bluuebunny/crossref_metadata_2025 huggingface dataset:
Discovering genetic linkage between periodontitis and type 1 diabetes: A bioinformatics study
Authors: Liu Junqi , Zhang Bo , Zhu Guanyin , Liu Chenlu , Wang Shuangcheng , Zhao Zhihe
Published: March 2023

Background: Relationship between periodontitis (PD) and type 1 diabetes (T1D) has been reported, but the detailed pathogenesis requires further elucidation. This study aimed to reveal the genetic linkage between PD and T1D through bioinformatics analysis, thereby providing novel insights into scientific research and clinical treatment of the two diseases.

Methods: PD-related datasets (GSE10334, GSE16134, GSE23586) and T1D-related datasets(GSE162689)were downloaded from NCBI Gene Expression Omnibus (GEO). Following batch correction and merging of PD-related datasets as one cohort, differential expression analysis was performed (adjusted p-value <0.05 and ∣log2  fold change| > 0.5), and common differentially expressed genes (DEGs) between PD and T1D were extracted. Functional enrichment analysis was conducted via Metascape website. The protein-protein interaction (PPI) network of common DEGs was generated in The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. Hub genes were selected by Cytoscape software and validated by receiver operating characteristic (ROC) curve analysis.

Results: 59 common DEGs of PD and T1D were identified. Among these DEGs, 23 genes were commonly upregulated, and 36 genes were commonly downregulated in both PD- and T1D-related cohorts. Functional enrichment analysis indicated that common DEGs were mainly enriched in tube morphogenesis, supramolecular fiber organization, 9 + 0 non-motile cilium, plasma membrane bounded cell projection assembly, glomerulus development, enzyme-linked receptor protein signaling pathway, endochondral bone morphogenesis, positive regulation of kinase activity, cell projection membrane and regulation of lipid metabolic process. After PPI construction and modules selection, 6 hub genes (CD34, EGR1, BBS7, FMOD, IGF2, TXN) were screened out and expected to be critical in linking PD and T1D. ROC analysis showed that the AUC values of hub genes were all greater than 70% in PD-related cohort and greater than 60% in T1D-related datasets.

Conclusion: Shared molecular mechanisms between PD and T1D were revealed in this study, and 6 hub genes were identified as potential targets in treating PD and T1D.
Lipoteichoic acid of Streptococcus gordonii as a negative regulator of human dendritic cell activation
Authors: Kim Sun Kyung , Im Jintaek , Ko Eun Byeol , Lee Dongwook , Seo Ho Seong , Yun Cheol-Heui , Han Seung Hyun
Published: March 2023

Streptococcus gordonii, an opportunistic Gram-positive bacterium, causes an infective endocarditis that could be fatal to human health. Dendritic cells (DCs) are known to be involved in disease progression and immune responses in S. gordonii infection. Since lipoteichoic acid (LTA) is a representative virulence factor of S. gordonii, we here investigated its role in the activation of human DCs stimulated with LTA-deficient (ΔltaS) S. gordonii or S. gordonii LTA. DCs were differentiated from human blood-derived monocytes in the presence of GM-CSF and IL-4 for 6 days. DCs treated with heat-killed ΔltaS S. gordonii (ΔltaS HKSG) showed relatively higher binding and phagocytic activities than those treated with heat-killed wild-type S. gordonii (wild-type HKSG). Furthermore, ΔltaS HKSG was superior to wild-type HKSG in inducing phenotypic maturation markers including CD80, CD83, CD86, PD-L1, and PD-L2, antigen-presenting molecule MHC class II, and proinflammatory cytokines such as TNF-α and IL-6. Concomitantly, DCs treated with the ΔltaS HKSG induced better T cell activities, including proliferation and activation marker (CD25) expression, than those treated with the wild-type. LTA, but not lipoproteins, isolated from S. gordonii weakly activated TLR2 and barely affected the expression of phenotypic maturation markers or cytokines in DCs. Collectively, these results demonstrated that LTA is not a major immuno-stimulating agent of S. gordonii but rather it interferes with bacteria-induced DC maturation, suggesting its potential role in immune evasion.
Clinical implications of gut microbiota and cytokine responses in coronavirus disease prognosis
Authors: Seong Hye , Kim Jun Hyoung , Han Young-Hee , Seo Ho Seong , Hyun Hak Jun , Yoon Jin Gu , Nham Eliel , Noh Ji Yun , Cheong Hee Jin , Kim Woo Joo , Lim Sooyeon , Song Joon Young
Published: March 2023

Objectives

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects gut luminal cells through the angiotensin-converting enzyme-2 receptor and disrupts the gut microbiome. We investigated whether the gut microbiome in the early stage of SARS-CoV-2 infection was associated with the prognosis of coronavirus disease (COVID-19).

Methods

Thirty COVID-19 patients and 16 healthy controls were prospectively enrolled. Blood and stool samples and clinical details were collected on days 0 (enrollment), 7, 14, and 28. Participants were categorized into four groups by their clinical course.

Results

Gut microbiota composition varied during the clinical course of COVID-19 and was closely associated with cytokine levels (p=0.003). A high abundance of the genus Dialister (linear discriminant analysis [LDA] effect size: 3.97856, p=0.004), species Peptoniphilus lacrimalis (LDA effect size: 4.00551, p=0.020), and Anaerococcus prevotii (LDA effect size: 4.00885, p=0.007) was associated with a good prognosis. Starch, sucrose, and galactose metabolism was highly activated in the gut microbiota of the poor prognosis group. Glucose-lowering diets, including whole grains, were positively correlated with a good prognosis.

Conclusion

Gut microbiota may mediate the prognosis of COVID-19 by regulating cytokine responses and controlling glucose metabolism, which is implicated in the host immune response to SARS-CoV-2.
Chromosome 11q13 amplification correlates with poor response and prognosis to PD-1 blockade in unresectable hepatocellular carcinoma
Authors: Yan Kai , Zhang Ding , Chen Yanan , Lu Wenfeng , Huang Mengli , Cai Jinping , Chen Shiqing , Bei Ting , Bai Yuezong , Lv Jian , Fu Yong , Zhang Haibin
Published: March 2023

Background & aims

Little is known about molecular biomarkers that predict the response and prognosis in unresectable hepatocellular carcinoma (HCC) treated with programmed death (PD)-1 inhibitors.

Methods

A total of 62 HCC patients who underwent next-generation sequencing were retrospectively included in our department for this study. Patients with unresectable disease were subjected to systemic therapy. PD-1 inhibitors intervention (PD-1Ab) group and nonPD-1Ab group included 20 and 13 patients, respectively. Primary resistance was defined as initial on-treatment progression or progression with an initial stable disease of less than 6 months.

Results

Chromosome 11q13 amplification (Amp11q13) was the most common copy number variation in our cohort. Fifteen (24.2%) patients harbored Amp11q13 in our dataset. Patients with Amp11q13 showed higher level of Des-γ-carboxy-prothrombin (DCP), tumor number and were more prone to be combined with portal vein tumor thrombosis (PVTT). In the PD-1Ab group, the proportion of progressive disease (PD) in patients with Amp11q13 was significantly higher than that in patients with nonAmp11q13 (100% vs 33.3%, P=0.03). In the nonPD-1Ab group, the proportion of PD in patients with Amp11q13 and nonAmp11q13 had no significant difference (0% vs 11.1%, P>0.99). In the PD-1Ab group, the median progression-free survival (PFS) was 1.5 months in Amp11q13 patients vs 16.2 months in non-Amp11q13 patients (HR, 0.05; 95% CI 0.01-0.45; P = 0.0003). No significant difference was observed in the nonPD-1Ab group. Notably, we found that hyperprogressive disease (HPD) might be associated with Amp11q13. The increased density of Foxp3+ Treg cells in HCC patients with Amp11q13 might be one of potential mechanisms.

Conclusion

HCC patients with Amp11q13 are less likely to benefit from PD-1 blockade therapies. These findings may help guide the use of immunotherapy for HCC in routine clinical practice.
Soluble immune checkpoints as correlates for HIV persistence and T cell function in people with HIV on antiretroviral therapy
Authors: Chiu Chris Y. , Schou Maya D. , McMahon James H. , Deeks Steven G. , Fromentin Rémi , Chomont Nicolas , Wykes Michelle N. , Rasmussen Thomas A. , Lewin Sharon R.
Published: March 2023

Introduction

In people with HIV (PWH) both off and on antiretroviral therapy (ART), the expression of immune checkpoint (IC) proteins is elevated on the surface of total and HIV-specific T-cells, indicating T-cell exhaustion. Soluble IC proteins and their ligands can also be detected in plasma, but have not been systematically examined in PWH. Since T-cell exhaustion is associated with HIV persistence on ART, we aimed to determine if soluble IC proteins and their ligands also correlated with the size of the HIV reservoir and HIV-specific T-cell function.

Methods

We used multiplex bead-based immunoassay to quantify soluble programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin domain and mucin domain 3 (TIM-3), PD-1 Ligand 1 (PD-L1) and PD-1 Ligand 2 (PD-L2) in plasma from PWH off ART (n=20), on suppressive ART (n=75) and uninfected controls (n=20). We also quantified expression of membrane-bound IC and frequencies of functional T-cells to Gag and Nef peptide stimulation on CD4+ and CD8+ T-cells using flow cytometry. The HIV reservoir was quantified in circulating CD4+ T-cells using qPCR for total and integrated HIV DNA, cell-associated unspliced HIV RNA and 2LTR circles.

Results

Soluble (s) PD-L2 level was higher in PWH off and on ART compared to uninfected controls. Higher levels of sPD-L2 correlated with lower levels of HIV total DNA and higher frequencies of gag-specific CD8+ T-cells expressing CD107a, IFNγ or TNFα. In contrast, the concentration of sLAG-3 was similar in uninfected individuals and PWH on ART, but was significantly elevated in PWH off ART. Higher levels of sLAG-3 correlated with higher levels of HIV total and integrated DNA, and lower frequency of gag-specific CD4+ T cells expressing CD107a. Similar to sLAG-3, levels of sPD-1 were elevated in PWH off ART and normalized in PWH on ART. sPD-1 was positively correlated with the frequency of gag-specific CD4+ T cells expressing TNF-a and the expression of membrane-bound PD-1 on total CD8+ T-cells in PWH on ART.

Discussion

Plasma soluble IC proteins and their ligands correlate with markers of the HIV reservoir and HIV-specific T-cell function and should be investigated further in in large population-based studies of the HIV reservoir or cure interventions in PWH on ART.
Multicenter, single-arm, phase II study (CAP) of radiotherapy plus liposomal irinotecan followed by camrelizumab and anti-angiogenic treatment in advanced solid tumors
Authors: Shen Jie , Yan Jing , Du Juan , Li Xiaoqin , Wei Jia , Liu Qin , Yong Hongmei , Wang Xiaolu , Chang Xiaofeng , Ding Zhou , Sun Wu , Liu Chenxi , Zhu Sihui , Guo Jingyi , Li Huajun , Liu Ying , Zhang Wulou , Liu Zonghang , Li Rutian , Liu Baorui
Published: March 2023

Introduction

Combination therapeutic mode is likely to be the key to enhance the efficacy of immunotherapy in a wider range of cancer patients. Herein, we conducted an open-label, single-arm, multicenter, phase II clinical trial that enrolled patients with advanced solid tumors who had progressed after standard treatments.

Methods

Radiotherapy of 24 Gy/3 fractions/3-10 days was given to the targeted lesions. Liposomal irinotecan (80mg/m2, dose could be adjusted to 60 mg/m2 for intolerable cases) was intravenously (IV) administered once within 48 hours after radiotherapy. Then, camrelizumab (200mg IV, q3w) and anti-angiogenic drugs were given regularly until disease progression. The primary endpoint was objective response rate (ORR) in the target lesions evaluated by investigators per RECIST 1.1. The secondary endpoints were disease control rate (DCR) and treatment-related adverse events (TRAEs).

Results

Between November 2020 and June 2022, 60 patients were enrolled. The median follow-up was 9.0 months (95% confidence interval (CI) 5.5-12.5). Of 52 evaluable patients, the overall ORR and DCR were 34.6% and 82.7%, respectively. Fifty patients with target lesions were evaluable, the ORR and DCR of the target lesions were 35.3% and 82.4%, respectively. The median progression-free survival was 5.3 months (95% CI 3.6, 6.2), and the median overall survival was not reached. TRAEs (all grades) occurred in 55 (91.7%) patients. The most common grade 3-4 TRAEs were lymphopenia (31.7%), anemia (10.0%), and leukopenia (10.0%).

Conclusion

The combination of radiotherapy, liposomal irinotecan, camrelizumab, and anti-angiogenesis therapy demonstrated promising anti-tumor activity and well tolerance in various advanced solid tumors.

Clinical trial registration

https://clinicaltrials.gov/ct2/home, identifier NCT04569916.
Role of NLRP3 in the pathogenesis and treatment of gout arthritis
Authors: Liu Ya-ru , Wang Jie-quan , Li Jun
Published: March 2023

Gout arthritis (GA) is a common and curable type of inflammatory arthritis that has been attributed to a combination of genetic, environmental and metabolic factors. Chronic deposition of monosodium urate (MSU) crystals in articular and periarticular spaces as well as subsequent activation of innate immune system in the condition of persistent hyperuricemia are the core mechanisms of GA. As is well known, drugs for GA therapy primarily consists of rapidly acting anti-inflammatory agents and life-long uric acid lowering agents, and their therapeutic outcomes are far from satisfactory. Although MSU crystals in articular cartilage detected by arthrosonography or in synovial fluid found by polarization microscopy are conclusive proofs for GA, the exact molecular mechanism of NLRP3 inflammasome activation in the course of GA still remains mysterious, severely restricting the early diagnosis and therapy of GA. On the one hand, the activation of Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome requires nuclear factor kappa B (NF-κB)-dependent transcriptional enhancement of NLRP3, precursor (pro)-caspase-1 and pro-IL-1β, as well as the assembly of NLRP3 inflammasome complex and sustained release of inflammatory mediators and cytokines such as IL-1β, IL-18 and caspase-1. On the other hand, NLRP3 inflammasome activated by MSU crystals is particularly relevant to the initiation and progression of GA, and thus may represent a prospective diagnostic biomarker and therapeutic target. As a result, pharmacological inhibition of the assembly and activation of NLRP3 inflammasome may also be a promising avenue for GA therapy. Herein, we first introduced the functional role of NLRP3 inflammasome activation and relevant biological mechanisms in GA based on currently available evidence. Then, we systematically reviewed therapeutic strategies for targeting NLRP3 by potentially effective agents such as natural products, novel compounds and noncoding RNAs (ncRNAs) in the treatment of MSU-induced GA mouse models. In conclusion, our present review may have significant implications for the pathogenesis, diagnosis and therapy of GA.
Projected effects of climate change on marine ecosystems in Southeast Asian seas
Authors: Kay Susan , Avillanosa Arlene L. , Cheung Victoria V. , Dao Hung N. , Gonzales Benjamin Jareta , Palla Herminie P. , Praptiwi Radisti A. , Queirós Ana M. , Sailley Sévrine F. , Sumeldan Joel D. C. , Syazwan Wan Mohd , Then Amy Yee-Hui , Wee Hin Boo
Published: March 2023

The seas of Southeast Asia are home to some of the world’s most diverse ecosystems and resources that support the livelihoods of millions of people. Climate change will bring temperature changes, acidification and other environmental change, with uncertain consequences for human and natural systems, but there has been little regional-scale climate modelling of the marine ecosystem. We present initial dynamically downscaled projections using a biogeochemical model suitable for coastal and shelf seas. A coupled physical-biogeochemical model with a resolution of 0.1° (approximately 11 km) was used to create projections of future environmental conditions under moderate (RCP4.5) and high (RCP8.5) greenhouse gas scenarios. Changes for different parts of the region are presented, including four sensitive coastal sites of key importance for biodiversity and sustainable development: UNESCO Biosphere Reserves at Cu Lao Cham-Hoi An in Vietnam, Palawan in the Philippines and Taka Bonerate-Kepulauan Selayar in Indonesia, and coastal waters of Sabah, Malaysia, which include several marine parks. The projections show a sea that is warming by 1.1 to 2.9°C through the 21st century, with dissolved oxygen decreasing by 5 to 13 mmol m-3 and changes in many other environmental variables. The changes reach all parts of the water column and many places are projected to experience conditions well outside the range seen at the start of the century. The resulting damage to coral reefs and altered species distribution would have consequences for biodiversity, the livelihoods of small-scale fishers and the food security of coastal communities. Further work using a range of global models and regional models with different biogeochemical components is needed to provide confidence levels, and we suggest some ways forward. Projections of this type serve as a key tool for communities and policymakers as they plan how they will adapt to the challenge of climate change.
Graphene-bioactive glass composites: Structural, Vickers hardness, and gamma-ray attenuation characteristics
Authors: Deliormanli Aylin M. , ALMisned Ghada , Ene Antoaneta , Tekin H.O.
Published: March 2023

Introduction: Graphene-based materials have gained increasing attention for use in radiation attenuation applications. In this study, pristine graphene nanoplatelet-containing (1, 3, 5, and 10 wt%) borate-based bioactive glass composites were prepared.

Methods: Structural properties, Vickers microhardness, and gamma-ray radiation shielding properties of the fabricated composites were examined in detail.

Results and Discussion: Results revealed that the inclusion of the graphene in the glass matrix led to a decrease in the bulk density of the glass-based composites from 2.41 to 2.31 g/cm3. Similarly, a decrease in Vickers hardness was obtained as the graphene concentration was increased due to a convoluted effect of the non-uniform distribution of graphene nanoplatelets in the bioactive glass matrix and the higher residual porosity. Vickers hardness of the bare and the 10 wt% graphene-containing bioactive glass discs were measured to be 5.03 ± 0.28 GPa and 1.87 ± 0.56 GPa, respectively. On the other hand, the incorporation of graphene starting from 3 wt% decreased the crack propagation after indentation which may be attributed to an increase in fracture toughness. In the study, fundamental gamma ray absorption properties of graphene-containing bioactive glasses were examined in the 0.015–15 MeV incident photon energy range. For this purpose, the Py-MLBUF code was employed to determine gamma ray absorption parameters. Results showed that linear attenuation coefficients of the glass-based composites decreased due to a decrease in the density of the samples. On the other hand, as graphene was incorporated into the bioactive glass structure, exposure buildup factor and energy absorption buildup factor values increased. The growing graphene ratio in the glass structure contributed negatively to the photon’s tendency to interact with the material.
The association of coital incontinence with clinical factors and single voiding cycle ambulatory urodynamic monitoring findings in women
Authors: Çetinkaya Şerife Esra , Seval Mehmet Murat , Varlı Bulut , Dökmeci Fulya
Published: March 2023

Introduction

Coital incontinence (CI) is a frequent problem in women with urinary incontinence (UI) with significant impact on female sexuality and quality of life. The underlying mechanism is controversial; it has been known that CI is associated with both stress urinary incontinence (SUI) and detrusor overactivity (DO). However, recently it has been reported that CI is mainly related with SUI and urethral incompetence, but not with DO. Ambulatory urodynamic monitoring (AUM) has been shown to be a sensitive tool for the detection of DO. The aim of this study was to investigate the clinical risk factors for CI and the association of CI with urodynamic diagnoses at single voiding cycle AUM.

Methods

Records of sexually active women with urinary incontinence attending the urogynaecology unit of a university hospital, who completed the PISQ-12 were reviewed retrospectively (n = 1,005). Patients were grouped using the 6th question; patients answering “never” to this question were considered as continent during coitus (n = 591) and patients reporting any urinary leakage at coitus were considered to have CI (n = 414). Demographics, clinical examination findings, incontinence severity measured by the Sandvik Incontinence Severity Index, scores of Turkish validated questionnaires (PFDI-20, IIQ-7, OAB-V8, and PISQ-12) and single voiding cycle AUM findings were compared, and univariate and multivariate logistic regression analyses were performed.

Results

Among all sexually active women with UI, 41.2% had CI; UI was more severe, symptom bother was higher, related quality of life (p < 0.001) and sexual function were worse (≤0.018) in these women. Younger age (OR 0.967, p < 0.001), history of vaginal delivery (OR 2.127, p = 0.019), smoking (OR 1.490, p = 0.041), postural UI (OR 2.012, p = 0.001), positive cough stress test (OR 2.193, p < 0.001), and positive SEST (OR 1.756, p = 0.01) were found as independent clinical factors associated with CI. Urodynamic SUI (OR 2.168, p = 0.001) and MUI (OR 1.874, p = 0.002) were found as significant and independent urodynamic diagnoses associated with CI, whereas no association was found with DO or UUI.

Conclusion

Both clinical and AUM findings supported that CI is a more severe form of UI that it is mainly related with SUI and urethral incompetence, but not with UUI or DO.
Dynamic nature and prognostic value of the neutrophil-to-lymphocyte ratio in critically ill patients with acute kidney injury on continuous renal replacement therapy: A multicenter cohort study
Authors: Ko Hyun Lee , Jung Jiyun , Lee Jangwook , Lim Jeong-Hoon , Im Dha Woon , Kim Yong Chul , Paek Jin Hyuk , Park Woo Yeong , Kim Kyeong Min , Lee Soyoung , Lee Sung Woo , Shin Sung Joon , Kim Dong Ki , Han Seung Seok , Baek Chung Hee , Kim Hyosang , Park Jae Yoon , Ban Tae Hyun , Kim Kipyo
Published: March 2023

Introduction

Patients with acute kidney injury (AKI) receiving renal replacement therapy constitute the subgroup of AKI with the highest risk of mortality. Despite recent promising findings on the neutrophil-to-lymphocyte ratio (NLR) in AKI, studies have not yet addressed the clinical implication of the NLR in this population. Therefore, we aimed to examine the prognostic value of NLR in critically ill patients requiring continuous renal replacement therapy (CRRT), especially focusing on temporal changes in NLR.

Methods

We enrolled 1,494 patients with AKI who received CRRT in five university hospitals in Korea between 2006 and 2021. NLR fold changes were calculated as the NLR on each day divided by the NLR value on the first day. We performed a multivariable Cox proportional hazard analysis to assess the association between the NLR fold change and 30-day mortality.

Results

The NLR on day 1 did not differ between survivors and non-survivors; however, the NLR fold change on day 5 was significantly different. The highest quartile of NLR fold change during the first 5 days after CRRT initiation showed a significantly increased risk of death (hazard ratio [HR], 1.65; 95% confidence intervals (CI), 1.27–2.15) compared to the lowest quartile. NLR fold change as a continuous variable was an independent predictor of 30-day mortality (HR, 1.14; 95% CI, 1.05–1.23).

Conclusion

In this study, we demonstrated an independent association between changes in NLR and mortality during the initial phase of CRRT in AKI patients receiving CRRT. Our findings provide evidence for the predictive role of changes in the NLR in this high-risk subgroup of AKI.
Deep-learning-based survival prediction of patients with cutaneous malignant melanoma
Authors: Yu Hai , Yang Wei , Wu Shi , Xi Shaohui , Xia Xichun , Zhao Qi , Ming Wai-kit , Wu Lifang , Hu Yunfeng , Deng Liehua , Lyu Jun
Published: March 2023

Background

This study obtained data on patients with cutaneous malignant melanoma (CMM) from the Surveillance, Epidemiology, and End Results (SEER) database, and used a deep learning and neural network (DeepSurv) model to predict the survival rate of patients with CMM and evaluate its effectiveness.

Methods

We collected information on patients with CMM between 2004 and 2015 from the SEER database. We then randomly divided the patients into training and testing cohorts at a 7:3 ratio. The likelihood that patients with CMM will survive was forecasted using the DeepSurv model, and its results were compared with those of the Cox proportional-hazards (CoxPH) model. The calibration curves, time-dependent area under the receiver operating characteristic curve (AUC), and concordance index (C-index) were used to assess the prediction abilities of the model.

Results

This study comprised 37,758 patients with CMM: 26,430 in the training cohort and 11,329 in the testing cohort. The CoxPH model demonstrated that the survival of patients with CMM was significantly influenced by age, sex, marital status, summary stage, surgery, radiotherapy, chemotherapy, postoperative lymph node dissection, tumor size, and tumor extension. The C-index of the CoxPH model was 0.875. We also constructed the DeepSurv model using the data from the training cohort, and its C-index was 0.910. We examined how well the aforementioned two models predicted outcomes. The 1-, 3-, and 5-year AUCs were 0.928, 0.837, and 0.855, respectively, for the CoxPH model, and 0.971, 0.947, and 0.942 for the DeepSurv model. The DeepSurv model presented a greater predictive effect on patients with CMM, and its reliability was better than that of the CoxPH model according to both the AUC value and the calibration curve.

Conclusion

The DeepSurv model, which we developed based on the data of patients with CMM in the SEER database, was found to be more effective than the CoxPH model in predicting the survival time of patients with CMM.
Role of gut microbiota in infectious and inflammatory diseases
Authors: Maciel-Fiuza Miriãn Ferrão , Muller Guilherme Cerutti , Campos Daniel Marques Stuart , do Socorro Silva Costa Perpétua , Peruzzo Juliano , Bonamigo Renan Rangel , Veit Tiago , Vianna Fernanda Sales Luiz
Published: March 2023

Thousands of microorganisms compose the human gut microbiota, fighting pathogens in infectious diseases and inhibiting or inducing inflammation in different immunological contexts. The gut microbiome is a dynamic and complex ecosystem that helps in the proliferation, growth, and differentiation of epithelial and immune cells to maintain intestinal homeostasis. Disorders that cause alteration of this microbiota lead to an imbalance in the host’s immune regulation. Growing evidence supports that the gut microbial community is associated with the development and progression of different infectious and inflammatory diseases. Therefore, understanding the interaction between intestinal microbiota and the modulation of the host’s immune system is fundamental to understanding the mechanisms involved in different pathologies, as well as for the search of new treatments. Here we review the main gut bacteria capable of impacting the immune response in different pathologies and we discuss the mechanisms by which this interaction between the immune system and the microbiota can alter disease outcomes.
Integrative epigenome profiling of 47XXY provides insights into whole genomic DNA hypermethylation and active chromatin accessibility
Authors: Miao Nan , Zeng Zhiwei , Lee Trevor , Guo Qiwei , Zheng Wenwei , Cai Wenjie , Chen Wanhua , Wang Jing , Sun Tao
Published: March 2023

Klinefelter syndrome (KS, 47XXY) is a disorder characterized by sex chromosomal aneuploidy, which may lead to changes in epigenetic regulations of gene expression. To define epigenetic architectures in 47XXY, we annotated DNA methylation in euploid males (46XY) and females (46XX), and 47XXY individuals using whole genome bisulfite sequencing (WGBS) and integrated chromatin accessbilty, and detected abnormal hypermethylation in 47XXY. Furthermore, we detected altered chromatin accessibility in 47XXY, in particular in chromosome X, using Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) in cultured amniotic cells. Our results construct the whole genome-wide DNA methylation map in 47XXY, and provide new insights into the early epigenomic dysregulation resulting from an extra chromosome X in 47XXY.
FleQ, FleN and c-di-GMP coordinately regulate cellulose production in Pseudomonas syringae pv. tomato DC3000
Authors: Martínez-Rodríguez Laura , López-Sánchez Aroa , García-Alcaide Andrea , Govantes Fernando , Gallegos María-Trinidad
Published: March 2023

The second messenger cyclic di-GMP (c-di-GMP) controls the transition between motility and sessility in many bacterial species by a variety of mechanisms, including the production of multiple exopolysaccharides. Pseudomonas syringae pv. tomato (Pto) DC3000 is a plant pathogenic bacteria able to synthesize acetylated cellulose under high c-di-GMP levels thanks to the expression of the wssABCDEFGHI operon. Increased cellulose production enhances air-liquid biofilm formation and generates a wrinkled colony phenotype on solid media. We previously showed that under low levels of c-di-GMP, the regulators FleQ and AmrZ bound to adjacent sequences at the wss promoter inhibiting its expression, but only FleQ responded to the presence of c-di-GMP by activating cellulose production. In the present work, we advance in the knowledge of this complex regulation in Pto DC3000 by shedding light over the role of FleN in this process. The distinctive features of this system are that FleN and FleQ are both required for repression and activation of the wss operon under low and high c-di-GMP levels, respectively. We have also identified three putative FleQ binding sites at the wss promoter and show that FleQ/FleN-ATP binds at those sites under low c-di-GMP levels, inducing a distortion of DNA, impairing RNA polymerase binding, and repressing wss transcription. However, binding of c-di-GMP induces a conformational change in the FleQ/FleN-ATP complex, which relieves the DNA distortion, allows promoter access to the RNA polymerase, and leads to activation of wss transcription. On the other hand, AmrZ is always bound at the wss promoter limiting its expression independently of FleQ, FleN and c-di-GMP levels.
Experiences with and perspectives on advance care planning in young- and late- onset dementia: A focus group study with physicians from various disciplines
Authors: Van Rickstal Romy , De Vleminck Aline , Engelborghs Sebastiaan , Van den Block Lieve
Published: March 2023

Introduction

Despite the relevance of advance care planning (ACP) for people with dementia, its uptake in this population is particularly low. Several challenges for ACP in dementia have been identified from physicians’ perspectives. However, the literature available mainly includes general practitioners and focuses exclusively on the context of late-onset dementia. This is the first study to inquire physicians from four highly relevant specialisms in dementia care, with a focus toward potential specificities based on patients’ age. The research question of this study is: “What are physicians’ experiences with and perspectives on discussing ACP with people with young- and/or late-onset dementia?”.

Methods

Five online focus groups were conducted with 21 physicians (general practitioners, psychiatrists, neurologists and geriatricians) in Flanders, Belgium. Verbatim transcripts were analyzed through the qualitative method of constant comparative analysis.

Results

Physicians believed that the societal stigma related to dementia influences people’s reaction to their diagnosis, at times characterized by catastrophic expectations for the future. In this regard, they explained that the topic of euthanasia is sometimes addressed by patients very early in the disease trajectory. Respondents paid ample attention to actual end-of-life decisions, including DNR directives, when discussing ACP in dementia. Physicians felt responsible for providing accurate information on both dementia as a condition, and the legal framework of end-of-life decisions. Most participants felt that patients’ and caregivers’ wish for ACP was more driven by who their personality than by their age. Nonetheless, physicians identified specificities for a younger dementia population in terms of ACP: they believed that ACP covered more domains of life than for older persons. A high consistency regarding the viewpoints of physicians from differing specialisms was noted.

Discussion

Physicians acknowledge the added value of ACP for people with dementia and especially their caregivers. However, they face several challenges for engaging in the process. Attending to specific needs in young-onset, in comparison to late-onset dementia, requires ACP to entail more than solely medical domains. However, a medicalized view on ACP still appears to be dominant in practice as opposed to its broader conceptualization in academia.
Effects of post-acute COVID-19 syndrome on the functional brain networks of non-hospitalized individuals
Authors: Churchill Nathan W. , Roudaia Eugenie , Chen J. Jean , Gilboa Asaf , Sekuler Allison , Ji Xiang , Gao Fuqiang , Lin Zhongmin , Jegatheesan Aravinthan , Masellis Mario , Goubran Maged , Rabin Jennifer S. , Lam Benjamin , Cheng Ivy , Fowler Robert , Heyn Chris , Black Sandra E. , MacIntosh Bradley J. , Graham Simon J. , Schweizer Tom A.
Published: March 2023

Introduction

The long-term impact of COVID-19 on brain function remains poorly understood, despite growing concern surrounding post-acute COVID-19 syndrome (PACS). The goal of this cross-sectional, observational study was to determine whether there are significant alterations in resting brain function among non-hospitalized individuals with PACS, compared to symptomatic individuals with non-COVID infection.

Methods

Data were collected for 51 individuals who tested positive for COVID-19 (mean age 41±12 yrs., 34 female) and 15 controls who had cold and flu-like symptoms but tested negative for COVID-19 (mean age 41±14 yrs., 9 female), with both groups assessed an average of 4-5 months after COVID testing. None of the participants had prior neurologic, psychiatric, or cardiovascular illness. Resting brain function was assessed via functional magnetic resonance imaging (fMRI), and self-reported symptoms were recorded.

Results

Individuals with COVID-19 had lower temporal and subcortical functional connectivity relative to controls. A greater number of ongoing post-COVID symptoms was also associated with altered functional connectivity between temporal, parietal, occipital and subcortical regions.

Discussion

These results provide preliminary evidence that patterns of functional connectivity distinguish PACS from non-COVID infection and correlate with the severity of clinical outcome, providing novel insights into this highly prevalent disorder.
Rescue thrombolysis for medium vessel occlusion (RESCUE-TNK): Rationale and design of a phase 2 randomized trial
Authors: Hu Hai-Zhou , Qiu Jing , Li Wei , Nguyen Thanh N. , Wang Feng , Li Di , Shi Huai-Zhang , Wang Shou-Chun , Wei Ming , Chen Hui-Sheng
Published: March 2023

Background

The best reperfusion strategy for medium-sized vessel occlusion (MeVO) is not well established. Given the proven treatment effect of intra-arterial thrombolysis in patients with large vessel occlusion (LVO), we hypothesized that intra-arterial tenecteplase (TNK) could increase the recanalization rate of MeVO and thus improve clinical outcome.

Aims

To explore the safety and efficacy of intra-arterial TNK in patients with MeVO.

Sample size estimates

A maximum of 80 patients are required to test the superiority hypothesis, using power = 80% and α = 0.025 to conduct the one-sided test.

Design

Rescue treatment for mEdium veSsel oCclUsion by intra-artErial TNK (RESCUE-TNK) is a pilot, randomized, open-label, blinded end point, and multicenter trial. Eligible patients including primary MeVO as detected by the first DSA examination or secondary MeVO after endovascular treatment (EVT) for LVO will be assigned into the experimental group and control group as a ratio of 1:1. The experimental group will be treated with intra-arterial TNK (0.2–0.3 mg/min, for 20–30 min) via a microcatheter placed proximal to the site of occlusion, and the control group will be treated with routine therapy. Both groups of patients will be given standard stroke care based on the guidelines.

Outcome

The primary efficacy end point is successful recanalization of MeVO, defined as the expanded treatment in cerebral ischemia (eTICI) score 2b67-3 after the procedure, while the primary safety end point is symptomatic intracranial hemorrhage (sICH), defined as National Institutes of Health Stroke Scale score increase ≥4 caused by intracranial hemorrhage within 24 (−6/+24) hours after randomization.

Conclusion

The results of RESCUE-TNK will provide evidence for the efficacy and safety of intra-arterial TNK in the recanalization of patients with MeVO.
Chemistry and Pharmacological Actions of Delphinidin, a Dietary Purple Pigment in Anthocyanidin and Anthocyanin Forms
Authors: Husain Asif , Chanana Harshit , Khan Shah Alam , Dhanalekshmi U. M. , Ali M. , Alghamdi Anwar A. , Ahmad Aftab
Published: March 2023

Anthocyanins are naturally occurring water-soluble flavonoids abundantly present in fruits and vegetables. They are polymethoxyderivatives of 2-phenyl-benzopyrylium or flavylium salts. Delphinidin (Dp) is a purple-colored plant pigment, which occurs in a variety of berries, eggplant, roselle, and wine. It is found in a variety of glycosidic forms ranging from glucoside to arabinoside. Dp is highly active in its aglycone form, but the presence of a sugar moiety is vital for its bioavailability. Several animal and human clinical studies have shown that it exerts beneficial effects on gut microbiota. Dp exhibits a variety of useful biological activities by distinct and complex mechanisms. This manuscript highlights the basic characteristics, chemistry, biosynthesis, stability profiling, chemical synthesis, physicochemical parameters along with various analytical methods developed for extraction, isolation and characterization, diverse biological activities and granted patents to this lead anthocyanin molecule, Dp. This review aims to open pathways for further exploration and research investigation on the true potential of the naturally occurring purple pigment (Dp) in its anthocyanidin and anthocyanin forms beyond nutrition.
Tissue clearing and immunostaining to visualize the spatial organization of vasculature and tumor cells in mouse liver
Authors: Frenkel Nicola , Poghosyan Susanna , van Wijnbergen Jan Willem , van den Bent Lotte , Wijler Liza , Verheem André , Borel Rinkes Inne , Kranenburg Onno , Hagendoorn Jeroen
Published: March 2023

The liver has a complex and hierarchical segmental organization of arteries, portal veins, hepatic veins and lymphatic vessels. In-depth imaging of liver vasculature and malignancies could improve knowledge on tumor micro-environment, local tumor growth, invasion, as well as metastasis. Non-invasive imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI) and positron-emission transmission (PET) are routine for clinical imaging, but show inadequate resolution at cellular and subcellular level. In recent years, tissue clearing – a technique rendering tissues optically transparent allowing enhanced microscopy imaging – has made great advances. While mainly used in the neurobiology field, recently more studies have used clearing techniques for imaging other organ systems as well as tumor tissues. In this study, our aim was to develop a reproducible tissue clearing and immunostaining model for visualizing intrahepatic blood microvasculature and tumor cells in murine colorectal liver metastases. CLARITY and 3DISCO/iDISCO+ are two established clearing methods that have been shown to be compatible with immunolabelling, most often in neurobiology research. In this study, CLARITY unfortunately resulted in damaged tissue integrity of the murine liver lobes and no specific immunostaining. Using the 3DISCO/iDISCO+ method, liver samples were successfully rendered optically transparent. After which, successful immunostaining of the intrahepatic microvasculature using panendothelial cell antigen MECA-32 and colorectal cancer cells using epithelial cell adhesion molecule (EpCAM) was established. This approach for tumor micro-environment tissue clearing would be especially valuable for allowing visualization of spatial heterogeneity and complex interactions of tumor cells and their environment in future studies.
The postoperative analgesic efficacy of different regional anesthesia techniques in breast cancer surgery: A network meta-analysis
Authors: An Ran , Wang Dan , Liang Xiao-Long , Chen Qi , Pang Qian-Yun , Liu Hong Liang
Published: March 2023

Background

Regional anesthesia have been successfully performed for pain management in breast cancer surgery, but it is unclear which is the best regional anesthesia technique. The aim of the present network meta-analysis was to assess the analgesic efficacy and disadvantages of regional anesthesia techniques.

Methods

Multiple databases were searched for randomized controlled trials (RCTs). The association between regional anesthesia and analgesic efficacy was evaluated by Bayesian network meta-analysis.

Results

We included 100 RCTs and 6639 patients in this study. The network meta-analysis showed that paravertebral nerve block, pectoral nerve-2 block, serratus anterior plane block, erector spinae plane block, rhomboid intercostal block, and local anesthetic infusion were associated with significantly decreased postoperative pain scores, morphine consumption and incidence of postoperative nausea and vomiting compared with no block. Regarding the incidence of chronic pain, no significance was detected between the different regional anesthesia techniques. In the cumulative ranking curve analysis, the rank of the rhomboid intercostal block was the for postoperative care unit pain scores, postoperative 24-hour morphine consumption, and incidence of postoperative nausea and vomiting.

Conclusion

Regional anesthesia techniques including, paravertebral nerve block, pectoral nerve-2 block, serratus anterior plane block, erector spinae plane block, rhomboid intercostal block, and local anesthetic infusion, can effectively alleviate postoperative acute analgesia and reduce postoperative morphine consumption, but cannot reduce chronic pain after breast surgery. The rhomboid intercostal block might be the optimal technique for postoperative analgesia in breast cancer surgery, but the strength of the evidence was very low.

Systematic review registration

https://www.crd.york.ac.uk/prospero/(PROSPERO), identifier CRD 42020220763.
Exploration of the methods of establishing the minimum clinical important difference based on anchors and their applications in the quality of life measurement scale QLICP-BR (V2.0) for breast cancer
Authors: Zhou Xuan , Liu Yuxi , Tan Jianfeng , Hu Liren , Chen Huanwei , Wan Chonghua
Published: March 2023

Objective

The measurement of the quality of life (QOL) in patients with breast cancer can evaluate the therapeutic effects of medical treatments and help to provide reference for clinical decisions. The minimum clinically important difference (MCID) can be better used in clinical interpretation than the traditional statistical significance. Based on the anchors, a variety of ways including traditional and updated anchor-based methods were used to explore most suitable MCID, so that to find better interpretation on scores of the scale QLICP-BR(V2.0) (Quality of Life Instruments for Cancer Patients-Breast cancer).

Methods

According to the investigation data of breast cancer patients before and after treatment, the most relevant indicators in various domains of QLICP-BR (V2.0) was found as an anchor to statistically analyze the value of MCID, and three analysis methods of anchors were used: Traditional anchor-based method, ROC curve method, multiple linear regression model analysis. Anchors are divided into four standards according to the degree of change in the treatment effect: one grade difference (Standard A), at least one grade difference (Standard B), one grade better (Standard C), better (Standard D). The final MCID value is selected from different statistical methods and classification standards that are most suitable for clinicians to use.

Results

Using Q29 of the EORTC QLQ-C30 as an anchor has the highest correlation with each domain of QLICP. The order of magnitude of MCID values among the four standard groups is: standard A< Standard C< Standard B< Standard D. The MCID value obtained by the ROC curve method is the most stable and is least affected by the sample size, and the MCID value obtained by the multiple linear regression model is the least. After comparisons and discussions, Standard C in the multiple linear regression model is used to determine the final MCID, which is the closest to other methods. After integer the MCID values of Physical domain (PHD), Psychological domain (PSD), Social domain (SOD), Common symptoms and side effect domain (SSD), Core/general module (CGD), Specific domain (SPD), Total score(TOT) can be taken as 15,10, 10, 11, 10, 9 and 9, respectively.

Conclusion

In the evaluation of the QOL of breast cancer patients, although the results of MCID values produced by different methods are different, the results are relatively close. The anchor-based methods make the results of MCID more clinically interpretable by introducing clinical variables, and clinicians and researchers can choose the appropriate method according to the research purpose.