bluuebunny/crossref_metadata_2025 huggingface dataset:
The clinical value of indirect immunofluorescence for screening anti-rods and rings antibodies: A retrospective study of two centers in China
Authors: Meng Jingjing , Yang Guoxiang , Li Siting , Luo Yueming , Bai Yina , Deng Chuiwen , Song Ning , Li Mengtao , Zeng Xiaofeng , Hu Chaojun
Published: September 2022

Objective

To investigate the distribution and clinical significance of the rods and rings (RR) pattern in various diseases.

Methods

A total of 169,891 patients in Peking Union Medical College Hospital (PUMCH) and 29,458 patients in Inner Mongolia People’s Hospital (IMPH) from January 2018 to December 2020 were included, and the results of ANA (antinuclear antibodies) and special antibodies were analyzed retrospectively.

Results

The positive rates of ANA and RR patterns were 34.84%, 0.16% in PUMCH, and 44.73%, 0.23% in IMPH. Anti-RR antibodies mainly appear in adults (≥ 41 years), mostly of low or medium fluorescence titers. Isolated RR patterns were mostly presented (60.30% and 69.12%, respectively), and the RR pattern mixed with the speckled pattern was most commonly observed among patients having two or more patterns. The RR pattern existed in a variety of diseases including hepatitis C, AIDs, pulmonary diseases, nephropathy diseases, and even healthy people. The highest prevalence of the RR pattern was observed in hepatic diseases, such as hepatic dysfunction (0.79%), hepatic cirrhosis (1.05%), PBC (0.85%), and AIH (0.65%), etc. The positive rate of specific antibodies in RR pattern cases was 31.25%, and anti-Ro52 (27, 20.61%) was the most common target antibody.

Conclusion

The RR pattern had a low prevalence in ANAs test samples and varied in different nationalities and regions. Except for hepatitis C, it could be observed in AIDs, pulmonary diseases, nephropathy, other hepatic diseases, and even healthy people, but the positive rate was slightly higher in hepatic diseases. Its mechanism of action and clinical relevance still need clarification.
SMRT and NCoR1 fine-tune inflammatory versus tolerogenic balance in dendritic cells by differentially regulating STAT3 signaling
Authors: Jha Atimukta , Ahad Abdul , Mishra Gyan Prakash , Sen Kaushik , Smita Shuchi , Minz Aliva Prity , Biswas Viplov Kumar , Tripathy Archana , Senapati Shantibhushan , Gupta Bhawna , Acha-Orbea Hans , Raghav Sunil Kumar
Published: September 2022

Dendritic cell (DC) fine-tunes inflammatory versus tolerogenic responses to protect from immune-pathology. However, the role of co-regulators in maintaining this balance is unexplored. NCoR1-mediated repression of DC immune-tolerance has been recently reported. Here we found that depletion of NCoR1 paralog SMRT (NCoR2) enhanced cDC1 activation and expression of IL-6, IL-12 and IL-23 while concomitantly decreasing IL-10 expression/secretion. Consequently, co-cultured CD4+ and CD8+ T-cells depicted enhanced Th1/Th17 frequency and cytotoxicity, respectively. Comparative genomic and transcriptomic analysis demonstrated differential regulation of IL-10 by SMRT and NCoR1. SMRT depletion represses mTOR-STAT3-IL10 signaling in cDC1 by down-regulating NR4A1. Besides, Nfkbia and Socs3 were down-regulated in Ncor2 (Smrt) depleted cDC1, supporting increased production of inflammatory cytokines. Moreover, studies in mice showed, adoptive transfer of SMRT depleted cDC1 in OVA-DTH induced footpad inflammation led to increased Th1/Th17 and reduced tumor burden after B16 melanoma injection by enhancing oncolytic CD8+ T-cell frequency, respectively. We also depicted decreased Ncor2 expression in Rheumatoid Arthritis, a Th1/Th17 disease.
NKp46+ natural killer cells develop an activated/memory-like phenotype and contribute to innate immunity against experimental filarial infection
Authors: Pionnier Nicolas , Furlong-Silva Julio , Colombo Stefano A. P. , Marriott Amy E. , Chunda Valerine C. , Ndzeshang Bertrand L. , Sjoberg Hanna , Archer John , Steven Andrew , Wanji Samuel , Taylor Mark J. , Turner Joseph D.
Published: September 2022

Lymphatic filariasis and onchocerciasis are major neglected tropical diseases affecting over 90 million people worldwide with painful and profoundly disfiguring pathologies (such as lymphoedema or blindness). Type 2 inflammation is a hallmark of filarial nematode tissue infection and is implicated both in eosinophil dependent immunity and lymphatic or ocular immunopathologies. Type-2 innate lymphoid cells (ILC2) are known to play an important role in the initiation of type 2 inflammation in helminth infection. We therefore tracked comparative IL-12Rβ2+ILC1, ST2+ILC2 and NKp46+natural killer (NK) innate lymphoid cell population expansions duringBrugia malayiexperimental peritoneal filarial infections using either immunocompetent or immunodeficient mice. In immunocompetent BALB/c animals, NKp46+NK cells rapidly expanded representing over 90% of the ILC population in the first week of infection, whereas, surprisingly, ST2+ILC2 failed to expand. NKp46+NK cell expansions were confirmed in RAG2 deficient mice lacking adaptive immunity. Ablation of the NKp46+NK cell compartment in RAG2 common gamma chain (gc) mice led to increased susceptibility to chronic adultB. malayiinfection. This data was recapitulated using anOnchocerca ochengimale worm peritoneal implant model. When NKp46+NK cells were depleted in RAG2 deficient mice using anti-NKp46 or asialo GM1 antibody injections over the first five weeks ofB. malayiinfection, susceptibility to adultB. malayiinfection was significantly increased by 2-3 fold with concomitant impairment in eosinophil or neutrophil recruitments. Finally, we demonstrate that in RAG2 deficient mice, drug clearance of a primary adultB. malayiinfection followed by challenge infection leads to resistance against early larvalB. malayiestablishment. This innate resistance is associated with bolstered NK and eosinophils whereby NKp46+NK cells express markers of memory-like/enhanced activation (increased expression of interferon gamma and Ly6C). Our data promotes a novel functional role for NKp46+NK cells in immunoprotection against experimental primary and secondary filarial infection which can proceed in the absence of adaptive immune regulation.
Using personalized prognosis in the treatment of relapsing multiple sclerosis: A practical guide
Authors: Van Wijmeersch Bart , Hartung Hans-Peter , Vermersch Patrick , Pugliatti Maura , Pozzilli Carlo , Grigoriadis Nikolaos , Alkhawajah Mona , Airas Laura , Linker Ralf , Oreja-Guevara Celia
Published: September 2022

The clinical course of multiple sclerosis (MS) is highly variable among patients, thus creating important challenges for the neurologist to appropriately treat and monitor patient progress. Despite some patients having apparently similar symptom severity at MS disease onset, their prognoses may differ greatly. To this end, we believe that a proactive disposition on the part of the neurologist to identify prognostic “red flags” early in the disease course can lead to much better long-term outcomes for the patient in terms of reduced disability and improved quality of life. Here, we present a prognosis tool in the form of a checklist of clinical, imaging and biomarker parameters which, based on consensus in the literature and on our own clinical experiences, we have established to be associated with poorer or improved clinical outcomes. The neurologist is encouraged to use this tool to identify the presence or absence of specific variables in individual patients at disease onset and thereby implement sufficiently effective treatment strategies that appropriately address the likely prognosis for each patient.
Cannabinoid receptor-2 attenuates neuroinflammation by promoting autophagy-mediated degradation of the NLRP3 inflammasome post spinal cord injury
Authors: Jiang Fan , Xia Mingjie , Zhang Yanan , Chang Jie , Cao Jiang , Zhang Zhongkai , Qian Zhanyang , Yang Lei
Published: September 2022

Background

Neuroinflammation following spinal cord injury (SCI) results in prolonged neurological damage and locomotor dysfunction. Polarization of microglia is vital to regulation of neuroinflammation, although the underlying mechanisms have not yet been elucidated. Endocannabinoid receptor subtype 2 (CB2R) is reported to ameliorate neurodegeneration via immunomodulation activities. However, the underlying machinery in the context of SCI remains unclear.

Methods

A lipopolysaccharide-induced microglia inflammation model and a mouse model of SCI were employed to investigate the regulatory role of CB2R in the polarization of microglia in response to excess neuroinflammation. Markers of inflammation and autophagy were measured by Western blot analysis, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent assays. Histological staining with hematoxylin and eosin, Nissl, and Luxol® fast blue was conducted using commercial kits. The locomotor function of the hindlimbs of the experimental mice was evaluated with the Basso Mouse Scale, Louisville Swim Scale, and footprint assay.

Results

The results showed that CB2R promoted M2 differentiation, increased interleukin (IL)-10 expression, and inhibited M1 differentiation with decreased expression of IL-1β and IL-6. CB2R activation also increased ubiquitination of the NLRP3 inflammasome and interacted with the autophagy-related proteins p62 and microtubule-associated proteins 1B light chain 3. Treatment with the CB2R activator JWH-133 reduced loss of myelin, apoptosis of neurons, and glial scarring, leading to improved functional recovery of the hindlimbs, while the CB2R antagonist AM630 produced opposite results.

Conclusion

Taken together, these results suggested that CB2R activation attenuated neuroinflammation targeting microglial polarization by promoting NLRP3 clearance, thereby facilitating functional recovery post-SCI.
Maternal and neonatal immune response to SARS-CoV-2, IgG transplacental transfer and cytokine profile
Authors: Rubio Rocío , Aguilar Ruth , Bustamante Mariona , Muñoz Erica , Vázquez-Santiago Miquel , Santano Rebeca , Vidal Marta , Melero Natalia Rodrigo , Parras Daniel , Serra Pau , Santamaria Pere , Carolis Carlo , Izquierdo Luis , Gómez-Roig Maria Dolores , Dobaño Carlota , Moncunill Gemma , Mazarico Edurne
Published: September 2022

SARS-CoV-2 infected pregnant women are at increased risk of severe COVID-19 than non-pregnant women and have a higher risk of adverse pregnancy outcomes like intrauterine/fetal distress and preterm birth. However, little is known about the impact of SARS-CoV-2 infection on maternal and neonatal immunological profiles. In this study, we investigated the inflammatory and humoral responses to SARS-CoV-2 in maternal and cord blood paired samples. Thirty-six pregnant women were recruited at delivery at Hospital Sant Joan de Déu, Barcelona, Spain, between April-August 2020, before having COVID-19 available vaccines. Maternal and pregnancy variables, as well as perinatal outcomes, were recorded in questionnaires. Nasopharyngeal swabs and maternal and cord blood samples were collected for SARS-CoV-2 detection by rRT-PCR and serology, respectively. We measured IgM, IgG and IgA levels to 6 SARS-CoV-2 antigens (spike [S], S1, S2, receptor-binding domain [RBD], nucleocapsid [N] full-length and C-terminus), IgG to N from 4 human coronaviruses (OC43, HKU1, 229E and NL63), and the concentrations of 30 cytokines, chemokines and growth factors by Luminex. Mothers were classified as infected or non-infected based on the rRT-PCR and serology results. Sixty-four % of pregnant women were infected with SARS-CoV-2 (positive by rRT-PCR during the third trimester and/or serology just after delivery). None of the newborns tested positive for rRT-PCR. SARS-CoV-2 infected mothers had increased levels of virus-specific antibodies and several cytokines. Those with symptoms had higher cytokine levels. IFN-α was increased in cord blood from infected mothers, and in cord blood of symptomatic mothers, EGF, FGF, IL-17 and IL-15 were increased, whereas RANTES was decreased. Maternal IgG and cytokine levels showed positive correlations with their counterparts in cord blood. rRT-PCR positive mothers showed lower transfer of SARS-CoV-2-specific IgGs, with a stronger effect when infection was closer to delivery. SARS-CoV-2 infected mothers carrying a male fetus had higher antibody levels and higher EGF, IL-15 and IL-7 concentrations. Our results show that SARS-CoV-2 infection during the third trimester of pregnancy induces a robust antibody and cytokine response at delivery and causes a significant reduction of the SARS-CoV-2-specific IgGs transplacental transfer, with a stronger negative effect when the infection is closer to delivery.
The ileal fungal microbiota is altered in Crohn's disease and is associated with the disease course
Authors: Olaisen Maya , Richard Mathias L. , Beisvåg Vidar , Granlund Atle van Beelen , Røyset Elin S. , Rué Olivier , Martinsen Tom Christian , Sandvik Arne Kristian , Sokol Harry , Fossmark Reidar
Published: September 2022

Introduction

Fungal microbiota's involvement in the pathogenesis of Crohn's disease (CD) is incompletely understood. The terminal ileum is a predilection site both for primary involvement and recurrences of CD. We, therefore, assessed the mucosa-associated mycobiota in the inflamed and non-inflamed ileum in patients with CD.

Methods

The mucosa-associated mycobiota was assessed by ITS2 sequencing in a total of 168 biopsies sampled 5 and 15 cm proximal of the ileocecal valve or ileocolic anastomosis in 44 CD patients and 40 healthy controls (HC). CD patients with terminal ileitis, with endoscopic inflammation at 5 cm and normal mucosa at 15 cm and no history of upper CD involvement, were analyzed separately. The need for additional CD treatment the year following biopsy collection was recorded.

Results

CD patients had reduced mycobiota evenness, increased Basidiomycota/Ascomycota ratio, and reduced abundance of Chytridiomycota compared to HC. The mycobiota of CD patients were characterized by an expansion of Malassezia and a depletion of Saccharomyces, along with increased abundances of Candida albicans and Malassezia restricta. Malassezia was associated with the need for treatment escalation during follow-up. Current anti-TNF treatment was associated with lower abundances of Basidiomycota. The alpha diversity of the inflamed and proximal non-inflamed mucosa within the same patients was similar. However, the inflamed mucosa had a more dysbiotic composition with increased abundances of Candida sake and reduced abundances of Exophiala equina and Debaryomyces hansenii.

Conclusions

The ileal mucosa-associated mycobiota in CD patients is altered compared to HC. The mycobiota in the inflamed and proximal non-inflamed ileum within the same patients harbor structural differences which may play a role in the CD pathogenesis. Increased abundance of Malassezia was associated with an unfavorable disease course.
Approaches for the establishment of optimized co-culture system of multiple Trichoderma strains for culture metabolites highly effective in cucumber growth promotion
Authors: Liu Hongyi , Hao Dazhi , Li Yaqian , Wang Xinhua , Chen Jie
Published: September 2022

In most cases, co-culture of Trichoderma and other microorganism principally takes advantage of biological control of plant diseases, which is superior to axenic culture. However, the approach to establish the optimal co-culture system of multiple Trichoderma strains was less studied, particularly for high production of microbial metabolites synergistically to promote plant growth and antagonistic activity against pathogens. The inoculation technique, fermentation kinetic modeling and response surface methodology were used to obtain the optimal inoculum sequence, fermentation time and co-culture nutrient formula. It was demonstrated that co-culture metabolites of Trichoderma strains obtained by simultaneous inoculation were more effective than those by sequence inoculation in promoting cucumber seedling growth. Furthermore, the optimal fermentation time was determined at 96–120 h by evaluating fermentation kinetic model, the activities of inhibitory potential of pathogenic Fusarium and cucumber seedling hypocotyl growth. Interestingly, the optimized nutrient formula was set to make co-culture metabolites of Trichoderma strains more effective in the plant growth promotion, which was determined through the assessment of cucumber test-tube plantlet. The components and each concentration in the optimized medium were confirmed at corn flour 16.22 g⋅L–1, potassium hydrogen phosphate 1.13 g⋅L–1, tryptophan 0.154 g⋅L–1, seaweed residue 30 g⋅L–1, ferrous sulfate heptahydrate 1 g⋅L–1 and ammonium sulfate 1.5 g⋅L–1. The hypocotyl length increased in the treatment with co-culture metabolites from the optimal medium by 2.3-fold compared with control. Thus, the results provide an optimal co-culture system of Trichoderma multiple strains aiming to produce high activity of metabolites in plant growth promotion.
Characterization and fungicide sensitivity of Colletotrichum godetiae causing sweet cherry fruit anthracnose in Guizhou, China
Authors: Peng Keqin , Pan Yintao , Tan Tingjun , Zeng Xiangyu , Lin Meiling , Jiang Shuang , Zhao Zhibo , Tian Fenghua , Zhao Xiaosheng
Published: September 2022

Sweet cherry is an important fruit crop with high economic and ornamental value in China. However, cherry fruit anthracnose, caused by Colletotrichum species, greatly impacts cherry yield and quality. Here, we surveyed cherry anthracnose in Guizhou, China from 2019–2020. Necrotic sweet cherry fruits were collected from different areas in Guizhou and examined. A total of 116 Colletotrichum strains were isolated from these symptomatic fruits. Based on the morphological characteristics of the isolates and phylogenetic analyses of concatenate internal transcribed spacer (ITS) region and ACT, CHS-1, GAPDH, TUB2, and HIS3 genes, the pathogen responsible for causing sweet cherry anthracnose was identified as Colletotrichum godetiae. Pathogenicity tests were conducted by inoculating healthy sweet cherry fruits with spore suspensions of the fungal pathogen, and Koch’s postulates were confirmed by pathogen re-isolation and identification. The Q-1 isolate showed different sensitivities to 13 fungicides, exhibiting seven different modes of action, and its EC50 values ranged from 0.04 to 91.26 μg ml−1. According to that, the sensitivity of 20 isolates from different samples to ten fungicides with better performance, were measured. The results showed that 6 of the 10 fungicides (difenoconazole, propiconazole, prochloraz-manganese, pyraclostrobin, trifloxystrobin-tebuconazole, and difenoconazole-azoxystrobin) all showed higher sensitive to the 20\u00B0C. godetiae isolates, and no resistance groups appeared. Its EC50 values ranged from 0.013 to 1.563 μg ml−1. In summary, this is the first report demonstrating that C. godetiae causes sweet cherry anthracnose and the results of this study provide insights into how sweet cherry anthracnose could be effectively controlled in China.
rAAV expressing recombinant neutralizing antibody for the botulinum neurotoxin type A prophylaxis
Authors: Derkaev Artem A. , Ryabova Ekaterina I. , Esmagambetov Ilias B. , Shcheblyakov Dmitry V. , Godakova Svetlana A. , Vinogradova Irina D. , Noskov Anatoly N. , Logunov Denis Y. , Naroditsky Boris S. , Gintsburg Alexander L.
Published: September 2022

Botulinum neurotoxin (BoNT) is one of the most dangerous bacterial toxins and a potential biological weapon component. BoNT mechanism of pathological action is based on inhibiting the release of neurotransmitters from nerve endings. To date, anti-BoNT therapy is reduced to the use of horse hyperimmune serum, which causes many side effects, as well as FDA-approved drug BabyBig which consists of human-derived anti-BoNT antibodies (IgG) for infant botulinum treatment. Therapeutics for botulism treatment based on safer monoclonal antibodies are undergoing clinical trials. In addition, agents have been developed for the specific prevention of botulism, but their effectiveness has not been proved. In this work, we have obtained a recombinant adeno-associated virus (rAAV-B11-Fc) expressing a single-domain antibody fused to the human IgG Fc-fragment (B11-Fc) and specific to botulinum toxin type A (BoNT/A). We have demonstrated that B11-Fc antibody, expressed via rAAV-B11-Fc treatment, can protect animals from lethal doses of botulinum toxin type A, starting from day 3 and at least 120 days after administration. Thus, our results showed that rAAV-B11-Fc can provide long-term expression of B11-Fc-neutralizing antibody in vivo and provide long-term protection against BoNT/A intoxication. Consequently, our study demonstrates the applicability of rAAV expressing protective antibodies for the prevention of intoxication caused by botulinum toxins.
Multi-omics analysis reveals the host–microbe interactions in aged rhesus macaques
Authors: Xu Jue , Lan Yue , Wang Xinqi , Shang Ke , Liu Xu , Wang Jiao , Li Jing , Yue Bisong , Shao Meiying , Fan Zhenxin
Published: September 2022

Aging is a complex multifactorial process that greatly affects animal health. Multi-omics analysis is widely applied in evolutionary biology and biomedical research. However, whether multi-omics can provide sufficient information to reveal comprehensive changes in aged non-human primates remains unclear. Here, we explored changes in host–microbe interactions with aging in Chinese rhesus macaques (Macaca mulatta lasiota, CRs) using multi-omics analysis. Results showed marked changes in the oral and gut microbiomes between young and aged CRs, including significantly reduced probiotic abundance and increased pathogenic bacterial abundance in aged CRs. Notably, the abundance of Lactobacillus, which can metabolize tryptophan to produce aryl hydrocarbon receptor (AhR) ligands, was decreased in aged CRs. Consistently, metabolomics detected a decrease in the plasma levels of AhR ligands. In addition, free fatty acid, acyl carnitine, heparin, 2-(4-hydroxyphenyl) propionic acid, and docosahexaenoic acid ethyl ester levels were increased in aged CRs, which may contribute to abnormal fatty acid metabolism and cardiovascular disease. Transcriptome analysis identified changes in the expression of genes associated with tryptophan metabolism and inflammation. In conclusion, many potential links among different omics were found, suggesting that aged CRs face multiple metabolic problems, immunological disorders, and oral and gut diseases. We determined that tryptophan metabolism is critical for the physiological health of aged CRs. Our findings demonstrate the value of multi-omics analyses in revealing host–microbe interactions in non-human primates and suggest that similar approaches could be applied in evolutionary and ecological research of other species.
Natural antisense transcripts as drug targets
Authors: Khorkova Olga , Stahl Jack , Joji Aswathy , Volmar Claude-Henry , Zeier Zane , Wahlestedt Claes
Published: September 2022

The recent discovery of vast non-coding RNA-based regulatory networks that can be easily modulated by nucleic acid-based drugs has opened numerous new therapeutic possibilities. Long non-coding RNA, and natural antisense transcripts (NATs) in particular, play a significant role in networks that involve a wide variety of disease-relevant biological mechanisms such as transcription, splicing, translation, mRNA degradation and others. Currently, significant efforts are dedicated to harnessing these newly emerging NAT-mediated biological mechanisms for therapeutic purposes. This review will highlight the recent clinical and pre-clinical developments in this field and survey the advances in nucleic acid-based drug technologies that make these developments possible.
Evaluation of multiple consensus criteria for autoimmune encephalitis and temporal analysis of symptoms in a pediatric encephalitis cohort
Authors: Pointon Tiffany , Ward Ryan , Yeshokumar Anusha , Piquet Amanda , Schreiner Teri , Kammeyer Ryan
Published: September 2022

Objective

To evaluate the sensitivity and specificity of current criteria for the diagnosis of autoimmune encephalitis (AE) and the temporal onset of neuropsychiatric symptoms (NP) in a pediatric encephalitis cohort.

Background

Multiple criteria for AE have been developed, including the Graus and pediatric-focused Cellucci consensus criteria, and the Determining Etiology in Encephalitis (DEE) score for patients with encephalitis. Early identification and treatment of AE is crucial to improve outcomes, but this can be difficult given the frequent overlap of clinical presentation between AE and infectious encephalitis (IE).

Design/methods

A retrospective review was conducted of patients seen at our institution from 2000 to 2021 with a final diagnosis of AE or IE. These were narrowed through multiple exclusions to etiology-confirmed IE or antibody-positive/negative AE. Time of onset or results of all symptoms and diagnostics were recorded. Sensitivity and specificity of each criterion under various clinical scenarios were calculated over the first month after initial NP symptom onset.

Results

A total of 23 antibody-positive AE, 9 antibody-negative AE and 23 IE patients were included in final analysis. Under an idealized scenario with rapid initial diagnostic evaluations, the sensitivity for pediatric AE by day 28 after onset of NP symptoms approached 90% for both Cellucci and Graus criteria. Specificity within these 28 days was low without infectious testing results, increasing the greatest with rapid PCR testing and second with infectious antibody testing—reaching ~90% with both. A DEE score of 3 provided a specificity of 100% in identifying IE, but low sensitivity (29%). Symptoms were noted to cluster within several days of onset in IE, but in AE were spread out. Personality/behavioral change, speech change, affective disorder, and sleep disturbance were noted more often in AE, while fever, elevated C-reactive protein or CSF protein, and abnormal MRI-Brain occurred more often in IE.

Conclusion

In this study, we provide the first evaluation of the Cellucci criteria and the first validation of the DEE score in the differentiation of pediatric AE and IE. Further refinement of AE criteria is needed to improve early detection and treatment of pediatric AE.
Identification of hub genes and pathophysiological mechanism related to acute unilateral vestibulopathy by integrated bioinformatics analysis
Authors: Cheng Yajing , Zheng Jianrong , Zhan Ying , Liu Cong , Lu Bihua , Hu Jun
Published: September 2022

Background

Although many pathological mechanisms and etiological hypotheses of acute unilateral vestibulopathy (AUVP) have been reported, but the actual etiology remains to be elucidated.

Objective

This study was based on comprehensive bioinformatics to identify the critical genes of AUVP and explore its pathological mechanism.

Methods

Gene expression profiles of AUVP and normal samples were collected from GSE146230 datasets of the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was constructed, and the WGCNA R-package extracted significant modules. The limma R-package was applied to identify differentially expressed genes (DEGs). The common genes of practical modules and DEGs were screened for GO and KEGG pathways analysis. The protein–protein interaction (PPI) layout and hub genes validation was created by Cytoscape software using the link from the STRING database. The functions of hub genes were predicted through the CTD (comparative genetics database).

Results

A total of 332 common genes were screened from practical modules and DEGs. Functional enrichment analysis revealed that these genes were predominantly associated with inflammation and infection. After construction of PPI, expressions of hub genes, and drawing ROC curves, LILRB2, FPR1, AQP9, and LILRA1 are highly expressed in AUVP (p < 0.05) and have a certain diagnostic efficacy for AUVP (AUC > 0.7), so they were selected as hub genes. The functions of hub genes suggested that the occurrence of AUVP may be related to inflammation, necrosis, hepatomegaly, and other conditions in CTD.

Conclusion

LILRB2, FPR1, AQP9, and LILRA1 may play essential roles in developing AUVP, providing new ideas for diagnosing and treating AUVP.
The effect of high-fructose corn syrup vs. sucrose on anthropometric and metabolic parameters: A systematic review and meta-analysis
Authors: Li Xiang , Luan Yunqi , Li Yuejin , Ye Shili , Wang Guihui , Cai Xinlun , Liang Yucai , Kord Varkaneh Hamed , Luan Yunpeng
Published: September 2022

High-fructose corn syrup (HFCS) has been speculated to have stronger negative metabolic effects than sucrose. However, given the current equivocality in the field, the aim of the present study was to determine the impact of HFCS use compared to sucrose on anthropometric and metabolic parameters. We searched PubMed, Scopus, Cochrane Central and web of sciences, from database inception to May 2022. A random effects model and the generic inverse variance method were applied to assess the overall effect size. Heterogeneity analysis was performed using the Cochran Q test and the I2 index. Four articles, with 9 arms, containing 767 participants were included in this meta-analysis. Average HFCS and sucrose usage equated to 19% of daily caloric intake. Combined data from three studies indicated that HFCS intake does not significantly change the weight (weighted mean difference (WMD): −0.29 kg, 95% CI: −1.34, 0.77, I2 = 0%) when compared to the sucrose group. Concordant results were found for waist circumstance, body mass index, fat mass, total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Moreover, overall results from three studies indicated a significant increase in CRP levels (WMD: 0.27 mg/l, 95% CI: 0.02, 0.52, I2 = 23%) in the HFCS group compared to sucrose. In conclusion, analysis of data from the literature suggests that HFCS consumption was associated with a higher level of CRP compared to sucrose, whilst no significant changes between the two sweeteners were evident in other anthropometric and metabolic parameters.
Evaluation of the clinical practice guidelines and consensuses on calcium and vitamin D supplementation in healthy children using the Appraisal of Guidelines for Research and Evaluation II instrument and Reporting Items for Practice Guidelines in Healthcare statement
Authors: He Lanzhi , Zhou Pengxiang , Zhou Xin , Tian Shuxia , Han Jing , Zhai Suodi
Published: September 2022

Background

This study aimed to assess the methodological and reporting quality of the guidelines and consensus on calcium and vitamin D supplementation in healthy children, and the consistency of these recommendations.

Methods

A systematic search of relevant guideline websites and databases, including PubMed, Embase, CNKI, WangFang, and SinoMed, was undertaken from inception to April 7, 2021, by two independent reviewers who assessed the eligible guidelines using the validated Appraisal of Guidelines for Research and Evaluation Instrument II (AGREE II) and the Reporting Items for Practice Guidelines in Healthcare (RIGHT) tools. Overall, the between-reviewer agreement was evaluated using an intra-class correlation coefficient.

Results

A total of 24 guidelines and consensuses from 2002 to 2022 were identified from China, the United States, Canada, France, Australia, New Zealand, Europe, and other countries and regions. These were of mixed quality, and scored poorly in the rigor of development, editorial independence, and applicability of the domains of AGREE II. Among the seven domains of the RIGHT checklist, domain one (basic information) had the highest reporting rate (69.3%), whereas domain five (review and quality assurance) had the lowest reporting rate (11.5%). The overall quality of the included guidelines and consensuses was low. Only 12 guidelines were recommended, with modifications. The recommended calcium intake for children of different ages varies greatly (400–1,150 mg/day). Among the included guidelines and consensuses, a vitamin D (VD) prevention dose of 400 IU/day in infants was generally considered safe, and 25-hydroxyvitamin-D [25(OH)D] levels of <20 ng/mL (50 nmol/L) or 20–30 ng/mL (50–75 nmol/L) indicated VD deficiency or insufficiency. However, the recommended amount of VD for children of different age groups and risk strata differed considerably (400–4,000 IU/day or 10–100 μg/day). The choice of VD2 or VD3 supplements and sunlight exposure also differed across the guidelines and consensuses.

Conclusion

There is considerable variability in calcium and VD guidelines and consensus development methods in calcium and VD supplementation for healthy children. Therefore, efforts are necessary to strengthen the methodological rigor of guideline development and utilize the best available evidence to underpin recommendations.
Clinicopathological characteristics and outcome of primary sarcomatoid carcinoma of the gallbladder
Authors: Zou Rui-Qi , Hu Hai-Jie , Lv Tian-Run , Liu Fei , Ma Wen-Jie , Wang Jun-Ke , Dai Yu-Shi , Yang Si-Qi , Hu Ya-Fei , Li Fu-Yu
Published: September 2022

Purpose

Our study aims to examine the clinicopathological features, disease progression, management, and outcomes of gallbladder sarcomatoid carcinoma (GBSC) patients.

Methods

Between January 2000 and December 2020, 50 gallbladder cancer (GBC) patients who received surgical treatment and were pathologically verified as GBSC at our institution were enrolled. The clinical and pathological features and survival of these patients were retrospectively reviewed.

Results

The median overall survival (OS) of GBSC patients was 14.5 months, and the 1-, 2- and 3-year OS rates were 68.0%, 32.0%, and 10.0%, respectively. The median progression-free survival (PFS) was 10.0 months, and the 1-, 2-, and 3-year PFS rates were 42.0%, 16.0%, and 2.0%, respectively. Patients who received radical resection had obviously better OS (18.0 vs. 7.0 months, P<0.001) and PFS (12.0 vs. 5.0 months, P<0.001) than those who underwent palliative resection. Multivariate analysis revealed that vascular invasion (P=0.033), curative operation (P<0.001) and postoperative chemotherapy (P=0.033) were independent risk factors for PFS. We further identified postoperative chemotherapy (P=0.010) and curative operation (P<0.001) as independent prognostic factors affecting the OS of GBSC patients. After curative surgery, patients who underwent S-1-based chemotherapy showed significantly longer recurrence-free survival (RFS) than those who underwent other chemotherapy regimens (20.0 vs 11.0 months, P=0.028).

Conclusion

GBSC patients always have aggressive biological behaviors and remarkably poor prognoses. Most GBSC patients are diagnosed in advanced stages, and timely radical operation together with postoperative chemotherapy is important. S-1-based chemotherapy may be a selectively efficient regimen to prolong the survival of GBSC patients.
Vasoactive intestinal peptide–VIPR2 signaling regulates tumor cell migration
Authors: Asano Satoshi , Yamasaka Misa , Ozasa Kairi , Sakamoto Kotaro , Hayata-Takano Atsuko , Nakazawa Takanobu , Hashimoto Hitoshi , Waschek James A. , Ago Yukio
Published: September 2022

Phosphoinositide metabolism is critically involved in human cancer cell migration and metastatic growth. The formation of lamellipodia at the leading edge of migrating cells is regulated by metabolism of the inositol phospholipid PI(4,5)P2 into PI(3,4,5)P3. The synthesized PI(3,4,5)P3 promotes the translocation of WASP family verprolin homologous protein 2 (WAVE2) to the plasma membrane and regulates guanine nucleotide exchange factor Rac-mediated actin filament remodeling. Here, we investigated if VIPR2, a receptor for vasoactive intestinal peptide (VIP), has a potential role in regulating cell migration via this pathway. We found that silencing of VIPR2 in MDA-MB-231 and MCF-7 human breast cancer cells inhibited VIP-induced cell migration. In contrast, stable expression of exogenous VIPR2 promoted VIP-induced tumor cell migration, an effect that was inhibited by the addition of a PI3-kinase (PI3K)γ inhibitor or a VIPR2-selective antagonist. VIPR2 stably-expressing cells exhibited increased PI3K activity. Membrane localization of PI(3,4,5)P3 was significantly attenuated by VIPR2-silencing. VIPR2-silencing in MDA-MB-231 cells suppressed lamellipodium extension; in VIPR2-overexpressing cells, VIPR2 accumulated in the cell membrane on lamellipodia and co-localized with WAVE2. Conversely, VIPR2-silencing reduced WAVE2 level on the cell membrane and inhibited the interaction between WAVE2, actin-related protein 3, and actin. These findings suggest that VIP–VIPR2 signaling controls cancer migration by regulating WAVE2-mediated actin nucleation and elongation for lamellipodium formation through the synthesis of PI(3,4,5)P3.
AMBRA1 and its role as a target for anticancer therapy
Authors: Li Xiang , Lyu Yuan , Li Junqi , Wang Xinjun
Published: September 2022

The activating molecule in Beclin1-regulated autophagy protein 1 (AMBRA1) is an intrinsically disordered protein that regulates the survival and death of cancer cells by modulating autophagy. Although the roles of autophagy in cancer are controversial and context-dependent, inhibition of autophagy under some circumstances can be a useful strategy for cancer therapy. As AMBRA1 is a pivotal autophagy-associated protein, targeting AMBRA1 similarly may be an underlying strategy for cancer therapy. Emerging evidence indicates that AMBRA1 can also inhibit cancer formation, maintenance, and progression by regulating c-MYC and cyclins, which are frequently deregulated in human cancer cells. Therefore, AMBRA1 is at the crossroad of autophagy, tumorigenesis, proliferation, and cell cycle. In this review, we focus on discussing the mechanisms of AMBRA1 in autophagy, mitophagy, and apoptosis, and particularly the roles of AMBRA1 in tumorigenesis and targeted therapy.
Hepcidin is upregulated and is a potential therapeutic target associated with immunity in glioma
Authors: Dong Tianyu , Zhang Bo , Zhang Runjiao , Wang Chang , Liu Xiaopeng , Wang Fei , Hao Nana , Tan Ke , Chang Yan-Zhong
Published: September 2022

Background

Glioma is the most common primary malignant brain tumor with high mortality and poor prognosis. Hepcidin is a fascinating iron metabolism regulator. However, the prognostic value of hepcidin HAMP in gliomas and its correlation with immune cell infiltration remain unclear. Here, we comprehensively elucidate the prognostic value and potential role of hepcidin in gliomas.

Methods

Hepcidin gene expression and clinical characteristics in glioma were analyzed using the CGGA, TCGA, Rembrandt and Gravendeel glioma databases. A survival analysis was conducted using Kaplan–Meier and Cox regression analyses. A gene set enrichment analysis (GSEA) was conducted to select the pathways significantly enriched for hepcidin associations. The correlations between hepcidin and immune cell infiltration and immunotherapy were analyzed using network platforms such as CIBERSORT and TIMER.

Results

In glioma tissues, the expression of hepcidin was significantly increased. High hepcidin expression is related to grade, age, PRS type, IDH mutation, chemotherapy status and 1p19q codeletion status, which significantly indicates the poor prognosis of glioma patients. Hepcidin can be used as an independent prognostic factor for glioma through the multivariate COX regression analysis. The results of Gene Ontology (GO), Kyoto Encyclopedia of Gene and Genome (KEGG) and gene set enrichment analysis (GSEA) indicated that hepcidin was involved in the immune response. In addition, hepcidin expression was positively correlated with the degree of immune cell infiltration, the expression of various immune cell markers and the efficacy of immunotherapy.

Conclusion

Our results indicate that hepcidin can be used as a candidate biomarker to judge the prognosis and immune cell invasion of gliomas.
Clinical implications of the tumor microenvironment using multiplexed immunohistochemistry in patients with advanced or metastatic renal cell carcinoma treated with nivolumab plus ipilimumab
Authors: Kim Jwa Hoon , Kim Gi Hwan , Ryu Yeon-Mi , Kim Sang-Yeob , Kim Hyung-Don , Yoon Shin Kyo , Cho Yong Mee , Lee Jae Lyun
Published: September 2022

Purpose

Immune checkpoint inhibitors (ICIs) such as nivolumab and ipilimumab (N/I) are important treatment options for advanced renal cell carcinoma (RCC). The tumor microenvironment (TME) in these ICI-treated patients is largely unknown.

Methods

Twenty-four patients treated with N/I between July 2015 and June 2020 were analyzed. Multiplexed immunohistochemistry (mIHC) was conducted to define the TME, including various T cell subsets, B cells, macrophages, and dendritic cells.

Results

The median age of the study patients was 61 years (range, 39–80) and 75.0% of these cases were men. The objective response rate with N/I was 50.0%. The densities of the CD8+ cytotoxic T cells (P=0.005), specifically CD137+ CD8+ T cells (P=0.017), Foxp3- CD4+ helper T cells (P=0.003), Foxp3+ CD4+ regulatory T cells (P=0.045), CD68+ CD206- M1 macrophages (P=0.008), and CD68+ CD206+ M2 macrophages (P=0.021) were significantly higher in the treatment responders. At a median follow-up duration of 24.7 months, the median progression-free survival (PFS) was 11.6 months. The high densities (≥median) of Foxp3- CD4+ helper T cells (P=0.016) and CD68+ CD206- M1 macrophages (P=0.008) were significantly associated with better PFS, and the density of CD137+ CD8+ cytotoxic T cells (P=0.079) was marginally associated with better PFS. After multivariate analysis, the higher density of Foxp3- CD4+ helper T cells was independently associated with better PFS (hazard ratio 0.19; P=0.016).

Conclusion

The properties and clinical implications of the TME properties in RCC indicate that Foxp3- CD4+ helper T cells, M1 macrophages, and CD137+ CD8+ T cells are potential predictive biomarkers and treatment targets.
Adaptive dose painting for prostate cancer
Authors: Fredén Emil , Tilly David , Ahnesjö Anders
Published: September 2022

Purpose

Dose painting (DP) is a radiation therapy (RT) strategy for patients with heterogeneous tumors delivering higher dose to radiation resistant regions and less to sensitive ones, thus aiming to maximize tumor control with limited side effects. The success of DP treatments is influenced by the spatial accuracy in dose delivery. Adaptive RT (ART) workflows can reduce the overall geometric dose delivery uncertainty. The purpose of this study is to dosimetrically compare ART and non-adaptive conventional RT workflows for delivery of DP prescriptions in the treatment of prostate cancer (PCa).

Materials and methods

We performed a planning and treatment simulation study of four study arms. Adaptive and conventional workflows were tested in combination with DP and Homogeneous dose. We used image data from 5 PCa patients that had been treated on the Elekta Unity MR linac; the patients had been imaged in treatment position before each treatment fraction (7 in total). The local radiation sensitivity from apparent diffusion coefficient maps of 15 high-risk PCa patients was modelled in a previous study. these maps were used as input for optimization of DP plans aiming for maximization of tumor control probability (TCP) under rectum dose constraints. A range of prostate doses were planned for the homogeneous arms. Adaptive plans were replanned based on the anatomy-of-the-day, whereas conventional plans were planned using a pre-treatment image and subsequently recalculated on the anatomy-of-the-day. The dose from 7 fractions was accumulated using dose mapping. The endpoints studied were the TCP and dose-volume histogram metrics for organs at risk.

Results

Accumulated DP doses (adaptive and conventional) resulted in high TCP, between 96-99%. The largest difference between adaptive and conventional DP was 2.6 percentage points (in favor of adaptive DP). An analysis of the dose per fraction revealed substantial target misses for one patient in the conventional workflow that—if systematic—could jeopardize the TCP. Compared to homogeneous prescriptions with equal mean prostate dose, DP resulted in slightly higher TCP.

Conclusion

Compared to homogeneous dose, DP maintains or marginally increases the TCP. Adaptive DP workflows could avoid target misses compared to conventional workflows.
Histone lysine methylation patterns in prostate cancer microenvironment infiltration: Integrated bioinformatic analysis and histological validation
Authors: Quan Yongjun , Zhang Xiaodong , Wang Mingdong , Ping Hao
Published: September 2022

Background

Epigenetic reprogramming through dysregulated histone lysine methylation (HLM) plays a crucial role in prostate cancer (PCa) progression. This study aimed to comprehensively evaluate HLM modification patterns in PCa microenvironment infiltration.

Materials and methods

Ninety-one HLM regulators in The Cancer Genome Atlas (TCGA) dataset were analyzed using bioinformatics. Differentially expressed genes (DEGs) and survival analyses were performed using TCGA-PRAD clinicopathologic and follow-up information. Consensus clustering analysis divided patients into subgroups. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the DEGs. Tumor mutation burden (TMB) and tumor microenvironment (TME) cell infiltration were evaluated in different HLM clusters. Quantitative real-time PCR (qPCR) analysis assessed HLM regulators in clinical PCa tissues.

Results

The tumor vs. normal (TN), Gleason score (GS) > 7 vs. GS < 7, pathological T stage (pT) = 2 vs. pT = 3, and TP53 mutation vs. wild-type comparisons using TCGA-PRAD dataset revealed 3 intersecting HLM regulators (EZH2, NSD2, and KMT5C) that were consistently upregulated in advanced PCa (GS > 7, pT3, HR > 1, and TP53 mutation) (P < 0.05) and verified in clinical PCa tissues. Consensus clustering analysis revealed three distinct HLM modification patterns (HLMclusters). However, no significant differences in recurrence-free survival (RFS) rates were found among the groups (P > 0.05). We screened 189 HLM phenotype-related genes that overlapped in the pairwise comparisons of HLMclusters and P < 0.01 in the Cox regression analysis. Three distinct subgroups (geneClusters) were revealed based on the 189 genes, in which cluster A involved the most advanced PCa (PSA > 10, T3-4, GS8-10, and biochemical recurrence) and the poorest RFS. The HLM score (HLMscore) was calculated by principal component analysis (PCA) of HLM phenotype-related genes that have positive predictive value for RFS (P < 0.001) and immune therapy responses (in the CTLA4-positive and -negative responses accompanied by a PD1-negative response).

Conclusion

We comprehensively evaluated HLM regulators in the PCa microenvironment using TCGA-PRAD, revealing a nonnegligible role of HLM patterns in PCa complexity and heterogeneity. Elucidating the effects of HLM regulators in PCa may enhance prognostics, aggressiveness assessments, and immunotherapy strategies.