, while phosphocholine was ineffective presumably because of instability. In human whole blood cultures pCF3-diEPP inhibited the LPS-induced secretion of IL-6, TNF-α and IL-1β. The ATP-mediated release of IL-1β by LPS-primed human peripheral blood mononuclear leukocytes, monocytic THP-1 cells and THP-1-derived M1-like macrophages was reduced by both phosphocholine and femtomolar concentrations of pCF3-diEPP. These effects were sensitive to mecamylamine and to conopeptides RgIA4 and [V11L; V16D]ArIB, suggesting the involvement of nAChR subunits α7, α9 and/or α10. In two-electrode voltage-clamp measurements pCF3-diEPP functioned as a partial agonist and a strong desensitizer of classical human α9 and α9α10 nAChRs. Interestingly, pCF3-diEPP was more effective as an ionotropic agonist at these nAChRs than at α7 nAChR. In conclusion, phosphocholine and pCF3-diEPP are potent agonists at unconventional nAChRs expressed by monocytic and macrophage-like cells. pCF3-diEPP inhibits the LPS-induced release of pro-inflammatory cytokines, while phosphocholine is ineffective. However, both agonists signal via nAChR subunits α7, α9 and/or α10 to efficiently down-modulate the ATP-induced release of IL-1β. Compared to phosphocholine, pCF3-diEPP is expected to have better pharmacological properties. Thus, low concentrations of pCF3-diEPP may be a therapeutic option for the treatment of inflammatory diseases including trauma-induced sterile inflammation.
Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis
Authors: Mirian Ario , Moszczynski Alexander , Soleimani Serena , Aubert Isabelle , Zinman Lorne , Abrahao Agessandro
Published: March 2022

Introduction

Recent studies have implicated changes in the blood-central nervous system barriers (BCNSB) in amyotrophic lateral sclerosis (ALS). The objective of this scoping review is to synthesize the current evidence for BCNSB structure and functional abnormalities in ALS studies and propose how BCNSB pathology may impact therapeutic development.

Methods

A literature search was conducted using Ovid Medline, EMBASE, and Web of Science, from inception to November 2021 and limited to entries in English language. Simplified search strategy included the terms ALS/motor neuron disease and [BCNSB or blood-brain barrier (BBB) or blood-spinal cord barrier (BSCB)]. Henceforth, BCNSB is used as a term that is inclusive of the BBB and BSCB. Four independent reviewers conducted a title and abstract screening, hand-searched the reference lists of review papers, and performed a full text review of eligible studies. Included studies were original peer-reviewed full text publications, evaluating the structure and function of the BCNSB in preclinical models of ALS, clinical ALS, or postmortem human ALS tissue. There was no restriction on study design. The four reviewers independently extracted the data.

Results

The search retrieved 2,221 non-duplicated articles and 48 original studies were included in the synthesis. There was evidence that the integrity of the BCNSB is disrupted throughout the course of the disease in rodent models, beginning prior to symptom onset and detectable neurodegeneration. Increased permeability, pharmacoresistance with upregulated efflux transporters, and morphological changes in the supporting cells of the BCNSB, including pericytes, astrocytes, and endothelial cells were observed in animal models. BCNSB abnormalities were also demonstrated in postmortem studies of ALS patients. Therapeutic interventions targeting BCNSB dysfunction were associated with improved motor neuron survival in animal models of ALS.

Conclusion

BCNSB structural and functional abnormalities are likely implicated in ALS pathophysiology and may occur upstream to neurodegeneration. Promising therapeutic strategies targeting BCNSB dysfunction have been tested in animals and can be translated into ALS clinical trials.
Case Report: Cerebral Venous Sinus Thrombosis in a Young Child With SARS-CoV-2 Infection: The Italian Experience
Authors: Silvestri Paola , Clemente Anna , Spalice Alberto , Febbo Alessandra , Matera Luigi , Accardo Fabiana , Barbieri Maria Antonietta , Villani Alberto , Midulla Fabio
Published: March 2022

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pediatric patients is usually characterized by fever, dry cough, and fatigue, or is asymptomatic and rarely presents with pneumonia. On the other hand, cerebral venous sinus thrombosis (CVST) could be a neurological sequela of the prothrombotic state triggered by coronavirus disease 2019 (COVID-19) both in adults and children.

Case Report

We present a case of a 15-year-old male child who was obese and had mild neurocognitive impairment. He was admitted to the pediatric emergency department and then diagnosed with CVST during SARS-CoV-2 infection.

Conclusion

During the COVID-19 pandemic, in patients presenting with neurological manifestations of CVST (headache, alteration of consciousness, focal deficit, or signs of endocranial hypertension), it is advisable to look for a current or recent infection of SARS-CoV-2, regardless of the presence of respiratory symptoms. In our patient, ongoing SARS-CoV-2 infection represents the only prothrombotic risk factor underlying the neurological disease.
Cortical and Subcortical Structural Abnormalities in Patients With Idiopathic Cervical and Generalized Dystonia
Authors: Wu Yunhao , Wang Tao , Ding Qiong , Li Hongxia , Wu Yiwen , Li Dianyou , Sun Bomin , Pan Yixin
Published: March 2022

Objectives

In this study, we sought to investigate structural imaging alterations of patients with idiopathic dystonia at the cortical and subcortical levels. The common and specific changes in two subtypes of dystonia, cervical dystonia (CD) and generalized dystonia (GD), were intended to be explored. Additionally, we sought to identify the morphometric measurements which might be related to patients' clinical characteristics, thus providing more clues of specific brain regions involved in the mechanism of idiopathic dystonia.

Methods

3D T1-weighted MRI scans were acquired from 56 patients with idiopathic dystonia and 30 healthy controls (HC). Patients were classified as CD or GD, according to the distinct symptom distributions. Cortical thickness (CT) of 30 CD and 26 GD were estimated and compared to HCs using Computational Anatomy Toolbox (CAT12), while volumes of subcortical structures and their shape alterations (29 CD, 25 GD, and 27 HCs) were analyzed via FSL software. Further, we applied correlation analyses between the above imaging measurements with significant differences and patients' clinical characteristics.

Results

The results of comparisons between the two patient groups and HCs were highly consistent, demonstrating increased CT of bilateral postcentral, superiorparietal, superiorfrontal/rostralmiddlefrontal, occipital gyrus, etc., and decreased CT of bilateral cingulate, insula, entorhinal, and fusiform gyrus (PFWE < 0.005 at the cluster level). In CD, trends of negative correlations were found between disease severity and CT alterations mostly located in pre/postcentral, rostralmiddlefrontal, superiorparietal, and supramarginal regions. Besides, volumes of bilateral putamen, caudate, and thalamus were significantly reduced in both patient groups, while pallidum volume reduction was also presented in GD compared to HCs. Caudate volume reduction had a trend of correlation to increasing disease severity in GD. Last, shape analysis directly demonstrated regional surface alterations in bilateral thalamus and caudate, where the atrophy located in the head of caudate had a trend of correlation to earlier ages of onset in GD.

Conclusions

Our study demonstrates wide-spread morphometric changes of CT, subcortical volumes, and shapes in idiopathic dystonia. CD and GD presented similar patterns of morphometric abnormalities, indicating shared underlying mechanisms in two different disease forms. Especially, the clinical associations of CT of multiple brain regions with disease severity, and altered volume/shape of caudate with disease severity/age of onset separately in CD and GD might serve as potential biomarkers for further disease exploration.
ALSA: Associative Learning Based Supervised Learning Algorithm for SNN
Authors: Mo Lingfei , Wang Gang , Long Erhong , Zhuo Mingsong
Published: March 2022

Spiking neural network (SNN) is considered to be the brain-like model that best conforms to the biological mechanism of the brain. Due to the non-differentiability of the spike, the training method of SNNs is still incomplete. This paper proposes a supervised learning method for SNNs based on associative learning: ALSA. The method is based on the associative learning mechanism, and its realization is similar to the animal conditioned reflex process, with strong physiological plausibility and rationality. This method uses improved spike-timing-dependent plasticity (STDP) rules, combined with a teacher layer to induct spikes of neurons, to strengthen synaptic connections between input spike patterns and specified output neurons, and weaken synaptic connections between unrelated patterns and unrelated output neurons. Based on ALSA, this paper also completed the supervised learning classification tasks of the IRIS dataset and the MNIST dataset, and achieved 95.7 and 91.58% recognition accuracy, respectively, which fully proves that ALSA is a feasible SNNs supervised learning method. The innovation of this paper is to establish a biological plausible supervised learning method for SNNs, which is based on the STDP learning rules and the associative learning mechanism that exists widely in animal training.
Preventing Phosphorylation of the GABAAR β3 Subunit Compromises the Behavioral Effects of Neuroactive Steroids
Authors: Vien Thuy N. , Ackley Michael A. , Doherty James J. , Moss Stephen J. , Davies Paul A.
Published: March 2022

Neuroactive steroids (NASs) have potent anxiolytic, anticonvulsant, sedative, and hypnotic actions, that reflect in part their efficacy as GABAAR positive allosteric modulators (PAM). In addition to this, NAS exert metabotropic effects on GABAergic inhibition via the activation of membrane progesterone receptors (mPRs), which are G-protein coupled receptors. mPR activation enhances the phosphorylation of residues serine 408 and 409 (S408/9) in the β3 subunit of GABAARs, increasing their accumulation in the plasma membrane leading to a sustained increase in tonic inhibition. To explore the significance of NAS-induced phosphorylation of GABAARs, we used mice in which S408/9 in the β3 subunit have been mutated to alanines, mutations that prevent the metabotropic actions of NASs on GABAAR function while preserving NAS allosteric potentiation of GABAergic current. While the sedative actions of NAS were comparable to WT, their anxiolytic actions were reduced in S408/9A mice. Although the induction of hypnosis by NAS were maintained in the mutant mice the duration of the loss of righting reflex was significantly shortened. Finally, ability of NAS to terminate diazepam pharmacoresistant seizures was abolished in S408/9A mice. In conclusion, our results suggest that S408/9 in the GABAAR β3 subunit contribute to the anxiolytic and anticonvulsant efficacy of NAS, in addition to their ability to regulate the loss of righting reflex.
Advances and Barriers in Understanding Presynaptic N-Methyl-D-Aspartate Receptors in Spinal Pain Processing
Authors: Dedek Annemarie , Hildebrand Michael E.
Published: March 2022

For decades, N-methyl-D-aspartate (NMDA) receptors have been known to play a critical role in the modulation of both acute and chronic pain. Of particular interest are NMDA receptors expressed in the superficial dorsal horn (SDH) of the spinal cord, which houses the nociceptive processing circuits of the spinal cord. In the SDH, NMDA receptors undergo potentiation and increases in the trafficking of receptors to the synapse, both of which contribute to increases in excitability and plastic increases in nociceptive output from the SDH to the brain. Research efforts have primarily focused on postsynaptic NMDA receptors, despite findings that presynaptic NMDA receptors can undergo similar plastic changes to their postsynaptic counterparts. Recent technological advances have been pivotal in the discovery of mechanisms of plastic changes in presynaptic NMDA receptors within the SDH. Here, we highlight these recent advances in the understanding of presynaptic NMDA receptor physiology and their modulation in models of chronic pain. We discuss the role of specific NMDA receptor subunits in presynaptic membranes of nociceptive afferents and local SDH interneurons, including their modulation across pain modalities. Furthermore, we discuss how barriers such as lack of sex-inclusive research and differences in neurodevelopmental timepoints have complicated investigations into the roles of NMDA receptors in pathological pain states. A more complete understanding of presynaptic NMDA receptor function and modulation across pain states is needed to shed light on potential new therapeutic treatments for chronic pain.
Effects of a 3-Week Inpatient Multidisciplinary Body Weight Reduction Program on Body Composition and Physical Capabilities in Adolescents and Adults With Obesity
Authors: Lazzer Stefano , D’Alleva Mattia , Vaccari Filippo , Tringali Gabriella , De Micheli Roberta , Sartorio Alessandro
Published: March 2022

Background

The aim of the present study was to examine the short-term changes in body composition and physical capabilities in subjects with obesity during a multidisciplinary inpatient body weight reduction program (BWRP).

Methods

One hundred thirty-nine adolescents (56 boys and 83 girls; BMI: 37.1 ± 6.5 kg/m2; Fat Mass, FM: 45.3 ± 7.2%) and 71 adults (27 males and 44 females; BMI: 44 ± 4.7 kg/m2; FM: 51.4 ± 4.7%) followed a 3-week inpatient BWRP consisting of regular physical activity, moderate energy restriction, nutritional education and psychological counseling. Before (T0) and after the end of the BWRP (T21), body composition was assessed with an impedancemeter, lower limb muscle power with Margaria Stair Climbing Test (SCT), lower limb functionality with Short Physical Performance Battery (SPPB), and the capacity of performing activity of daily living (ADL) with Physical Performance Test (PPT).

Results

At T21, obese adolescents showed a 4% reduction in body mass (BM) (p < 0.001), associated with a FM reduction in boys (−10%) and girls (−6%) (p < 0.001) and with a 3% reduction in fat-free mass (FFM) recorded only in boys (p = 0.013). Obese adults showed a 5% BM reduction (p < 0.001), associated with a 2% FFM and 9% FM reduction (p < 0.001) in males, and 7% FM reduction in females (p < 0.001). Regarding physical capabilities, at T21 in obese adolescents, PPT score increased by 4% (p < 0.001), SCT decreased by −5% (boys) and −7% (girls) (p < 0.001), while SPPB score did not change significantly. In obese adults at T21, PPT score increased by 9% (p < 0.001), SCT decreased by −16% (p < 0.001) only in females, and SPPB score increased by 7% (males) and 10% (females) (p < 0.01).

Conclusion

In conclusion, moderate energy restriction and regular physical activity determine a 4-5% BM reduction during a 3-week inpatient BWRP, improve physical capabilities and induce beneficial changes in body composition in adolescents and adults with obesity.

Trial registration

This study was approved by the Ethical Committee of the Istituto Auxologico Italiano (Milan, Italy; research code: 01C124; acronym: PRORIPONATFIS). Registered 11 November 2020 - Retrospectively registered.
N-Glycosylation at Asn291 Stabilizes TIM-4 and Promotes the Metastasis of NSCLC
Authors: Chen Siyuan , Wang Yuzhen , Liu Wen , Liang Yan , Wang Yingchun , Wu Zhuanchang , Xu Liyun , Liang Xiaohong , Ma Chunhong , Gao Lifen
Published: March 2022

T-cell immunoglobulin domain and mucin domain 4 (TIM-4) is a transmembrane protein that promotes epithelial-mesenchymal transition (EMT), migration and invasion of non-small cell lung cancer (NSCLC) cells. Most transmembrane proteins are modified by N-glycosylation and the importance of protein N-glycosylation in cancer cell metastasis has been well appreciated. However, whether TIM-4 is modified by N-glycosylation and the role of TIM-4 N-glycosylation in NSCLC remains largely unknown. In the current study, we reported that TIM-4 was extensively N-glycosylated at Asn291. After the removal of N-glycosylation, the stability of TIM-4 protein was decreased and TIM-4 was more susceptible to degradation by ER-localized ubiquitin ligase-mediated ERAD. Thus, the expression of TIM-4 on the cell surface was decreased, which suppressed TIM-4-mediated metastasis in NSCLC. In summary, the present study identifies TIM-4 N-glycosylation and its role in NSCLS migration, which would provide a valuable biomarker for developing drugs targeting N-glycosylation at Asn291 on TIM-4.
Effective Systemic Treatment of Choroidal Metastases NSCLC With Surgery After Crizotinib: A Case Report
Authors: Liu Shilan , Liu Xiao , Wang Ting , Zeng Chunhua , Ren Baichen , Yu Xiaodan , Xu Min , Li Wenjuan , Qiao Zhihui , You Chuanyun , Yang Qinghui , Chen Mei
Published: March 2022

Choroidal metastasis as an initial presenting feature of lung cancer with EML4-ALK translocation is exceedingly rare and greatly impacts patient quality of life (QOL). There are no recommended treatments for such patients, and palliative care remains limited. It is unclear whether surgical resection of primary pulmonary lesions, systemic antitumor therapy, targeted therapy, or localized ocular therapy are effective in treating choroidal metastases in EML4-ALK rearranged oligometastatic non-small cell lung cancer (NSCLC). Here, we present the case of choroidal metastases secondary to lung cancer and EML4-ALK translocation in a 57-year-old woman who firstly underwent resection of lung lesions followed by oral administration of crizotinib without local treatment or systemic chemotherapy. Since then she had a rapid and complete response to crizotinib with 27 months of progression-free survival.
Preoperative Platelet Distribution Width Represents a Novel Prognostic Biomarker in Patients With Nonmetastatic Renal Cell Carcinoma: A Retrospective Clinical Analysis
Authors: Xiao Ruotao , Yang Bin , Liu Cheng , Liu Lei , Ma Lulin
Published: March 2022

Purpose

The study aimed to explore the prognostic value of platelet distribution width (PDW) in patients with nonmetastatic renal cell carcinoma (RCC).

Methods

We retrospective analyzed 706 patents with nonmetastatic RCC from January 2015 to December 2017. Clinicopathologic data and platelet indices were collected and analyzed by univariable and multivariable cox proportional hazard model. Progression-free survival (PFS) was analyzed using the Kaplan–Meier curve. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were performed to evaluate the improvement of predictive accuracy.

Results

Patients were divided into low PDW (N = 241, PDW ≤11.7%), intermediate PDW (N = 232, 11.7%< PDW ≤15.6%), and high PDW (N = 233, PDW >15.6%) groups according to the tertiles. Patients with low PDW were associated with more symptoms at presentation, larger tumor size, higher AJCC tumor stage, and more sarcomatoid differentiation. Besides, patients with low PDW had significantly shorter PFS compared to intermediate PDW and high PDW groups. On the multivariable model, AJCC tumor stage, nuclear grade, and PDW (either continuous or categorical variables) were independent factors correlated with PFS. The NRI and IDI showed adding PDW to SSIGN score improves its predictive accuracy related to 2-, 3-, and 4-year PFS.

Conclusions

Low PDW was related to advanced clinicopathologic features and worse prognosis in patients with nonmetastatic RCC. Thus, PDW could serve as a novel biomarker for risk stratification in these patients when used pre-or postoperatively.
Proton Magnetic Resonance Spectroscopy at 3.0T in Rabbit With VX2 Liver Cancer: Diagnostic Efficacy and Correlations With Tumor Size
Authors: Liao Ruikun , Tang Zhuoyue , Li Xiaojiao , Lv Liang , Yang Chao , Xiong Hua , Zhou Bi , Yu Jiayi , Zhang Dan
Published: March 2022

Purposes

The purpose of this study was to explore the diagnostic performance of Cho peak area (Cho Are), Cho peak amplitude (Cho Amp), and the combined approach (Cho Are_Amp) in detecting rabbit VX2 liver cancer at the early stage via hydrogen-1 proton magnetic resonance spectroscopy (1H-MRS), as well as the correlations between Cho Are, Cho Amp, and tumor parameters like diameter and volume.

Methods

Conventional magnetic resonance imaging (MRI) and MRS were performed to scan the VX2 liver cancer in rabbit. The tumor diameter was measured on T2-weighted imaging (T2WI), and the tumor volume was accordingly calculated. Cho Are and Cho Amp were obtained from MRS. The diagnostic performance of Cho Are, Cho Amp, and Cho Are_Amp was assessed by a receiver operating characteristic (ROC) curve and area under ROC curve (AUC), whereas specificity and sensitivity were calculated by the maximum Youden’s index. Spearman’s correlation analysis was performed to evaluate the relevance between tumor parameters (diameter, volume) and radiological indexes (Cho Are, Cho Amp).

Results

ROC curve analysis showed that Cho Amp, Cho Are, and Cho Are_Amp were effective in diagnosing VX2 liver cancer. The AUC of Cho Amp was 0.883, and the specificity and sensitivity were 0.944 and 0.722, respectively (p < 0.001). The AUC of Cho Are was 0.807, and the specificity and sensitivity were 0.778 and 0.833, respectively (p < 0.05). The AUC of Cho Are_Amp was 0.892, and the specificity and sensitivity were 0.833 and 0.833, respectively (p < 0.001). Cho Are and Cho Amp exhibited a high positive correlation with tumor diameter and tumor volume, among which Cho Amp demonstrated better correlations to tumor diameter and tumor volume (r = 0.956 and 0.946) than that of Cho Are (r = 0.787 and 0.794). A high positive correlation was detected between Cho Are and Cho Amp (r = 0.787), as well as tumor diameter and tumor volume (r = 0.965).

Conclusion

Cho Are_Amp can be used as an effective tool in diagnosing early-stage VX2 liver cancer with satisfied diagnostic accuracy. Cho Are and Cho Amp were positively correlated with tumor volume and tumor diameter. The results of this study provide further evidence that Cho Amp and Cho Are_Amp of MRS could aid in the early diagnosis of liver cancer.
Rationale for Utilization of Hydrogel Rectal Spacers in Dose Escalated SBRT for the Treatment of Unfavorable Risk Prostate Cancer
Authors: Repka Michael C. , Creswell Michael , Lischalk Jonathan W. , Carrasquilla Michael , Forsthoefel Matthew , Lee Jacqueline , Lei Siyuan , Aghdam Nima , Kataria Shaan , Obayomi-Davies Olusola , Collins Brian T. , Suy Simeng , Hankins Ryan A. , Collins Sean P.
Published: March 2022

In this review we outline the current evidence for the use of hydrogel rectal spacers in the treatment paradigm for prostate cancer with external beam radiation therapy. We review their development, summarize clinical evidence, risk of adverse events, best practices for placement, treatment planning considerations and finally we outline a framework and rationale for the utilization of rectal spacers when treating unfavorable risk prostate cancer with dose escalated Stereotactic Body Radiation Therapy (SBRT).
Iron Administration Overcomes Resistance to Erastin-Mediated Ferroptosis in Ovarian Cancer Cells
Authors: Battaglia Anna Martina , Sacco Alessandro , Perrotta Ida Daniela , Faniello Maria Concetta , Scalise Mariangela , Torella Daniele , Levi Sonia , Costanzo Francesco , Biamonte Flavia
Published: March 2022

Objectives

Developing novel therapeutic approaches to defeat chemoresistance is the major goal of ovarian cancer research. Induction of ferroptosis has shown promising antitumor effects in ovarian cancer cells, but the existence of still undefined genetic and metabolic determinants of susceptibility has so far limited the application of ferroptosis inducers in vivo.

Methods

Erastin and/or the iron compound ferlixit were used to trigger ferroptosis in HEY, COV318, PEO4, and A2780CP ovarian cancer cell lines. Cell viability and cell death were measured by MTT and PI flow cytometry assay, respectively. The “ballooning” phenotype was tested as ferroptosis specific morphological feature. Mitochondrial dysfunction was evaluated based on ultrastructural changes, mitochondrial ROS, and mitochondrial membrane polarization. Lipid peroxidation was tested through both C11-BODIPY and malondialdehyde assays. VDAC2 and GPX4 protein levels were quantified as additional putative indicators of mitochondrial dysfunction or lipid peroxidation, respectively. The effect of erastin/ferlixit treatments on iron metabolism was analyzed by measuring intracellular labile iron pool and ROS. FtH and NCOA4 were measured as biomarkers of ferritinophagy.

Results

Here, we provide evidence that erastin is unable to induce ferroptosis in a series of ovarian cancer cell lines. In HEY cells, provided with a high intracellular labile iron pool, erastin treatment is accompanied by NCOA4-mediated ferritinophagy and mitochondrial dysfunction, thus triggering ferroptosis. In agreement, iron chelation counteracts erastin-induced ferroptosis in these cells. COV318 cells, with low baseline intracellular labile iron pool, appear resistant to erastin treatment. Notably, the use of ferlixit sensitizes COV318 cells to erastin through a NCOA4-independent intracellular iron accumulation and mitochondrial dysfunction. Ferlixit alone mimics erastin effects and promotes ferroptosis in HEY cells.

Conclusion

This study proposes both the baseline and the induced intracellular free iron level as a significant determinant of ferroptosis sensitivity and discusses the potential use of ferlixit in combination with erastin to overcome ferroptosis chemoresistance in ovarian cancer.
Non-bullous Impetigo: Incidence, Prevalence, and Treatment in the Pediatric Primary Care Setting in Italy
Authors: Barbieri Elisa , Porcu Gloria , Dona' Daniele , Falsetto Nathalie , Biava Mirella , Scamarcia Antonio , Cantarutti Luigi , Cantarutti Anna , Giaquinto Carlo
Published: March 2022

Impetigo is a common skin infection in children. The worldwide prevalence in children is estimated to be 12%, but this may be lower since high-income countries are under-represented. This research aims to evaluate the incidence, prevalence, and management of children with non-bullous impetigo (NBI) residing in Italy. This retrospective cohort study included children up to 14 years of age enrolled in the Pedianet database from January 2004 to June 2018. Events were identified searching ICD9-CM codes (684 and 694.3) and free text fields for a diagnosis of NBI reported during a primary care visit. Diagnoses were manually validated, and events registered within 30-days after the index date were considered follow-ups. Incidence (IR) and prevalence (PR) rates of NBI were stratified by sex, age group, and calendar year. Topical and systemic antibiotic treatments were grouped based on ATC codes. 15,136 NBI episodes occurred in a total cohort of 225,979 children. The overall IR of NBI was 9.5 per 1,000 person-years, and children aged 1–4 years had the highest IR (13.2 per 1,000 person-years). A significant decrease in NBI IR from 13 per 1,000 person-years in 2004 to 7.46 per 1,000 person-years in 2018 (p < 0.0001) was noted. Most of the episodes were treated; systemic antibiotics were preferred over topical.

Conclusion

The prevalence of NBI in children in Italy is less than one third than the global estimate and the trend in time is decreasing. Over prescriptions of systemic antibiotics pose a threat to the diffusion of antimicrobial resistance.
CD44-Targeted Nanocarrier for Cancer Therapy
Authors: Kesharwani Prashant , Chadar Rahul , Sheikh Afsana , Rizg Waleed Y. , Safhi Awaji Y
Published: March 2022

Cluster of differentiation 44 (CD44) is a cell surface glycoprotein overexpressed in varieties of solid tumors including pancreatic, breast, ovary, brain, and lung cancers. It is a multi-structural glycoprotein of the cell surface which is majorly involved in cell proliferation, cell-to-cell interaction, cellular migration, inflammation, and generation of immune responses. Numerous studies focus on the development of nanocarriers for active targeting of the CD44 receptor to improve efficacy of targeting chemotherapy and achieve precise chemotherapy by defining the release, uptake, and accumulation of therapeutic agents. The CD44 receptor has a selective binding affinity towards hyaluronic and chondroitin sulfate (CS). Taking this into consideration, this review focused on the role of CD44 in cancer and its therapy using several nanocarriers such as polymeric/non-polymeric nanoparticles, dendrimer, micelles, carbon nanotubes, nanogels, nanoemulsions etc., for targeted delivery of several chemotherapeutic molecules and nucleic acid. This review also illuminates the role of hyaluronic acid (HA) in cancer therapy, interaction of HA with CD44, and various approaches to target CD44-overexpressed neoplastic cells.
The AT1 Receptor Blocker Telmisartan Reduces Intestinal Mucus Thickness in Obese Mice
Authors: Nickel Laura , Sünderhauf Annika , Rawish Elias , Stölting Ines , Derer Stefanie , Thorns Christoph , Matschl Urte , Othman Alaa , Sina Christian , Raasch Walter
Published: March 2022

The angiotensin II (type 1) (AT1) receptor blocker telmisartan (TEL) is beneficial for the treatment of individuals suffering from metabolic syndrome. As we have shown that TEL has an impact on gut microbiota, we investigated here whether TEL influences gut barrier function. C57BL/6N mice were fed with chow or high-fat diet (HFD) and treated with vehicle or TEL (8 mg/kg/day). Mucus thickness was determined by immunohistochemistry. Periodic Acid-Schiff staining allowed the number of goblet cells to be counted. Using western blots, qPCR, and immunohistochemistry, factors related to mucus biosynthesis (Muc2, St6galnac), proliferation (Ki-67), or necroptosis (Rip3) were measured. The influence on cell viability was determined in vitro by using losartan, as the water solubility of TEL was too low for in vitro experiments. Upon HFD, mice developed obesity as well as leptin and insulin resistance, which were prevented by TEL. Mucus thickness upon HFD-feeding was diminished. Independent of feeding, TEL additionally reduced mucus thickness. Numbers of goblet cells were not affected by HFD-feeding and TEL. St6galnac expression was increased by TEL. Rip3 was increased in TEL-treated and HFD-fed mice, while Ki-67 decreased. Cell viability was diminished by using >1 mM losartan. The anti-obese effect of TEL was associated with a decrease in mucus thickness, which was likely not related to a lower expression of Muc2 and goblet cells. A decrease in Ki-67 and increase in Rip3 indicates lower cell proliferation and increased necroptosis upon TEL. However, direct cell toxic effects are ruled out, as in vivo concentrations are lower than 1 mM.
Zhilong Huoxue Tongyu Capsules Ameliorate Early Brain Inflammatory Injury Induced by Intracerebral Hemorrhage via Inhibition of Canonical NFкβ Signalling Pathway
Authors: Mazhar Maryam , Yang Guoqiang , Mao Linshen , Liang Pan , Tan Ruizhi , Wang Li , Xu Houping , Yang Luyin , Ren Wei , Yang Sijin
Published: March 2022

Background: Intracerebral hemorrhage (ICH) is a debilitating and fatal condition with continuously rising incidence globally, without effective treatment available. Zhilong Huoxue Tongyu (ZLHXTY) capsule is a traditional Chinese medicine that is used for ICH treatment in China. However, the evidence based mechanism is not clear.

Purpose: To study the protective effects of ZLHXTY capsules against ICH pathogenesis via targetting nuclear factor kappa β (NFкβ) canonical signalling pathway.

Methods: C57BL/6 J mice ICH models using autologous blood injection were used to study the effect of ZLHXTY (1.4 g/kg P.O.) after 24 and 72 hrs of ICH induction. The neurological scoring, corner turn test and balance beam with scoring was performed to assess neurological damage. Hematoxylin/eosin and nissl staining was used for histopathological evaluation. Levels of TNFα, NFкB, iNOS, COX2, IL1, IL6 were measured using real time qPCR and western blotting. Protein levels of IKKβ and IкBα were analyzed through western blotting. Immunofluorescence for co-expression of NeuN/TNFα, NeuN/NFкB, Iba1/TNFα, and Iba1/NFкB was also performed.

Results: Treatment with ZLHXTY capsules after ICH ameliorated inflammatory brain injury after 24 and 72 h; revealed by neurological scoring, hematoxylin/eosin and nissl staining. The qPCR and western blot analyses demonstrated significant downregulation of TNFα, NFкB, iNOS, COX2, IL1β and IL6. Further, the IKKβ and IкBα revealed significant downregulation and upregulation respectively in western blot. Immunofluorescence also revealed attenuated expression of TNFα and NFкB in neurons and also low expression of Iba1.

Conclusion: ZLHXTY capsules elicit its neuroprotective effect by targetting the NFкβ canonical signalling pathway, thereby ameliorating the ICH induced brain injury.