bluuebunny/crossref_metadata_2025 huggingface dataset:
Case report: Bullous pemphigoid arising in a patient with scleroderma and multiple sclerosis
Authors: Moro Francesco , Mariotti Feliciana , Pira Anna , De Luca Naomi , Didona Biagio , Pagnanelli Gianluca , Di Zenzo Giovanni
Published: December 2022

Background

Bullous pemphigoid (BP) is the most common autoimmune-blistering disease, clinically characterized by erythematous urticarial plaques, blisters, and intense pruritus, induced by autoantibodies against two proteins of the dermo-epidermal junction, BP180 and BP230. A large number of autoimmune diseases are reported in the literature as BP comorbidities, such as multiple sclerosis, but only a few cases are in association with scleroderma and none in association with both.

Case presentation

We present the case of a 68-year-old woman affected by multiple sclerosis and scleroderma who developed severe bullous pemphigoid with a bullous pemphigoid disease area index of 60 and high titers of anti-BP180 and anti-BP230 autoantibodies by enzyme-linked immunosorbent assays. After 2 months of therapy with both intravenous and oral corticosteroids, the active lesions of bullous pemphigoid were remitted with no relapse.

Conclusion

Autoimmune diseases affecting the skin or organs where BP180 and BP230 are present could trigger an immune response to these antigens through an epitope-spreading phenomenon and, over the years, induce bullous pemphigoid onset.
Sex difference in circulating soluble form of ACE2 protein in moderate and severe COVID-19 and healthy controls
Authors: Robertson Josefina , Nellgård Bengt , Hultén Lillemor Mattsson , Nilsson Staffan , Dalla Keti , Börjesson Mats , Zetterberg Henrik , Svanvik Joar , Gisslén Magnus
Published: December 2022

Introduction

Membrane-bound angiotensin-converting enzyme-2 (ACE2) in epithelial cells is the main receptor for SARS-CoV-2. The extracellular portion of ACE2 may be shedded to plasma in which process ADAM17 (a disintegrin and metalloproteinase 17) is important. Results on the relationship between circulating levels of the soluble form of ACE2 (sACE2) and disease severity are inconclusive. This study investigates if sACE2 concentration correlates with COVID-19 severity, and whether this is affected by sex.

Materials and methods

Soluble form of ACE2 was analyzed in three groups: 104 patients (23 women and 81 men) with severe COVID-19 admitted to an intensive care unit (ICU), patients with moderate COVID-19 who required hospital care (n = 19, 4 women and 15 men), and age and sex matched healthy controls (n = 20, 4 women and 16 men). Blood samples were collected at hospital admission between 18 March 2020, and 3 May 2021, and at follow-up between 27 October 2020, and 19 October 2021. Circulating sACE2 (μg/L) was measured in EDTA plasma with a sensitive enzyme-linked immunosorbent assay. Additionally, CRP, ferritin, and lymphocyte count were analyzed during hospital stay.

Results

In total, 23 patients (22%) died in the ICU. When comparing healthy controls [mean age 58.1 (SD 11.4) years] and patients with moderate COVID-19 [mean age 61.0 (SD 13.2) years] with patients in the ICU [mean age 63.6 (SD 11.6) years], we found that sACE2 concentration decreased (70% reduction) with disease severity in men (p = 0.002) but increased 3.7-fold with severity in women (p = 0.043), suggesting a sex-related difference in how COVID-19 severity is related to sACE2 concentration. Moreover, we identified a relationship between inflammatory biomarkers and sACE2 concentration during the intensive care treatment, such that higher CRP and higher ferritin concentration correlated with lower sACE2 concentration in men.

Conclusion

The decrease in sACE2 concentration, selectively in men, in severe COVID-19 is of pathophysiological interest since men are affected more severely by the disease compared to women. Additionally, the inflammatory biomarkers, CRP and ferritin, correlated inversely with sACE2 concentration, suggesting a role in severe disease. Our findings imply that sACE2 is a possible biomarker of disease severity in a sex-specific manner.
Sugammadex versus neostigmine for neuromuscular blockade reversal in outpatient surgeries: A randomized controlled trial to evaluate efficacy and associated healthcare cost in an academic center
Authors: Fiorda Diaz Juan , Echeverria-Villalobos Marco , Esparza Gutierrez Alan , Dada Olufunke , Stoicea Nicoleta , Ackermann Wiebke , Abdel-Rasoul Mahmoud , Heard Jarrett , Uribe Alberto , Bergese Sergio D.
Published: December 2022

Introduction

Neuromuscular blockade is an essential component of the general anesthesia as it allows for a better airway management and optimal surgical conditions. Despite significant reductions in extubation and OR readiness-for-discharge times have been associated with the use of sugammadex, the cost-effectiveness of this drug remains controversial. We aimed to compare the time to reach a train-of-four (TOF) response of ≥0.9 and operating room readiness for discharge in patients who received sugammadex for moderate neuromuscular blockade reversal when compared to neostigmine during outpatient surgeries under general anesthesia. Potential reduction in time for OR discharge readiness as a result of sugammadex use may compensate for the existing cost-gap between sugammadex and neostigmine.

Methods

We conducted a single-center, randomized, double arm, open-label, prospective clinical trial involving adult patients undergoing outpatient surgeries under general anesthesia. Eligible subjects were randomized (1:1 ratio) into two groups to receive either sugammadex (Groups S), or neostigmine/glycopyrrolate (Group N) at the time of neuromuscular blockade reversal. The primary outcome was the time to reverse moderate rocuronium-induced neuromuscular blockade (TOF ratio ≥0.9) in both groups. In addition, post-anesthesia care unit (PACU)/hospital length of stay (LOS) and perioperative costs were compared among groups as secondary outcomes.

Results

Thirty-seven subjects were included in our statistical analysis (Group S= 18 subjects and Group N= 19 subjects). The median time to reach a TOF ratio ≥0.9 was significantly reduced in Group S when compared to Group N (180 versus 540 seconds; p = 0.0052). PACU and hospital LOS were comparable among groups. Postoperative nausea and vomiting was the main adverse effect reported in Group S (22.2% versus 5.3% in Group N; p = 0.18), while urinary retention (10.5%) and shortness of breath (5.3%) were only experienced by some patients in Group N. Moreover, no statistical differences were found between groups regarding OR/anesthesia, PACU, and total admission costs.

Discussion

Sugammadex use was associated with a significantly faster moderate neuromuscular blockade reversal. We found no evidence of increased perioperative costs associated with the use of sugammadex in patients undergoing outpatient surgeries in our academic institution.

Clinical trial registration

[https://clinicaltrials.gov/] identifier number [NCT03579589].
Risk factors for clinical failure of peroral endoscopic myotomy in achalasia
Authors: Quénéhervé Lucille , Vauquelin Blandine , Berger Arthur , Coron Emmanuel , Olivier Raphael
Published: December 2022

The recent development of per oral endoscopic myotomy (POEM) has been a game changer in the management of patients with achalasia. However, approximately 1 in 10 patients will not experience clinical success. The aim of this mini-review is to describe the current state of knowledge about the risk factors associated with POEM failure for the treatment of achalasia. Suspected risk factors are detailed into pre-, intra-, and post-procedural factors and put into perspective. Pre-procedural factors have been described, such as pre-treatment Eckardt score, previous treatments for achalasia, sigmoid type esophagus, significant esophageal dilatation, non-type II achalasia, young age and long duration of symptoms. An intra-procedural factor, mucosal injury during POEM, has also been associated with POEM failure. The occurrence of post-POEM GERD was identified as a controversial post-procedural factor associated with failure. The presumed mechanisms of POEM failure are incomplete myotomy or ineffective LES disruption, as confirmed by high-resolution manometry. However, when manometry confirms a significant decrease in LES pressure, it is likely that either impaired peristalsis or a morphologic abnormality such as extreme esophageal dilatation or severe tortuosity, which are not treated by POEM, should be suspected. Notably, a recently described adverse effect of POEM is the formation of a pseudo-diverticulum at the site of the myotomy (blown out myotomy). We finally stress the importance of performing a complete workup in case of POEM failure as different mechanisms of POEM failure should lead to different management.
Case series of progressive familial intrahepatic cholestasis type 3: Characterization of variants in ABCB4 in China
Authors: Cheng Jinlin , Gong Ling , Mi Xiaoxiao , Wu Xiangyan , Zheng Jun , Yang Wenjun
Published: December 2022

Objective

To improve the accuracy of the diagnosis of familial progressive intrahepatic cholestasis type 3 (PFIC3, https://www.omim.org/entry/602347).

Materials and methods

Between September 2019 and March 2021, we recruited four patients with PFIC3 from two liver centers in East China. Molecular genetic findings of ATP-binding cassette subfamily B member 4 [ATP binding cassette transporter A4 (ABCB4), https://www.omim.org/entry/171060] were prospectively examined, and clinical records, laboratory readouts, and macroscopic and microscopic appearances of the liver were analyzed.

Results

Four patients experienced cholestasis, mild jaundice, and elevated levels of serum direct bilirubin, γ-glutamyltransferase, or total bile acids. All patients had moderate-to-severe liver fibrosis or biliary cirrhosis, and their liver biopsy specimens stained positive with rhodamine. Molecular immunohistochemistry revealed reduced or absent MDR3 expression in all liver specimens. A novel mutation of ABCB4 (c.1560 + 2T > A) was identified in patients with PFIC3, which is of high clinical significance and may help understand mutant ABCB4 pathogenesis.

Conclusion

MDR3 immunohistochemistry and molecular genetic analyses of ABCB4 are essential for the accurate diagnosis of PFIC3.
A new contribution to Megasporoporia sensu lato: Six new species and three new combinations
Authors: Wang Ya-Rong , Dai Yu-Cheng , Liu Hong-Gao , Vlasák Josef , Buchanan Peter , Yuan Yuan , Wu Ying-Da
Published: December 2022

Megasporoporia sensu lato has recently been intensively studied in China and South America, and four independent clades representing four genera have been recognized phylogenetically. In this study, more samples, mostly from subtropical and tropical Asia, Oceania, and East Africa, are analyzed. A phylogeny based on a 4-gene dataset of sequences (ITS + nLSU + mtSSU + tef) has confirmed the presence of four genera in Megasporoporia sensu lato: Jorgewrightia, Mariorajchenbergia, Megasporia, and Megasporoporia sensu stricto. Six new species, Jorgewrightia austroasiana, Jorgewrightia irregularis, Jorgewrightia tenuis, Mariorajchenbergia subleucoplaca, Megasporia olivacea, and Megasporia sinuosa, are described based on morphology and phylogenetic analysis. Three new combinations are proposed, viz. Jorgewrightia kirkii, Mariorajchenbergia epitephra, and Mariorajchenbergia leucoplaca. To date, 36 species of Megasporoporia sensu lato are accepted and an identification key to these species is provided. In addition, the identification of Dichomitus amazonicus, Dichomitus cylindrosporus, and Megasporoporia hexagonoides is discussed.
In-process real-time probiotic phenotypic strain identity tracking: The use of Fourier transform infrared spectroscopy
Authors: Deidda Francesca , Cordovana Miriam , Bozzi Cionci Nicole , Graziano Teresa , Di Gioia Diana , Pane Marco
Published: December 2022

Probiotic bacteria, capable of conferring benefits to the host, can present challenges in design, development, scale-up, manufacturing, commercialization, and life cycle management. Strain identification is one of the main quality parameters; nevertheless, this task can be challenging since established methodologies can lack resolution at the strain level for some microorganisms and\or are labor-intensive and time-consuming. Fourier transform infrared spectroscopy (FTIRS) has been largely used for the investigation of pathogenic species in the clinical field, whereas only recently has been proposed for the identification of probiotic strains. Within the probiotic industrial production, bacterial strains can be subjected to stressful conditions that may affect genomic and phenotypic characteristics; therefore, real-time monitoring of all the sequential growth steps is requested. Considering the fast, low-cost, and high-throughput features, FTIRS is an innovative and functional technology for typing probiotic strains from bench-top experiments to large-scale industrial production, allowing the monitoring of stability and identity of probiotic strains. In this study, the discriminatory power of FTIRS was assessed for four Lactiplantibacillus plantarum probiotic strains grown under different conditions, including temperatures (30 and 37°C) and medium (broth and agar), after consecutive sub-culturing steps. A comparison between the generated spectra with pulsed-field gel electrophoresis (PFGE) profiles was also performed. FTIRS was not only able to distinguish the strains of L. plantarum under different growth conditions but also to prove the phenotypic stability of L. plantarum type strain LP-CT after six growing steps. Regardless of the growth conditions, FTIRS spectra related to LP-CT constituted a unique hierarchical cluster, separated from the other L. plantarum strains. These results were confirmed by a PFGE analysis. In addition, based on FTIRS data, broth cultures demonstrated a higher reproducibility and discriminatory power with respect to agar ones. These results support the introduction of FTIRS in the probiotic industry, allowing for the step-by-step monitoring of massive microbial production while also guaranteeing the stability and purity of the probiotic strain. The proposed novel approach can constitute an impressive improvement in the probiotic manufacturing process.
Genotype classification of Moraxella bovis using MALDI-TOF MS profiles
Authors: Olson Hannah G. , Loy John Dustin , Clawson Michael L. , Wynn Emily L. , Hille Matthew M.
Published: December 2022

Moraxella bovis(M. bovis) is regarded as a causative agent of infectious bovine keratoconjunctivitis (IBK), the most common ocular disease of cattle. Recently, whole genome sequencing identified the presence of two distinct genotypes withinM. bovisthat differ in chromosome content, potential virulence factors, as well as prophage and plasmid profiles. It is unclear if the genotypes equally associate with IBK or if one is more likely to be isolated from IBK lesions. We utilized 39 strains ofM. bovisthat had previously undergone whole genome sequencing and genotype classification to determine the utility of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) to accurately genotypeM. bovisstrains. We successfully developed two biomarker models that accurately classified strains according to genotype with an overall accuracy of 85.8–100% depending upon the model and sample preparation method used. These models provide a practical tool to enable studies of genotype associations with disease, allow for epidemiological studies at the sub-species level, and can be used to enhance disease prevention strategies.
CRISPR-Cas13a system: A novel tool for molecular diagnostics
Authors: Zhao Lixin , Qiu Minyue , Li Xiaojia , Yang Juanzhen , Li Jintao
Published: December 2022

The clustered regularly interspaced short palindromic repeats (CRISPR) system is a natural adaptive immune system of prokaryotes. The CRISPR-Cas system is currently divided into two classes and six types: types I, III, and IV in class 1 systems and types II, V, and VI in class 2 systems. Among the CRISPR-Cas type VI systems, the CRISPR/Cas13a system has been the most widely characterized for its application in molecular diagnostics, gene therapy, gene editing, and RNA imaging. Moreover, because of the trans-cleavage activity of Cas13a and the high specificity of its CRISPR RNA, the CRISPR/Cas13a system has enormous potential in the field of molecular diagnostics. Herein, we summarize the applications of the CRISPR/Cas13a system in the detection of pathogens, including viruses, bacteria, parasites, chlamydia, and fungus; biomarkers, such as microRNAs, lncRNAs, and circRNAs; and some non-nucleic acid targets, including proteins, ions, and methyl groups. Meanwhile, we highlight the working principles of some novel Cas13a-based detection methods, including the Specific High-Sensitivity Enzymatic Reporter UnLOCKing (SHERLOCK) and its improved versions, Cas13a-based nucleic acid amplification-free biosensors, and Cas13a-based biosensors for non-nucleic acid target detection. Finally, we focus on some issues that need to be solved and the development prospects of the CRISPR/Cas13a system.
First molecular evidence of hybridization in endosymbiotic ciliates (Protista, Ciliophora)
Authors: Obert Tomáš , Zhang Tengyue , Rurik Ivan , Vďačný Peter
Published: December 2022

Hybridization is an important evolutionary process that can fuel diversification via formation of hybrid species or can lead to fusion of previously separated lineages by forming highly diverse species complexes. We provide here the first molecular evidence of hybridization in wild populations of ciliates, a highly diverse group of free-living and symbiotic eukaryotic microbes. The impact of hybridization was studied on the model of Plagiotoma, an obligate endosymbiont of the digestive tube of earthworms, using split decomposition analyses and species networks, 2D modeling of the nuclear rRNA molecules and compensatory base change analyses as well as multidimensional morphometrics. Gene flow slowed down and eventually hampered the diversification of Lumbricus-dwelling plagiotomids, which collapsed into a single highly variable biological entity, the P. lumbrici complex. Disruption of the species boundaries was suggested also by the continuum of morphological variability in the phenotypic space. On the other hand, hybridization conspicuously increased diversity in the nuclear rDNA cistron and somewhat weakened the host structural specificity of the P. lumbrici complex, whose members colonize a variety of phylogenetically closely related anecic and epigeic earthworms. By contrast, another recorded species, P. aporrectodeae sp. n., showed no signs of introgression, no variability in the rDNA cistron, and very high host specificity. These contrasting eco-evolutionary patterns indicate that hybridization might decrease the alpha-diversity by dissolving species boundaries, weaken the structural host specificity by broadening ecological amplitudes, and increase the nuclear rDNA variability by overcoming concerted evolution within the P. lumbrici species complex.
Prokaryotic and eukaryotic microbial diversity from three soda lakes in the East African Rift Valley determined by amplicon sequencing
Authors: Jeilu Oliyad , Gessesse Amare , Simachew Addis , Johansson Eva , Alexandersson Erik
Published: December 2022

Soda lakes are unique poly-extreme environments with high alkalinity and salinity that support diverse microbial communities despite their extreme nature. In this study, prokaryotic and eukaryotic microbial diversity in samples of the three soda lakes, Lake Abijata, Lake Chitu and Lake Shala in the East African Rift Valley, were determined using amplicon sequencing. Culture-independent analysis showed higher diversity of prokaryotic and eukaryotic microbial communities in all three soda lakes than previously reported. A total of 3,603 prokaryotic and 898 eukaryotic operational taxonomic units (OTUs) were found through culture-independent amplicon sequencing, whereas only 134 bacterial OTUs, which correspond to 3%, were obtained by enrichment cultures. This shows that only a fraction of the microorganisms from these habitats can be cultured under laboratory conditions. Of the three soda lakes, samples from Lake Chitu showed the highest prokaryotic diversity, while samples from Lake Shala showed the lowest diversity. Pseudomonadota (Halomonas), Bacillota (Bacillus, Clostridia), Bacteroidota (Bacteroides), Euryarchaeota (Thermoplasmata, Thermococci, Methanomicrobia, Halobacter), and Nanoarchaeota (Woesearchaeia) were the most common prokaryotic microbes in the three soda lakes. A high diversity of eukaryotic organisms were identified, primarily represented by Ascomycota and Basidiomycota. Compared to the other two lakes, a higher number of eukaryotic OTUs were found in Lake Abijata. The present study showed that these unique habitats harbour diverse microbial genetic resources with possible use in biotechnological applications, which should be further investigated by functional metagenomics.
The effects of microbiota abundance on symptom severity in Parkinson’s disease: A systematic review
Authors: Papić Eliša , Rački Valentino , Hero Mario , Tomić Zoran , Starčević-Čižmarević Nada , Kovanda Anja , Kapović Miljenko , Hauser Goran , Peterlin Borut , Vuletić Vladimira
Published: December 2022

Introduction

Parkinson’s disease (PD) is neurodegenerative disease with a multifactorial etiopathogenesis with accumulating evidence identifying microbiota as a potential factor in the earliest, prodromal phases of the disease. Previous research has already shown a significant difference between gut microbiota composition in PD patients as opposed to healthy controls, with a growing number of studies correlating gut microbiota changes with the clinical presentation of the disease in later stages, through various motor and non-motor symptoms. Our aim in this systematic review is to compose and assess current knowledge in the field and determine if the findings could influence future clinical practice as well as therapy in PD.

Methods

We have conducted a systematic review according to PRISMA guidelines through MEDLINE and Embase databases, with studies being selected for inclusion via a set inclusion and exclusion criteria.

Results

20 studies were included in this systematic review according to the selected inclusion and exclusion criteria. The search yielded 18 case control studies, 1 case study, and 1 prospective case study with no controls. The total number of PD patients encompassed in the studies cited in this review is 1,511.

Conclusion

The link between gut microbiota and neurodegeneration is a complex one and it depends on various factors. The relative abundance of various microbiota taxa in the gut has been consistently shown to have a correlation with motor and non-motor symptom severity. The answer could lie in the products of gut microbiota metabolism which have also been linked to PD. Further research is thus warranted in the field, with a focus on the metabolic function of gut microbiota in relation to motor and non-motor symptoms.
Semantic and right temporal variant of FTD: Next generation sequencing genetic analysis on a single-center cohort
Authors: Rossi Giacomina , Salvi Erika , Mehmeti Elkadia , Ricci Martina , Villa Cristina , Prioni Sara , Moda Fabio , Di Fede Giuseppe , Tiraboschi Pietro , Redaelli Veronica , Coppola Cinzia , Koch Giacomo , Canu Elisa , Filippi Massimo , Agosta Federica , Giaccone Giorgio , Caroppo Paola
Published: December 2022

Semantic and right temporal variant of frontotemporal dementia (svFTD and rtvFTD) are rare clinical phenotypes in which, in most cases, the underlying pathology is TDP-43 proteinopathy. They are usually sporadic disorders, but recent evidences suggest a higher frequency of genetic mutations for the right temporal versus the semantic variant. However, the genetic basis of these forms is not clear. In this study we performed a genetic screening of a single-center cohort of svFTD and rtvFTD patients, aiming at identifying the associated genetic variants. A panel of 73 dementia candidate genes has been analyzed by NGS target sequencing including both causal and risk/modifier genes in 23 patients (15 svFTD and 8 rtvFTD) and 73 healthy age-matched controls. We first performed a single variant analysis considering rare variants and then a gene-based aggregation analysis to evaluate the cumulative effects of multiple rare variants in a single gene. We found 12 variants in nearly 40% of patients (9/23), described as pathogenic or classified as VUS/likely pathogenic. The overall rate was higher in svFTD than in rtvFTD. Three mutations were located in MAPT gene and single mutations in the following genes: SQSTM1, VCP, PSEN1, TBK1, OPTN, CHCHD10, PRKN, DCTN1. Our study revealed the presence of variants in genes involved in pathways relevant for the pathology, especially autophagy and inflammation. We suggest that molecular analysis should be performed in all svFTD and rtvFTD patients, to better understand the genotype–phenotype correlation and the pathogenetic mechanisms that could drive the clinical phenotypes in FTD.
Advanced cueing of auditory stimulus to the head induces body sway in the direction opposite to the stimulus site during quiet stance in male participants
Authors: Hamada Naoki , Kunimura Hiroshi , Matsuoka Masakazu , Oda Hitoshi , Hiraoka Koichi
Published: December 2022

Under certain conditions, a tactile stimulus to the head induces the movement of the head away from the stimulus, and this is thought to be caused by a defense mechanism. In this study, we tested our hypothesis that predicting the stimulus site of the head in a quiet stance activates the defense mechanism, causing a body to sway to keep the head away from the stimulus. Fourteen healthy male participants aged 31.2 ± 6.8 years participated in this study. A visual cue predicting the forthcoming stimulus site (forehead, left side of the head, right side of the head, or back of the head) was given. Four seconds after this cue, an auditory or electrical tactile stimulus was given at the site predicted by the cue. The cue predicting the tactile stimulus site of the head did not induce a body sway. The cue predicting the auditory stimulus to the back of the head induced a forward body sway, and the cue predicting the stimulus to the forehead induced a backward body sway. The cue predicting the auditory stimulus to the left side of the head induced a rightward body sway, and the cue predicting the stimulus to the right side of the head induced a leftward body sway. These findings support our hypothesis that predicting the auditory stimulus site of the head induces a body sway in a quiet stance to keep the head away from the stimulus. The right gastrocnemius muscle contributes to the control of the body sway in the anterior–posterior axis related to this defense mechanism.
Pre-attentive fundamental frequency processing in Mandarin-speaking children with cochlear implants as revealed by the peak latency of positive mismatch response
Authors: Huang Wanting , Wong Lena L. N. , Chen Fei
Published: December 2022

Introduction

Fundamental frequency (F0) serves as the primary acoustic cue for Mandarin tone perception. Recent behavioral studies suggest that F0 information may be differently processed between Mandarin-speaking normal-hearing (NH) children and children with cochlear implants (CIs), which may partially explain the unsatisfactory outcome of lexical tone recognition using CIs with tonal language-oriented speech processing strategies. The aim of the current study was to provide neural evidence of F0 processing in Mandarin-speaking kindergarten-aged children with CIs compared with NH children.

Methods

Positive mismatch responses (p-MMRs) to the change of the two acoustic dimensions of F0 (F0 contour and F0 level) in Mandarin-speaking kindergarten-aged children with CIs (n = 19) and their age-matched NH peers (n = 21).

Results

The two groups of children did not show any significant difference on the mean amplitude of p-MMR to either F0 contour or F0 level change. While the CI group exhibited a significantly shorter peak latency of p-MMR to F0 contour change than to F0 level change, an opposite pattern was observed in the NH group.

Discussion

This study revealed a higher sensitivity to F0 contour change than to F0 level change in children with CIs, which was different from that in NH children. The neural evidence of discrepant F0 processing between children with CIs and NH children in this study was consistent with the previously reported behavioral findings and may serve as a reference for the development and improvement of tonal language-oriented speech processing strategies.
Solid-state NMR of paired helical filaments formed by the core tau fragment tau(297-391)
Authors: Al-Hilaly Youssra K. , Hurt Connor , Rickard Janet E. , Harrington Charles R. , Storey John M. D. , Wischik Claude M. , Serpell Louise C. , Siemer Ansgar B.
Published: December 2022

Aggregation of the tau protein into fibrillar cross-β aggregates is a hallmark of Alzheimer’s diseases (AD) and many other neurodegenerative tauopathies. Recently, several core structures of patient-derived tau paired helical filaments (PHFs) have been solved revealing a structural variability that often correlates with a specific tauopathy. To further characterize the dynamics of these fibril cores, to screen for strain-specific small molecules as potential biomarkers and therapeutics, and to develop strain-specific antibodies, recombinant in-vitro models of tau filaments are needed. We recently showed that a 95-residue fragment of tau (from residue 297 to 391), termed dGAE, forms filaments in vitro in the absence of polyanionic co-factors often used for in vitro aggregation of full-length tau. Tau(297-391) was identified as the proteolytic resistant core of tau PHFs and overlaps with the structures characterized by cryo-electron microscopy in ex vivo PHFs, making it a promising model for the study of AD tau filaments in vitro. In the present study, we used solid-state NMR to characterize tau(297-391) filaments and show that such filaments assembled under non-reducing conditions are more dynamic and less ordered than those made in the presence of the reducing agent DTT. We further report the resonance assignment of tau(297-391)+DTT filaments and compare it to existing core structures of tau.
A postbiotic fermented oat gruel may have a beneficial effect on the colonic mucosal barrier in patients with irritable bowel syndrome
Authors: Bednarska Olga , Biskou Olga , Israelsen Hans , Winberg Martin E. , Walter Susanna , Keita Åsa V.
Published: December 2022

Background

Impaired intestinal permeability and microbial dysbiosis are important pathophysiological mechanisms underlying irritable bowel syndrome (IBS). ReFerm®, also called Profermin®, is a postbiotic product of oat gruel fermented with Lactobacillus plantarum 299v. In this study, we investigated whether ReFerm® has a beneficial effect on the intestinal epithelial barrier function in patients with IBS.

Materials and methods

Thirty patients with moderate to severe IBS-diarrhoea (IBS-D) or IBS-mixed (IBS-M) were treated with enema containing ReFerm® or placebo. The patients underwent sigmoidoscopy with biopsies obtained from the distal colon at baseline and after 14 days of treatment with ReFerm® or placebo twice daily. The biopsies were mounted in Ussing chambers, and paracellular and transcellular permeabilities were measured for 120 min. In addition, the effects of ReFerm® or placebo on the epithelial barrier were investigated in vitro using Caco-2 cells.

Results

ReFerm® reduced paracellular permeability (p < 0.05) and increased transepithelial resistance (TER) over time (p < 0.01), whereas the placebo had no significant effect in patients. In ReFerm®-treated Caco-2 cells, paracellular and transcellular permeabilities were decreased compared to the control (p < 0.05) and placebo (p < 0.01). TER was increased in Caco-2 ReFerm®-treated cells, and normalised TER was increased in ReFerm®-treated Caco-2 cells compared to control (p < 0.05) and placebo-treated (p < 0.05) cells.

Conclusion

ReFerm® significantly reduced paracellular permeability and improved TER in colonic biopsies collected from patients with IBS and in a Caco-2 cell model. Our results offer new insights into the potential benefits of ReFerm® in IBS management. Further studies are needed to identify the molecular mechanisms underlying the barrier-protective properties of ReFerm®.

Clinical trial registration

[https://clinicaltrials.gov/], identifier [NCT05475314].
Risk factors of cervical lymph node metastasis in multifocal papillary thyroid cancer
Authors: Zhang Ting , He Liang , Wang Zhihong , Dong Wenwu , Sun Wei , Zhang Ping , Zhang Hao
Published: December 2022

Introduction

Identifying risk variables for cervical lymph node metastases in multifocality papillary thyroid cancer (MPTC) could assist surgeons in determining whether cervical lymph node dissection would be an appropriate surgical option.

Methods

A retrospective cohort of 2006 patients with papillary thyroid cancer were selected. MPTC (N = 460) was defined as the presence of two or more foci of PTC. The risk factors for central lymph node metastasis (CLNM) and lateral lymph node metastasis (LLNM) in MPTC were investigated by univariate and multivariate analyses, including the following items: age at diagnosis, gender, Hashimoto’s thyroiditis, extrathyroidal extension (ETE), maximal axial diameter (MAD) and the sum of axial diameters (SAD) of tumor. In addition, CLNM was used to evaluate LLNM.

Results

The incidence of CLNM and LLNM was 44.57% and 17.17%, respectively. The multivariate analysis demonstrated that gender, extrathyroidal extension (ETE), age, maximal axial diameter (MAD), and the sum of axial diameters (SAD) were related to increased risk for CLNM in MPTC (p < 0.05). The area under the receiver operating characteristic (ROC) curve (AUC) for age at diagnosis of CLNM was 0.647, the cut-off value was 50 years old. Additionally, by multivariate analysis, CLNM, ETE, MAD, and SAD were independent risk factors for LLNM in MPTC (p < 0.05). ROC curve analysis demonstrates that AUC for MAD and SAD diagnosis of LLNM were 0.639 and 0.757, and the cut-off values were 16 and 26 mm, respectively.

Conclusions

MPTC patients who have risk factors for CLNM were advised to perform prophylactic central lymph node dissection (CLND). Additionally, the presence of risk factors for LLNM should be individually evaluated and analyzed for the necessity of lateral lymph node dissection.
Imaging based body composition profiling and outcomes after oncologic liver surgery
Authors: Bernardi Lorenzo , Roesel Raffaello , Vagelli Filippo , Majno-Hurst Pietro , Cristaudi Alessandra
Published: December 2022

Body composition profiling is gaining attention as a pre-operative factor that can play a role in predicting the short- and long- term outcomes of patients undergoing oncologic liver surgery. Existing evidence is mostly limited to retrospective and single-institution series and in many of these studies, the evaluation of body composition is based on parameters which are derived from CT-scan imaging. Among body composition phenotypes, sarcopenia is the most well studied but this is only one of the possible profiles which can impact the outcomes of oncologic hepatic surgery. Interest has recently grown in studying the effect of sarcopenic obesity, central obesity, or visceral fat amount, myosteatosis, and bone mineral density on -such patients. The objective of this review is to summarize the current evidence on whether imaging-based parameters of body composition have an impact on the outcome of patients undergoing liver surgery for each of the most frequent indications for liver resection in clinical practice: hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and colorectal liver metastases (CRLM).
Endoscopic and pathohistologic features of early gastric signet ring cell carcinoma presented as elevated type: A case report
Authors: Di Lianjun , Wu Xinglong , Tuo Biguang
Published: December 2022

Background

Almost all early gastric signet ring cell carcinomas (SRCCs) are the flat or depressed type, and the elevated type is rare. Here, we report the endoscopic and pathohistologic features of a rare case of SRCCs presented as the elevated type.

Case presentation

A 54-year-old man underwent esophagogastroduodenoscopy in our hospital because of intermittent upper abdominal pain for 6 years. White light endoscopy revealed an elevated lesion that is smooth and reddish and covered with normal mucosa and looked like a polyp. Magnifying endoscopy with narrow-band imaging showed broadened intervening parts, an elongated pit, and a dense microvascular network with focal irregularity. The lesion was considered as early gastric cancer and completely resected with endoscopic submucosal dissection. Pathohistological examination confirmed that the lesion was pure early SRCC that was limited within the mucosal lamina propria (T1a).

Conclusion

Elevated pure gastric SRCC is rare. This is a report of early pure gastric SRCC presented as the elevated type and the description of its endoscopic and pathohistologic features, which will contribute to the early detection of gastric SRCC.
Inter and intra-tumor heterogeneity of paediatric type diffuse high-grade gliomas revealed by single-cell mass cytometry
Authors: Petrilli Lucia Lisa , Fuoco Claudia , Palma Alessandro , Pasquini Luca , Pericoli Giulia , Grabovska Yura , Mackay Alan , Rossi Sabrina , Carcaboso Angel M. , Carai Andrea , Mastronuzzi Angela , Jones Chris , Cesareni Gianni , Locatelli Franco , Vinci Maria
Published: December 2022

Paediatric-type diffuse high-grade gliomas (PDHGG) are aggressive tumors affecting children and young adults, with no effective treatment. These highly heterogeneous malignancies arise in different sites of the Central Nervous System (CNS), carrying distinctive molecular alterations and clinical outcomes (inter-tumor heterogeneity). Moreover, deep cellular and molecular profiling studies highlighted the coexistence of genetically and phenotypically different subpopulations within the same tumor mass (intra-tumor heterogeneity). Despite the recent advances made in the field, the marked heterogeneity of PDHGGs still impedes the development of effective targeted therapies and the identification of suitable biomarkers. In order to fill the existing gap, we used mass cytometry to dissect PDHGG inter- and intra-heterogeneity. This is one of the most advanced technologies of the “-omics” era that, using antibodies conjugated to heavy metals, allows the simultaneous measurement of more than 40 markers at single-cell level. To this end, we analyzed eight PDHGG patient-derived cell lines from different locational and molecular subgroups. By using a panel of 15 antibodies, directly conjugated to metals or specifically customized to detect important histone variants, significant differences were highlighted in the expression of the considered antigens. The single-cell multiparametric approach realized has deepened our understanding of PDHGG, confirming a high degree of intra- and inter-tumoral heterogeneity and identifying some antigens that could represent useful biomarkers for the specific PDHGG locational or molecular subgroups.
The prognosis analysis of organ metastatic patterns in lung large cell neuroendocrine carcinoma: A population-based study
Authors: Chen Kai , Dai Peiling , Ni Jiangwei , Xiang Yili , Gu Lizhong
Published: December 2022

Lung large cell neuroendocrine carcinoma (LCNEC) is a rare and highly aggressive malignancy with a dismal prognosis. This study was designed to depict patterns of distant organ metastatic and to analyze prognosis of LCNEC patients. We gathered data from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. We conducted the Kaplan–Meier method to calculate overall survival (OS) and compare different variables. Cox proportional hazards regression models in univariate and multivariate analyses were employed to further explore prognostic factors. A total of 1335 LCNEC patients were eventually selected from the SEER database, of which 348 patients (26.0%) had single organ metastasis and 197 patients (14.8%) had multiple metastases. Our study indicates that patients with single organ metastasis generally have a poor prognosis, with a median OS of 8 months for both lung and brain metastasis with 1-year survival rates of 33% and 29% respectively. Patients with multiple metastases exhibited the worst prognosis, with a median OS of only 4 months and a 1-year OS of 8%. Multivariate analysis revealed that age, T stage, N stage, chemotherapy and radiation in metastatic patients were independently associated with OS. In conclusion, LCNEC exhibits a high metastatic rate when diagnosed. The most common metastatic organ is the brain in single-site metastatic patients. Patients with single or multiple metastases exhibit a significantly worse prognosis than those with non-organ metastases. In the group of single organ metastases, patients with brain and lung metastases had a better prognosis than those with bone and liver metastases.
DDB2 represses epithelial-to-mesenchymal transition and sensitizes pancreatic ductal adenocarcinoma cells to chemotherapy
Authors: Dardare Julie , Witz Andréa , Betz Margaux , Francois Aurélie , Meras Morgane , Lamy Laureline , Lambert Aurélien , Grandemange Stéphanie , Husson Marie , Rouyer Marie , Demange Jessica , Merlin Jean-Louis , Harlé Alexandre , Gilson Pauline
Published: December 2022

Introduction

Damage specific DNA binding protein 2 (DDB2) is an UV-indiced DNA damage recognition factor and regulator of cancer development and progression. DDB2 has dual roles in several cancers, either as an oncogene or as a tumor suppressor gene, depending on cancer localization. Here, we investigated the unresolved role of DDB2 in pancreatic ductal adenocarcinoma (PDAC).

Methods

The expression level of DDB2 in pancreatic cancer tissues and its correlation with patient survival were evaluated using publicly available data. Two PDAC cell models with CRISPR-modified DDB2 expression were developed: DDB2 was repressed in DDB2-high T3M4 cells (T3M4 DDB2-low) while DDB2 was overexpressed in DDB2-low Capan-2 cells (Capan-2 DDB2-high). Immunofluorescence and qPCR assays were used to investigate epithelial-to-mesenchymal transition (EMT) in these models. Migration and invasion properties of the cells were also determined using wound healing and transwell assays. Sensitivity to 5-fluorouracil (5-FU), oxaliplatin, irinotecan and gemcitabine were finally investigated by crystal violet assays.

Results

DDB2 expression level was reduced in PDAC tissues compared to normal ones and DDB2-low levels were correlated to shorter disease-free survival in PDAC patients. DDB2 overexpression increased expression of E-cadherin epithelial marker, and decreased levels of N-cadherin mesenchymal marker. Conversely, we observed opposite effects in DDB2 repression and enhanced transcription of SNAIL, ZEB1, and TWIST EMT transcription factors (EMT-TFs). Study of migration and invasion revealed that these properties were negatively correlated with DDB2 expression in both cell models. DDB2 overexpression sensitized cells to 5-fluorouracil, oxaliplatin and gemcitabine.

Conclusion

Our study highlights the potential tumor suppressive effects of DDB2 on PDAC progression. DDB2 could thus represent a promising therapeutic target or biomarker for defining prognosis and predicting chemotherapy response in patients with PDAC.
The molecular basis of the dichotomous functionality of MAP4K4 in proliferation and cell motility control in cancer
Authors: Jovanovic Dejana , Yan Shen , Baumgartner Martin
Published: December 2022

The finely tuned integration of intra- and extracellular cues by components of the mitogen-activated protein kinase (MAPK) signaling pathways controls the mutually exclusive phenotypic manifestations of uncontrolled growth and tumor cell dissemination. The Ser/Thr kinase MAP4K4 is an upstream integrator of extracellular cues involved in both proliferation and cell motility control. Initially identified as an activator of the c-Jun N-terminal kinase (JNK), the discovery of diverse functions and additional effectors of MAP4K4 beyond JNK signaling has considerably broadened our understanding of this complex kinase. The implication of MAP4K4 in the regulation of cytoskeleton dynamics and cell motility provided essential insights into its role as a pro-metastatic kinase in cancer. However, the more recently revealed role of MAP4K4 as an activator of the Hippo tumor suppressor pathway has complicated the understanding of MAP4K4 as an oncogenic driver kinase. To develop a better understanding of the diverse functions of MAP4K4 and their potential significance in oncogenesis and tumor progression, we have collected and assessed the current evidence of MAP4K4 implication in molecular mechanisms that control proliferation and promote cell motility. A better understanding of these mechanisms is particularly relevant in the brain, where MAP4K4 is highly expressed and under pathological conditions either drives neuronal cell death in neurodegenerative diseases or cell dissemination in malignant tumors. We review established effectors and present novel interactors of MAP4K4, which offer mechanistic insights into MAP4K4 function and may inspire novel intervention strategies. We discuss possible implications of novel interactors in tumor growth and dissemination and evaluate potential therapeutic strategies to selectively repress pro-oncogenic functions of MAP4K4.
High efficacy of azacitidine combined with homoharringtonine, idarubicin, and cytarabine in newly diagnosed patients with AML: A single arm, phase 2 trial
Authors: Li Jun , Huang Yanqing , Hou Yue , Gu Yan , Song Chunhua , Ge Zheng
Published: December 2022

Introduction

This study aims to evaluate the efficacy and safety of the novel combination of Aza and HIA as the frontline induction therapy in newly diagnosed AML patients eligible for intensive chemotherapy (IC) (registered on ClinicalTrials.gov, number NCT04248595).

Methods

Aza (75mg/m2/d on days1-5 subcutaneous) is administered in combination with HIA [HHT 2mg/m2/d on days 4-8 intravenous over 3 hours, idarubicin 6mg/m2/d on days 4-6 intravenous, and cytarabine 100mg/m2/d on days 4-10 intravenous]. The primary endpoint was complete remission (CR) or CR with incomplete blood count recovery (CRi). Secondary endpoints were overall survival (OS), relapse-free survival (RFS), and adverse events (AEs).

Results

A total of 20 AML patients (aged 18-70 years) were enrolled between Jan 2020 and Sep 2022. 95% (19/20) of patients achieved CR/CRi, and 89.5% (17/19) had undetectable MRD, in which 94.7% (18/19) reached CR/CRi, and 88.9% (16/18) obtained MRD negative after the 1st cycle of induction therapy. Median OS and RFS were both not reached during the follow-up. The estimated 2-year OS and RFS were 87.5% (95%CI, 58.6% to 96.7%) and 87.1% (95%CI, 57.3% to 96.6%), respectively. No patient discontinued the treatment for AEs.

Discussion

This study provides preliminary evidence for this novel combination therapy as the first-line induction therapy for young or older AML patients fit for IC.