bluuebunny/crossref_metadata_2025 huggingface dataset:
Chicken antibodies are highly suitable for particle enhanced turbidimetric assays
Authors: Larsson Anders , Campbell Andrew , Eriksson Mats
Published: October 2022

Antibody-based assays are commonly used in clinical laboratories for analyzing plasma, serum and other samples for particular protein markers. Although such assays have been traditionally based on antibodies raised in mammals (e.g., mice, rabbits, goats), there are several advantages of using avian antibodies (IgY) raised in chickens, including production volumes, costs, and ethical/animal welfare considerations. A further disadvantage of using mammalian IgG in such assays is the potential for agglutination when exposed to rheumatoid factor (RF) in serum. However, when used in the free form the immune complexes formed with avian antibodies have been reported to have less ability than those formed with mammalian antibodies to cause the light scatter which are used for instrument measurement. In addition, when the amount of antigen exceeds the maximum precipitating point in relation to the amount of antibody, there is a rapid decline in the absorbance values of the immune complexes (antigen excess) when IgY is used. However, when avian antibodies are conjugated to a substrate and used in particle enhanced turbidimetric assays (PETIA), these problems are avoided. Here we investigated three clinical assays using chicken antibodies, one using free (unbound) IgY and two with IgY-based PETIA. The IgY PETIA demonstrated a strong scatter response, even at high antigen concentrations in contrast to the steep decline seen with free IgY antibodies. IgY PETIA reagents can provide test results with low coefficient of variation (<1% for duplicate samples). We also investigated the effect of RF on agglutination of mammalian antibodies (IgG from mouse, rabbit, sheep, and human) and chicken antibodies. Whereas agglutination was observed with all the mammalian antibodies in the presence of RF, this was not observed at all with chicken IgY. Our results support the growing body of evidence that chicken egg yolks can thus be a valuable source of antibodies for use in PETIA in clinical laboratories.
Adherence to Sars-CoV2 vaccination in hematological patients
Authors: Narinx Justine , Houbiers Margaux , Seidel Laurence , Beguin Yves
Published: October 2022

Background

SARS-CoV2 vaccination efficiently prevents severe COVID-19, although hematological patients, particularly under therapy, respond less well. Besides vaccine efficacy, adherence to vaccination is essential for ensuring adequate protection of this vulnerable population.

Methods

We evaluated the impact of a program aimed at maximizing patient adherence by comparing the rate of SARS-CoV2 vaccination of our hematological patients and a matched sample of the general population.

Results

Vaccination rates were 88.9% among 2,156 patients, aged 65.2 ± 15.8 years (M ± SD, range 19-86 years). Rates differed considerably with age, i.e. 84.2% between 18-64 years and 92.4% above 65 years (p<0.0001), but not with sex. In the general population, rates were 76.3% overall, 73.0% between 18-64 and 86.7% above 65 years, all significantly lower than among patients, overall (Standardized Incidence ratio (SIR) 1.17; 95%CI 1.12-1.22, p<0.0001) as well as among younger (SIR 1.15; 1.07-1.24, p<0.0001) or older (SIR 1.06; 1.00-1.13, p=0.046) people. Vaccination rates increased to 92.2% overall (SIR 1.21; 1.16-1.27, p<0.0001), 88.5% in younger (SIR 1.21; 1.13-1.30, p<0.0001) and 94.8% in older (SIR 1.09; 1.03-1.12, p=0.0043) patients, after excluding those with medical contraindications, and further to 95.6% overall (SIR 1.26; 1.20-1.32, p<0.0001), 93.8% in younger (SIR 1.29; 1.20-1.38, p<0.0001) and 96.9% in older (SIR 1.11; 1.05-1.18, p=0.0004) patients, after excluding those not seen in hematology in 2021.

Conclusions

Vaccination rates were significantly higher in hematological patients compared to the general population regardless of age, sex and municipality. Acceptance of Covid vaccines by hematological patients may be improved by targeted information campaigns carried out by trusted health care professionals.
Gracilaria gracilis and Nannochloropsis oceanica, singly or in combination, in diets alter the intestinal microbiota of European seabass (Dicentrarchus labrax)
Authors: Ferreira Mariana , Abdelhafiz Yousri , Abreu Helena , Silva Joana , Valente Luisa M. P. , Kiron Viswanath
Published: October 2022

Algae feeds and fish gut microbiota have been given importance in the past few years because of the necessity to rely on sustainable ingredients in aquafeeds and the link of host-associated microbes to organismal health. But little is known about the potential of algae, particularly of micro- and macroalgae combination, to shape the intestinal bacterial communities. Hence, in the present work, the 16S rRNA gene sequencing technique was employed to unravel the effects of the seaweed Gracilaria gracilis and the microalga Nannochloropsis oceanica - included either singly or in combination in the diets of European seabass - on the diversities and composition of the gut bacterial communities. Results indicated that 8% inclusion of either G. gracilis (GRA) or N. oceanica (NAN) led to a reduction in the gut microbial diversity. On the other hand, inclusion of the micro- and macroalga in a blend (NANGRA) mitigated these plausible effects on the intestinal bacterial communities. The core microbiota of European seabass was composed of both beneficial (Lactobacillus and Cetobacterium) and potentially pathogenic (Flavobacterium) bacteria. The GRA diet was associated with a lower abundance of carbohydrate degraders and also promoted the growth of bacteria capable of outcompeting fish pathogens (Sulfitobacter and Methylobacterium). On the other hand, the NAN diet led to a higher representation of the genus Bacillus, with probiotic potential, accompanied by a decrease in Vibrio, a genus encompassing several fish pathogenic species. These findings demonstrate the ability of micro- and macroalgae to modulate the gut microbiota of European seabass, with plausible implications to host gut homeostasis.
Mechanical and toxicological effects of deep-sea mining sediment plumes on a habitat-forming cold-water octocoral
Authors: Carreiro-Silva Marina , Martins Inês , Riou Virginie , Raimundo Joana , Caetano Miguel , Bettencourt Raul , Rakka Maria , Cerqueira Teresa , Godinho António , Morato Telmo , Colaço Ana
Published: October 2022

Deep-sea mining activities are expected to impact deep-sea biota through the generation of sediment plumes that disperse across vast areas of the ocean. Benthic sessile suspension-feeding fauna, such as cold-water corals, may be particularly susceptible to increased suspended sediments. Here, we exposed the cold-water octocoral, Dentomuricea aff. meteor to suspended particles generated during potential mining activities in a four weeks experimental study. Corals were exposed to three experimental treatments: (1) control conditions (no added sediments); (2) suspended polymetallic sulphide (PMS) particles; (3) suspended quartz particles. The two particle treatments were designed to distinguish between potential mechanical and toxicological effects of mining particles. PMS particles were obtained by grinding PMS inactive chimney rocks collected at the hydrothermal vent field Lucky Strike. Both particle types were delivered at a concentration of 25 mg L-1, but achieved suspended concentrations were 2-3 mg L-1 for the PMS and 15-18 mg L-1 for the quartz particles due to the different particle density. Results of the experiment revealed a significant increase in dissolved cobalt, copper and manganese concentrations in the PMS treatment, resulting from the oxidation of sulphides in contact with seawater. Negative effects of PMS exposure included a progressive loss in tissue condition with necrosis and bioaccumulation of copper in coral tissues and skeletons, and death of all coral fragments by the end of the experiment. Physiological changes under PMS exposure, included increased respiration and ammonia excretion rates in corals after 13 days of exposure, indicating physiological stress and potential metabolic exhaustion. Changes in the cellular stress biomarkers and gene expression profiles were more pronounced in corals exposed to quartz particles, suggesting that the mechanical effect of particles although not causing measurable changes in the physiological functions of the coral, can still be detrimental to corals by eliciting cellular stress and immune responses. We hypothesize that the high mortality of corals recorded in the PMS treatment may have resulted from the combined and potentially synergistic mechanical and toxicological effects of the PMS particles. Given the dispersal potential of mining plumes and the highly sensitive nature of octocorals, marine protected areas, buffer areas or non-mining areas may be necessary to protect deep-sea coral communities.
Description of three novel species of Scandinavium: Scandinavium hiltneri sp. nov., Scandinavium manionii sp. nov. and Scandinavium tedordense sp. nov., isolated from the oak rhizosphere and bleeding cankers of broadleaf hosts
Authors: Maddock Daniel , Kile Helene , Denman Sandra , Arnold Dawn , Brady Carrie
Published: October 2022

While investigating the bacterial populations of environmental samples taken from a mix of healthy and Acute Oak Decline afflicted Quercus robur (pedunculate or English oak) rhizosphere soil samples and swabs of bleeding lesions on Tilia spp. (lime) and Quercus rubra (red oak) trees, several strains belonging to the order Enterobacterales were isolated using selective media and enrichment broth. Seven strains from the Q. robur rhizosphere, three strains from Tilia spp. and one from Q. rubra were investigated, with their taxonomic status determined via a polyphasic taxonomic approach. Initially stains were identified as potential members of the recently described genus Scandinavium, based on the partial sequencing of three housekeeping genes. Further analysis of phenotypic traits, including fatty acid profiles, coupled with 16S rRNA gene and phylogenomic analysis of whole genome sequences were applied to a subset of the strains. Phylogenetic and phylogenomic analysis repeatedly placed the isolates in a monophyletic clade within Scandinavium, with four distinct clusters observed, one of which corresponded to Scandinavium goeteborgense, the type species of the genus. The remaining three clusters could be phenotypically and genotypically differentiated from each other and S. goeteborgense. As such, we describe three novel species of the genus, for which we propose the names Scandinavium hiltneri sp. nov. (type strain H11S7T = LMG 32612T = CCUG 76179T), Scandinavium manionii sp. nov. (type strain H17S15T = LMG 32613T = CCUG 76183T) and Scandinavium tedordense sp. nov. (type strain TWS1aT = LMG 32614T = CCUG 76188T). Additionally, the descriptions of the genus Scandinavium and the type species, S. goeteborgense, are emended.
MiR-27a-3p and miR-30b-5p inhibited-vitamin D receptor involved in the progression of tuberculosis
Authors: Xiao Min , Yang Song , Zhou An , Li Tongxin , Liu Jingjing , Chen Yang , Luo Ya , Qian Chunfang , Yang Fuping , Tang Bo , Li Chunhua , Su Na , Li Jing , Jiang Mingying , Yang Shiming , Lin Hui
Published: October 2022

Background

MicroRNAs (miRNAs) play a vital role in tuberculosis (TB). Vitamin D receptor (VDR), an miRNA target gene, and its ligand, vitamin D3 (VitD3), have been reported to exert protective effects against TB. However, whether miRNAs can affect the progression of TB by targeting VDR has not been reported.

Materials and methods

Research subjects were selected according to defined inclusion criteria. A clinical database of 360 samples was established, including the subjects’ demographic information, miRNA expression profiles and cellular experimental results. Two candidate miRNAs, miR-27a-3p, and miR-30b-5p, were identified by a high-throughput sequencing screen and validated by qRT–PCR assays. Univariate and multivariate statistical analyses were performed. VDR and NF-kB p65 protein levels were detected by Western blot assays. Proinflammatory cytokine expression levels were detected by enzyme-linked immunosorbent assay (ELISA). Luciferase assays and fluorescence-activated cell sorting (FACS) were further applied to elucidate the detailed mechanisms.

Results

Differential miRNA expression profiles were obtained, and miR-27a-3p and miR-30b-5p were highly expressed in patients with TB. These results showed that the two miRNAs were able to induce M1 macrophage differentiation and inhibit M2 macrophage differentiation. Further experiments showed that the two miRNAs decreased the VDR protein level and increased proinflammatory cytokine secretion by macrophages. Mechanistically, the miRNAs targeted the 3′ untranslated region (3′UTR) of the VDR mRNA and thereby downregulated VDR protein levels by post-transcriptional regulation. Then, due to the reduction in VDR protein levels, the NF-kB inflammatory cytokine signaling pathway was activated, thus promoting the progression of TB.

Conclusion

Our study not only identified differentially expressed miRNAs between the TB and control groups but also revealed that miR-27a-3p and miR-30b-5p regulate proinflammatory cytokine secretion and macrophage differentiation through VDR in macrophages. Thus, these two miRNAs influence the progression of TB.
Alpha-Synuclein species in oral mucosa as potential biomarkers for multiple system atrophy
Authors: Zheng Yuanchu , Cai Huihui , Zhao Jiajia , Yu Zhenwei , Feng Tao
Published: October 2022

Background

The definitive diagnosis of Multiple system atrophy (MSA) requires the evidence of abnormal deposition of α-Synuclein (α-Syn) through brain pathology which is unable to achieve in vivo. Deposition of α-Syn is not limited to the central nervous system (CNS), but also extended to peripheral tissues. Detection of pathological α-Syn deposition in extracerebral tissues also contributes to the diagnosis of MSA. We recently reported the increased expressions of α-Syn, phosphorylated α-Synuclein at Ser129 (pS129), and α-Syn aggregates in oral mucosal cells of Parkinson’s disease (PD), which serve as potential biomarkers for PD. To date, little is known about the α-Syn expression pattern in oral mucosa of MSA which is also a synucleinopathy. Here, we intend to investigate whether abnormal α-Syn deposition occurs in oral mucosal cells of MSA, and to determine whether α-Syn, pS129, and α-Syn aggregates in oral mucosa are potential biomarkers for MSA.

Methods

The oral mucosal cells were collected by using cytobrush from 42 MSA patients (23 MSA-P and 19 MSA-C) and 47 age-matched healthy controls (HCs). Immunofluorescence analysis was used to investigate the presence of α-Syn, pS129, and α-Syn aggregates in the oral mucosal cells. Then, the concentrations of α-Syn species in oral mucosa samples were measured using electrochemiluminescence assays.

Results

Immunofluorescence images indicated elevated α-Syn, pS129, and α-Syn aggregates levels in oral mucosal cells of MSA than HCs. The concentrations of three α-Syn species were significantly higher in oral mucosal cells of MSA than HCs (α-Syn, p < 0.001; pS129, p = 0.042; α-Syn aggregates, p < 0.0001). In MSA patients, the oral mucosa α-Syn levels negatively correlated with disease duration (r = −0.398, p = 0.009). The area under curve (AUC) of receiver operating characteristic (ROC) analysis using an integrative model including age, gender, α-Syn, pS129, and α-Syn aggregates for MSA diagnosis was 0.825, with 73.8% sensitivity and 78.7% specificity.

Conclusion

The α-Syn levels in oral mucosal cells elevated in patients with MSA, which may be promising biomarkers for MSA.
The effect and mechanism of traditional Chinese exercise for chronic low back pain in middle-aged and elderly patients: A systematic review
Authors: Wang Xue-Qiang , Xiong Huan-Yu , Du Shu-Hao , Yang Qi-Hao , Hu Li
Published: October 2022

Background

Increasing lines of evidence indicate that traditional Chinese exercise (TCE) has potential benefits in improving chronic low back pain (CLBP) symptoms. To assess the clinical efficacy of TCE in the treatment of CLBP, we performed a systematic review of existing randomized controlled trials (RCTs) of CLBP and summarized the neural mechanisms underlying TCE in the treatment of CLBP.

Methods

A systematic search was conducted in four electronic databases: PubMed, Embase, the Cochrane Library, and EBSCO from January 1991 to March 2022. The quality of all included RCTs was evaluated by the Physiotherapy Evidence Database Scale (PEDro). The primary outcomes included pain severity and pain-related disability.

Results

A total of 11 RCTs with 1,256 middle-aged and elderly patients with CLBP were included. The quality of all 11 included RCTs ranged from moderate to high according to PEDro. Results suggested that TCE could considerably reduce pain intensity in patients with CLBP. Overall, most studies did not find any difference in secondary outcomes (quality of life, depression, and sleep quality).

Conclusion

The neurophysiological mechanism of TCE for treating CLBP could be linked to meditation and breathing, posture control, strength and flexibility training, and regulation of pain-related brain networks. Our systematic review showed that TCE appears to be effective in alleviating pain in patients with CLBP.
Comparison of two behavioral tests for tinnitus assessment in mice
Authors: Fabrizio-Stover Emily M. , Nichols Grace , Corcoran Jamie , Jain Avni , Burghard Alice L. , Lee Christopher M. , Oliver Douglas L.
Published: October 2022

Animal research focused on chronic tinnitus associated with noise-induced hearing loss can be expensive and time-consuming as a result of the behavioral training required. Although there exist a number of behavioral tests for tinnitus; there have been few formal direct comparisons of these tests. Here, we evaluated animals in two different tinnitus assessment methods. CBA/CaJ mice were trained in an operant conditioning, active avoidance (AA) test, and a reflexive, gap-induced pre-pulse inhibition of acoustic startle (GPIAS) test, or both. Tinnitus was induced in awake mice by unilateral continuous sound exposure using a 2-kHz- or 12 octave-wide noise centered at 16 kHz and presented at 113- or 116-dB SPL. Tinnitus was assessed 8 weeks after sound overexposure. Most mice had evidence of tinnitus behavior in at least one of the two behaviors. Of the mice evaluated in AA, over half (55%) had tinnitus positive behavior. In GPIAS, fewer animals (13%) were positive than were identified using the AA test. Few mice were positive in both tests (10%), and only one was positive for tinnitus behavior at the same spectral frequency in both tests. When the association between tinnitus behavior and spontaneous activity recorded in the inferior colliculus was compared, animals with tinnitus behavior in AA exhibited increased spontaneous activity, while those positive in GPIAS did not. Thus, it appears that operant conditioning tests, like AA, maybe more reliable and accurate tests for tinnitus than reflexive tests.
Neuroinflammation of microglia polarization in intracerebral hemorrhage and its potential targets for intervention
Authors: Yang Guoqiang , Fan Xuehui , Mazhar Maryam , Guo Wubin , Zou Yuanxia , Dechsupa Nathupakorn , Wang Li
Published: October 2022

Microglia are the resident immune cells of the central nervous system (CNS) and play a key role in neurological diseases, including intracerebral hemorrhage (ICH). Microglia are activated to acquire either pro-inflammatory or anti-inflammatory phenotypes. After the onset of ICH, pro-inflammatory mediators produced by microglia at the early stages serve as a crucial character in neuroinflammation. Conversely, switching the microglial shift to an anti-inflammatory phenotype could alleviate inflammatory response and incite recovery. This review will elucidate the dynamic profiles of microglia phenotypes and their available shift following ICH. This study can facilitate an understanding of the self-regulatory functions of the immune system involving the shift of microglia phenotypes in ICH. Moreover, suggestions for future preclinical and clinical research and potential intervention strategies are discussed.
Kölliker’s organ-supporting cells and cochlear auditory development
Authors: Chen Jianyong , Gao Dekun , Sun Lianhua , Yang Jun
Published: October 2022

The Kölliker’s organ is a transient cellular cluster structure in the development of the mammalian cochlea. It gradually degenerates from embryonic columnar cells to cuboidal cells in the internal sulcus at postnatal day 12 (P12)–P14, with the cochlea maturing when the degeneration of supporting cells in the Kölliker’s organ is complete, which is distinct from humans because it disappears at birth already. The supporting cells in the Kölliker’s organ play a key role during this critical period of auditory development. Spontaneous release of ATP induces an increase in intracellular Ca2+ levels in inner hair cells in a paracrine form via intercellular gap junction protein hemichannels. The Ca2+ further induces the release of the neurotransmitter glutamate from the synaptic vesicles of the inner hair cells, which subsequently excite afferent nerve fibers. In this way, the supporting cells in the Kölliker’s organ transmit temporal and spatial information relevant to cochlear development to the hair cells, promoting fine-tuned connections at the synapses in the auditory pathway, thus facilitating cochlear maturation and auditory acquisition. The Kölliker’s organ plays a crucial role in such a scenario. In this article, we review the morphological changes, biological functions, degeneration, possible trans-differentiation of cochlear hair cells, and potential molecular mechanisms of supporting cells in the Kölliker’s organ during the auditory development in mammals, as well as future research perspectives.
Clinical application of prion-like seeding in α-synucleinopathies: Early and non-invasive diagnosis and therapeutic development
Authors: Li Jiaqi , Luo Haiyang , Zheng Honglin , Duan Suying , Zhao Taiqi , Yuan Yanpeng , Liu Yutao , Zhang Xiaoyun , Wang Yangyang , Yang Jing , Xu Yuming
Published: October 2022

The accumulation and deposition of misfolded α-synuclein (α-Syn) aggregates in the brain is the central event in the pathogenesis of α-synucleinopathies, including Parkinson’s disease, dementia with Lewy bodies, and multiple-system atrophy. Currently, the diagnosis of these diseases mainly relies on the recognition of advanced clinical manifestations. Differential diagnosis among the various α-synucleinopathies subtypes remains challenging. Misfolded α-Syn can template its native counterpart into the same misfolded one within or between cells, behaving as a prion-like seeding. Protein-misfolding cyclic amplification and real-time quaking-induced conversion are ultrasensitive protein amplification assays initially used for the detection of prion diseases. Both assays showed high sensitivity and specificity in detection of α-synucleinopathies even in the pre-clinical stage recently. Herein, we collectively reviewed the prion-like properties of α-Syn and critically assessed the detection techniques of α-Syn-seeding activity. The progress of test tissues, which tend to be less invasive, is presented, particularly nasal swab, which is now widely known owing to the global fight against coronavirus disease 2019. We highlight the clinical application of α-Syn seeding in early and non-invasive diagnosis. Moreover, some promising therapeutic perspectives and clinical trials targeting α-Syn-seeding mechanisms are presented.
Effect of high glucose supplementation on pulmonary fibrosis involving reactive oxygen species and TGF-β
Authors: Ning Wenjuan , Xu Xiaoxiao , Zhou Shican , Wu Xiao , Wu Hang , Zhang Yijie , Han Jichang , Wang Junpeng
Published: October 2022

This study explored the profibrotic impact of high glucose in the lung and potential mechanisms using latent TGF-β1-induced human epithelial cell pulmonary fibrosis and bleomycin (BLM)-induced pulmonary fibrosis models. Results demonstrated that high glucose administration induced epithelial–mesenchymal transition (EMT) in human epithelial cells in a dose-dependent manner via activating latent TGF-β1, followed by increased expression of mesenchymal-related proteins and decreased expression of epithelial marker protein E-cadherin. Further mechanism analysis showed that administration of high glucose dose-dependently promoted total and mitochondrial reactive oxygen species (ROS) accumulation in human epithelial cells, which promoted latent TGF-β1 activation. However, N-acetyl-L-cysteine, a ROS eliminator, inhibited such effects. An in vivo feed study found that mice given a high-glucose diet had more seriously pathological characteristics of pulmonary fibrosis in BLM-treated mice, including increasing infiltrated inflammatory cells, collagen I deposition, and the expression of mesenchymal-related proteins while decreasing the expression of the epithelial marker E-cadherin. In addition, high glucose intake further increased TGF-β1 concentration and upregulated p-Smad2/3 and snail in lung tissues from BLM-treated mice when compared to BLM-treated mice. Finally, supplementation with high glucose further increased the production of lipid peroxidation metabolite malondialdehyde and decreased superoxide dismutase activity in BLM-treated mice. Collectively, these findings illustrate that high glucose supplementation activates a form of latent TGF-β1 by promoting ROS accumulation and ultimately exacerbates the development of pulmonary fibrosis.
Heart dose and cardiac comorbidities influence death with a cardiac cause following hypofractionated radiotherapy for lung cancer
Authors: Banfill Kathryn , Abravan Azadeh , van Herk Marcel , Sun Fei , Franks Kevin , McWilliam Alan , Faivre-Finn Corinne
Published: October 2022

Background

There is increasing evidence of cardiac toxicity of thoracic radiotherapy however, it is difficult to draw conclusions on cardiac dose constraints due to the heterogeneity of published studies. Moreover, few studies record data on cause of death. The aim of this paper is to investigate the relationship between conventional cardiac dosimetric parameters and death with cardiac causes using data from the UK national cause of death registry.

Methods

Data on cancer diagnosis, treatment and cause of death following radical lung cancer radiotherapy were obtained from Public Health England for all patients treated at the Christie NHS Foundation Trust between 1/1/10 and 31/12/16. Individuals with metastatic disease and those who received multiple courses of thoracic radiotherapy where excluded. All patients who received > 45Gy in 20 fractions were included. Cardiac cause of death was defined as the following ICD-10 codes on death certificate: I20-I25; I30-I32; I34-I37; I40-I52. Cardiac V5Gy, V30Gy, V50Gy and mean heart dose (MHD) were extracted. Cumulative incidence of death with cardiac causes were plotted for each cardiac dosimetric parameter. Multi-variable Fine and Gray competing risk analysis was used to model predictors for cardiac death with non-cardiac death as a competing risk.

Results

Cardiac dosimetric parameters were available for 967 individuals, 110 died with a cardiac cause (11.4%). Patients with a cardiac comorbidity had an increased risk of death with a cardiac cause compared with those without a cardiac comorbidity (2-year cumulative incidence 21.3% v 6.2%, p<0.001). In patients with a pre-existing cardiac comorbidity, heart V30Gy ≥ 15% was associated with higher cumulative incidence of death with a cardiac cause compared to patients with heart V30Gy <15% (2-year rate 25.8% v 17.3%, p=0.05). In patients without a cardiac comorbidity, after adjusting for tumour and cardiac risk factors, MHD (aHR 1.07, 1.01-1.13, p=0.021), heart V5Gy (aHR 1.01, 1-1.13, p=0.05) and heart V30Gy (aHR 1.04, 1-1.07, p=0.039) were associated with cardiac death.

Conclusion

The effect of cardiac radiation dose on cardiac-related death following thoracic radiotherapy is different in patients with and without cardiac comorbidities. Therefore patients’ cardiovascular risk factors should be identified and managed alongside radiotherapy for lung cancer.
The prominent role of the S100A8/S100A9-CD147 axis in the progression of penile cancer
Authors: Mohr Tobias , Zwick Anabel , Hans Muriel Charlotte , Bley Isabelle Ariane , Braun Felix Leon , Khalmurzaev Oybek , Matveev Vsevolod Borisovich , Loertzer Philine , Pryalukhin Alexey , Hartmann Arndt , Geppert Carol-Immanuel , Loertzer Hagen , Wunderlich Heiko , Naumann Carsten Maik , Kalthoff Holger , Junker Kerstin , Smola Sigrun , Lohse Stefan
Published: October 2022

Currently, no established biomarkers are recommended for the routine diagnosis of penile carcinoma (PeCa). The rising incidence of this human papillomavirus (HPV)–related cancer entity highlights the need for promising candidates. The Calprotectin subunits S100A8 and S100A9 mark myeloid-derived suppressor cells in other HPV-related entities while their receptor CD147 was discussed to identify patients with PeCa at a higher risk for poor prognoses and treatment failure. We thus examined their expression using immunohistochemistry staining of PeCa specimens from 74 patients on tissue microarrays of the tumor center, the invasion front, and lymph node metastases. Notably, whereas the tumor center was significantly more intensively stained than the invasion front, lymph node metastases were thoroughly positive for both S100 subunits. An HPV-positive status combined with an S100A8+S100A9+ profile was related with an elevated risk for metastases. We observed several PeCa specimens with S100A8+S100A9+-infiltrating immune cells overlapping with CD15 marking neutrophils. The S100A8+S100A9+CD15+ profile was associated with dedifferentiated and metastasizing PeCa, predominantly of HPV-associated subtype. These data suggest a contribution of neutrophil-derived suppressor cells to the progression of HPV-driven penile carcinogenesis. CD147 was elevated, expressed in PeCa specimens, prominently at the tumor center and in HPV-positive PeCa cell lines. CD147+HPV+ PeCa specimens were with the higher-frequency metastasizing cancers. Moreover, an elevated expression of CD147 of HPV-positive PeCa cell lines correlated negatively with the susceptibility to IgA-based neutrophil-mediated tumor cell killing. Finally, stratifying patients regarding their HPV/S100A8/S100A9/CD15/CD147 profile may help identify patients with progressing cancer and tailor immunotherapeutic treatment strategies.
Impact of automated methods for quantitative evaluation of immunostaining: Towards digital pathology
Authors: Elie Nicolas , Giffard Florence , Blanc-Fournier Cécile , Morice Pierre-Marie , Brachet Pierre-Emmanuel , Dutoit Soizic , Plancoulaine Benoît , Poulain Laurent
Published: October 2022

Introduction

We sought to develop a novel method for a fully automated, robust quantification of protein biomarker expression within the epithelial component of high-grade serous ovarian tumors (HGSOC). Rather than defining thresholds for a given biomarker, the objective of this study in a small cohort of patients was to develop a method applicable to the many clinical situations in which immunomarkers need to be quantified. We aimed to quantify biomarker expression by correlating it with the heterogeneity of staining, using a non-subjective choice of scoring thresholds based on classical mathematical approaches. This could lead to a universal method for quantifying other immunohistochemical markers to guide pathologists in therapeutic decision-making.

Methods

We studied a cohort of 25 cases of HGSOC for which three biomarkers predictive of the response observed ex vivo to the BH3 mimetic molecule ABT-737 had been previously validated by a pathologist. We calibrated our algorithms using Stereology analyses performed by two experts to detect immunohistochemical staining and epithelial/stromal compartments. Immunostaining quantification within Stereology grids of hexagons was then performed for each histological slice. To define thresholds from the staining distribution histograms and to classify staining within each hexagon as low, medium, or high, we used the Gaussian Mixture Model (GMM).

Results

Stereology analysis of this calibration process produced a good correlation between the experts for both epithelium and immunostaining detection. There was also a good correlation between the experts and image processing. Image processing clearly revealed the respective proportions of low, medium, and high areas in a single tumor and showed that this parameter of heterogeneity could be included in a composite score, thus decreasing the level of discrepancy. Therefore, agreement with the pathologist was increased by taking heterogeneity into account.

Conclusion and discussion

This simple, robust, calibrated method using basic tools and known parameters can be used to quantify and characterize the expression of protein biomarkers within the different tumor compartments. It is based on known mathematical thresholds and takes the intratumoral heterogeneity of staining into account. Although some discrepancies need to be diminished, correlation with the pathologist’s classification was satisfactory. The method is replicable and can be used to analyze other biological and medical issues. This non-subjective technique for assessing protein biomarker expression uses a fully automated choice of thresholds (GMM) and defined composite scores that take the intra-tumor heterogeneity of immunostaining into account. It could help to avoid the misclassification of patients and its subsequent negative impact on therapeutic care.
Global trends and regional differences in the burden of cancer attributable to secondhand smoke in 204 countries and territories, 1990–2019
Authors: Maimaitiming Mailikezhati , Wang Minmin , Luo Yanan , Wang Jia , Jin Yinzi , Zheng Zhi-Jie
Published: October 2022

Background

To describe the status quo and trends in the global burden of all cancers caused by secondhand smoke during 1990–2019.

Methods

Data on cancer associated with secondhand smoke were extracted from the Global Heath Data Exchange. Cancer burden was measured by cancer-related deaths, disability-adjusted life years (DALYs), years lived with disability (YLDs), and years of life lost (YLLs).

Results

In 2019, age-standardized rates of death, DALYs and YLLs among the cancer population globally caused by secondhand smoke were 1.60, 38.54 and 37.77, respectively. The proportions of these in the total cancer burden for all risk factors combined decreased slightly from 1990 to 2003 and then increased from 2004 to 2019. In 2019, >50% of the cancer burden was concentrated in men aged 55–75 years and women aged 50–70 years. Between 1990 and 2019, there was an increase in age-standardized rates of death, DALYs, YLDs and YLLs among those aged ≥70 years. The age-standardized YLDs rate attributable to secondhand smoke was higher among women; it decreased in men but increased in women, causing a wider gap between the sexes. A greater cancer burden was mainly seen in North America in 1990 and Europe in 2019. Reductions in the annual rate change of cancer burden were found mainly in North America and Oceania, while increases were found in Africa and Asia. In 2019, high–middle- and middle-SDI countries had higher age-standardized rates of deaths, DALYs, YLDs and YLLs than the global level. During 1990 and 2019, the largest decline in cancer burden was seen in high-SDI countries, while middle- or low-SDI countries experienced increases in all age-standardized rates.

Conclusions

Cancer burden attributable to secondhand smoke is concerning given the increasing health loss and differences in distribution of cancer burden worldwide. Further studies are needed to investigate the causes of disparities in cancer burden attributable to secondhand smoke and to improve understanding of the contribution of secondhand smoke to the burden of different types of cancer.
Chronic oral mucocutaneous candidiasis, recurrent respiratory infection, hepatosplenomegaly, and autoimmune diabetes mellitus: A case report of a gain-of-function mutation of STAT1 in a Chinese boy
Authors: Cao Bingyan , Liu Meijuan , Zhao Yun , Gong Chunxiu
Published: October 2022

Background

Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations are characterized by chronic mucocutaneous candidiasis and autoimmune diseases. Type 1 diabetes mellitus is one of the well-characterized autoimmune conditions.

Case presentation

We reported a 5-year-old boy who presented with polydipsia and polyuria, with a medical history of chronic oral mucocutaneous candidiasis, recurrent respiratory infection, hepatosplenomegaly, and abnormal liver function. Genetic analysis identified a heterozygous GOF mutation (c.866A > G, p.Y289C) in STAT1.

Results

Various medicines were given to the boy during the follow-up, including insulin to keep blood glucose stable, intravenous immunoglobulin and antifungal agents for recurrent infections, and antituberculosis drugs (isoniazid, rifampicin) to combat tuberculosis infection. He did not show recurrent infection, but chronic oral mucocutaneous candidiasis still occurred twice per month. The blood glucose level was well controlled.

Conclusion

This article illustrates that early diagnosis and identification of STAT1 mutation are essential for assessing the severity of the disease and determining reasonable treatment options.
Hepatotoxic metabolites in Polygoni Multiflori Radix— Comparative toxicology in mice
Authors: Wang Shixiao , Kong Xiang , Chen Ning , Hu Pengwei , Boucetta Hamza , Hu Zhaoliang , Xu Xin , Zhang Pei , Zhan Xiang , Chang Ming , Cheng Rui , Wu Wei , Song Min , Lu Yuting , Hang Taijun
Published: October 2022

Polygoni Multiflori Radix (PM) and Rhei radix et rhizoma (rhubarb) contain similar hepatocyte-toxic anthraquinones such as emodin (major free anthraquinone in PM), physcion and their glycosides. In clinical practice, PM hepatotoxicity has been widely reported, although rhubarb is not recognized as hepatotoxic. To clarify the substances basis (key components) of PM hepatotoxicity, based on the characteristic components’ similarity within PM, rhubarb and their concocted forms, a comparative sub-acute toxicity study was designed in mice. Nine groups of mice with 28 days of oral administration of these herbal extracts or 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (TSG, major and unique characteristic component in PM)-herb combinations were set as follows: Group-1, control; Group-2, PM ethanol-extract (PME); Group-3, PM praeparata ethanol-extract (PMPE); Group-4, Rhubarb ethanol-extract (RME); Group-5, Steamed rhubarb ethanol-extract (RMPE); Group-6, TSG; Group-7, PMPE-TSG combination; Group-8, RME-TSG combination; Group-9, RMPE-TSG combination. Each experimental group received an equivalent emodin dose of 29 mg/kg except for the TSG group, and an equivalent TSG dose of 1,345 mg/kg except for the PMPE, RME and RMPE groups. The results showed that PME, PMPE-TSG and RME-TSG induced liver lesions and biochemical abnormalities of liver function compared with the control. In contrast, PMPE, RME, RMPE, TSG and RMPE-TSG caused no liver lesions and fewer biochemical abnormalities. Considering the related components, only the co-administration of high doses of TSG and emodin-8-O-β-D-glucoside (EMG, major anthraquinone glycoside in PM) in these groups could cause liver lesions. According to tissue distribution and correlation analysis, EMG dose was positively correlated with the high hepatic emodin and TSG exposure, and the hepatic emodin and TSG exposure were positively correlated with the biochemical abnormalities of liver function. Cell viability test in vitro showed emodin was more hepatotoxic than TSG and EMG, and mainly emodin and TSG of the three had synergistic hepatotoxic effects. Therefore, creatively using rhubarb as a reference, this study revealed that PM hepatotoxicity in mice mainly came from the integrative contribution of TSG, EMG and emodin.
Traditional Chinese medicine promotes the control and treatment of dementia
Authors: Tao Pengyu , Xu Wenxin , Gu Simeng , Shi Haiyan , Wang Qian , Xu Yuzhen
Published: October 2022

Dementia is a syndrome that impairs learning and memory. To date, there is no effective therapy for dementia. Current prescription drugs, such as cholinesterase inhibitors, fail to improve the condition of dementia and are often accompanied by severe adverse effects. In recent years, the number of studies into the use of traditional Chinese medicine (TCM) for dementia treatment has increased, revealing a formula that could significantly improve memory and cognitive dysfunctions in animal models. TCM showed fewer adverse effects, lower costs, and improved suitability for long-term use compared with currently prescribed drugs. Due to the complexity of ingredients and variations in bioactivity of herbal medicines, the multi-target nature of the traditional Chinese formula affected the outcome of dementia therapy. Innovations in TCM will create a platform for the development of new drugs for the prevention and treatment of dementia, further strengthening and enhancing the current influence of TCM.
Voltage dependence of the cannabinoid CB1 receptor
Authors: Goldberger Esty , Tauber Merav , Ben-Chaim Yair
Published: October 2022

Cannabinoids produce their characteristic effects mainly by binding to two types of G-protein coupled receptors (GPCRs), the CB1 and CB2 cannabinoid receptors. The CB1 receptor is the main cannabinoid receptor in the central nervous system, and it participates in many brain functions. Recent studies showed that membrane potential may serve as a novel modulatory modality of many GPCRs. Here, we used Xenopus oocytes as an expression system to examine whether membrane potential modulates the activity of the CB1 receptor. We found that the potencies of the endocannabinoid 2-AG and the phytocannabinoid THC in activating the receptor are voltage dependent; depolarization enhanced the potency of these agonists and decreased their dissociation from the receptor. This voltage dependence appears to be agonist dependent as the potency of the endocannabinoid anandamide (AEA) was voltage independent. The finding of this agonist-specific modulatory factor for the CB1 receptor may contribute to our future understanding of various physiological functions mediated by the endocannabinoid system.
The therapeutic potential of ultra-short-acting β-receptor antagonists in perioperative analgesic: Evidence from preclinical and clinical studies
Authors: Fu Linbin , Yu Buwei , Li Zheng , Liu Zhiheng
Published: October 2022

Perioperative multimodal analgesia can reduce the side effects of a high concentration of opioids, improving the comfort of the patient. However, insufficient analgesia of this model has prompted researchers to explore new adjuvant analgesics. Recently, an increasing number of studies have found a low-grade analgesic effect in the clinical application of ultra-short-acting β-adrenergic receptor antagonists, which are conventionally used as pharmacologic agents in the cardiovascular system. The mechanism by which ultra-short-acting β-antagonists exert antinociceptive effects has not been clarified yet. In this review, we intend to address its potential reasons from the side of neurotransmitters, inflammatory cytokines, and signaling pathways, providing theoretical proof for the application of β-adrenergic receptor antagonists in analgesia.
Incidence, characteristics and risk factors of hypofibrinogenemia associated with tigecycline: A multicenter retrospective study in China
Authors: Leng Bing , Shen Chengwu , Gao Tiantian , Zhao Kai , Zhao Xuemei , Guo Yujin , Wu Jiyong , Yang Jing , Fang Wei , Zhang Jicheng , Zhang Yahui , Sun Chao , Duan Lei , Huang Jing , Qi Yougang , Yan Genquan
Published: October 2022

Background: Tigecycline was recently found to cause coagulation disorders, especially hypofibrinogenemia, which may interfere with the administration of antimicrobial therapy. This study aimed to investigate the incidence and clinical characteristics of and risk factors for tigecycline-associated hypofibrinogenemia.

Methods: In this multicenter retrospective study, patients receiving tigecycline or imipenem–cilastatin to treat Gram-negative bacterial infections in nine Chinese tertiary hospitals between January 2020 and December 2020 were enrolled. Baseline data and coagulation variables were compared using cohort and case–control studies.

Results: Totals of 485 patients treated with tigecycline and 490 patients treated with imipenem–cilastatin were included in this study. Compared with imipenem–cilastatin, tigecycline was associated with reduced fibrinogen and prolonged activated partial thromboplastin time and prothrombin time (all p < 0.001), with the most remarkable change in fibrinogen (down by 48.0%). The incidence of hypofibrinogenemia in patients treated with tigecycline was >50%, with propensity score-matched analysis or not. The relative risk of hypofibrinogenemia with tigecycline versus imipenem–cilastatin was 2.947 (95% CI: 2.151–4.039) at baseline balance. Tigecycline-associated hypofibrinogenemia led to a higher incidence (12.1%) of bleeding events. However, none of supplemental therapies after withdrawal had an effect on the normalization of fibrinogen levels. The risk factors for tigecycline-associated hypofibrinogenemia were treatment duration ≥6 days (odds ratio [OR] 5.214, 95% confidence interval [CI] 2.957–9.191, p < 0.001), baseline fibrinogen <4 g/L (OR 4.625, 95% CI 2.911–7.346, p < 0.001), cumulative dose ≥1,000 mg (OR 2.637, 95% CI 1.439–4.832, p = 0.002), receiving CRRT (OR 2.436, 95% CI 1.179–5.031, p = 0.016), baseline PT > 14 s (OR 2.110, 95% CI 1.317–3.380, p = 0.002) and baseline total bilirubin >21 μmol/L (OR 1.867, 95% CI 1.107–3.147, p = 0.019), while the protective factor was skin and soft tissue infection (OR 0.110, 95% CI 0.026–0.473, p = 0.003).

Conclusion: The clinical characteristics of and risk factors for tigecycline-associated hypofibrinogenemia identified in this study can offer practical reference for the clinical management of patients.