bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of microbial secreted proteins in gut microbiota-host interactions
Authors: Vidal-Veuthey Boris , González Dámariz , Cárdenas Juan P.
Published: July 2022

The mammalian gut microbiota comprises a variety of commensals including potential probiotics and pathobionts, influencing the host itself. Members of the microbiota can intervene with host physiology by several mechanisms, including the secretion of a relatively well-reported set of metabolic products. Another microbiota influence mechanism is the use of secreted proteins (i.e., the secretome), impacting both the host and other community members. While widely reported and studied in pathogens, this mechanism remains understood to a lesser extent in commensals, and this knowledge is increasing in recent years. In the following minireview, we assess the current literature covering different studies, concerning the functions of secretable proteins from members of the gut microbiota (including commensals, pathobionts, and probiotics). Their effect on host physiology and health, and how these effects can be harnessed by postbiotic products, are also discussed.
Recall of Own Speech Following Interaction With L2 Speakers: Is There Evidence for Fuzzier Representations?
Authors: Baxter Frances , Khattab Ghada , Krug Andreas , Du Fengting
Published: July 2022

The aim of this study was to test claims that speakers of a first language (L1) incur cognitive and linguistic processing costs when interacting with second language (L2) speakers. This is thought to be due to the extra cognitive effort required for mapping incoming L2 speech signals onto stored phonological, lexical and semantic representations. Recent work suggests that these processing costs may lead to poorer memory of not only the L2 speech, but of one's own produced speech during an interaction with an L2 speaker. Little is known about whether this is also moderated by working memory (WM) capacity and/or the L2 interlocutor's proficiency. In a partial replication study of Lev-Ari et al., 54 healthy L1 English participants performed a WM test and then read a story and answered inference questions about it from a confederate in one of three conditions: the confederate was either a) a fellow L1 speaker; b) a Chinese L2 speaker of English with advanced proficiency or c) a Chinese L2 speaker of English with intermediate proficiency. Following a distractor task, participants were asked to recall their own answers in a surprise response-recognition questionnaire. Participants recognized their responses more accurately after interacting with the L1 speaker compared with the advanced L2 speaker but not compared with the intermediate L2 speaker. WM capacity correlated with higher accuracy when interacting with the L1 speaker, but with lower accuracy when interacting with the intermediate L2 speaker. These results suggest that effortful processing of input may lead to fuzzier lexical and/or semantic representations of one's own produced speech. However, the lack of significance in recall accuracy between the L1 and the intermediate L2 condition suggests other factors may be at play. Qualitative analyses of the conversations provided insights into strategies that individuals adopt to reduce cognitive load and achieve successful communication.
Early antithrombotic post-discharge therapy using prophylactic DOAC or dipyridamole improves long-term survival and cardiovascular outcomes in hospitalized COVID-19 survivors
Authors: Motloch Lukas J. , Jirak Peter , Mirna Moritz , Fiedler Lukas , Davtyan Paruir A. , Lakman Irina A. , Gareeva Diana F. , Tyurin Anton V. , Gumerov Ruslan M. , Matskeplishvili Simon T. , Pavlov Valentin N. , Cai Benzhi , Kopp Kristen , Topf Albert , Hoppe Uta C. , Pistulli Rudin , Zagidullin Naufal S.
Published: July 2022

Introduction

Cardiovascular events are common in COVID-19. While the use of anticoagulation during hospitalization has been established in current guidelines, recommendations regarding antithrombotic therapy in the post-discharge period are conflicting.

Methods

To investigate this issue, we conducted a retrospective follow-up (393 ± 87 days) of 1,746 consecutive patients, hospitalized with and surviving COVID-19 pneumonia at a single tertiary medical center between April and December 2020. Survivors received either 30-day post-discharge antithrombotic treatment regime using prophylactic direct oral anticoagulation (DOAC; n = 1,002) or dipyridamole (n = 304), or, no post-discharge antithrombotic treatment (Ctrl; n = 440). All-cause mortality, as well as cardiovascular mortality (CVM) and further cardiovascular outcomes (CVO) resulting in hospitalization due to pulmonary embolism (PE), myocardial infarction (MI) and stroke were investigated during the follow-up period.

Results

While no major bleeding events occured during follow-up in the treatment groups, Ctrl showed a high but evenly distributed rate all-cause mortality. All-cause mortality (CVM) was attenuated by prophylactic DOAC (0.6%, P < 0.001) and dipyridamole (0.7%, P < 0.001). This effect was also evident for both therapies after propensity score analyses using weighted binary logistic regression [DOAC: B = −3.33 (0.60), P < 0.001 and dipyridamole: B = −3.04 (0.76), P < 0.001]. While both treatment groups displayed a reduced rate of CVM [DOAC: B = −2.69 (0.74), P < 0.001 and dipyridamole: B = −17.95 (0.37), P < 0.001], the effect in the DOAC group was driven by reduction of both PE [B−3.12 (1.42), P = 0.012] and stroke [B = −3.08 (1.23), P = 0.028]. Dipyridamole significantly reduced rates of PE alone [B = −17.05 (1.01), P < 0.001].

Conclusion

Late cardiovascular events and all-cause mortality were high in the year following hospitalization for COVID-19. Application of prophylactic DOAC or dipyridamole in the early post-discharge period improved mid- and long-term CVO and all-cause mortality in COVID-19 survivors.
The relationship of remnant cholesterol and abdominal obesity in children: A cross-sectional study
Authors: Tong Jishuang , Li Xinggui , Liang Xiaoyue , Tang Fang , Ren Yanling , Hao Guang , Peng Xin , Luo Sunqing , Feng Ye , Huang Daochao , Zhao Li , Liang Xiaohua
Published: July 2022

Background

Previous studies found that remnant cholesterol (RC) is a risk factor for cardiovascular diseases and childhood obesity is associated with cardiometabolic diseases. This study aimed to explore the relationship between RC and abdominal obesity in children.

Methods

A total of 5,959 children, aged 6−12 years old, were selected from a cross-sectional study in urban-rural areas of Chongqing, China. RC was calculated by total cholesterol (TC)—high-density lipoprotein (HDL-C) cholesterol—low-density lipoprotein (LDL-C) cholesterol and was divided into four groups by quartiles (Q1–Q4).

Results

Compared to children with the lowest RC (Q1), children with higher RC had significantly higher odds of abdominal obesity (Q2: OR = 1.450, 95% CI: 1.131−1.859, p < 0.05; Q3: OR = 2.127, 95% CI: 1.632−2.772, p < 0.001; Q4: OR = 2.386, 95% CI: 1.819−3.130, p < 0.001). In the stratified analyses by urban-rural areas, the odds ratios were greater in rural areas (Q2: OR = 2.228, 95% CI: 1.572−3.160, p < 0.001; Q3: OR = 3.668, 95% CI: 2.191−6.140, p < 0.001; Q4: OR = 6.490, 95% CI: 2.271−18.551, p < 0.001) than in urban areas (Q2: OR = 1.644, 95% CI: 1.192−2.266, p < 0.05; Q3: OR = 2.266, 95% CI: 1.667−3.082, p < 0.001; Q4: OR = 2.711, 95% CI: 2.005−3.665, p < 0.001).

Conclusions

Our study found that RC was positively correlated with abdominal obesity in children, and this association was higher for children living in rural areas.
Effectiveness and safety of oral anticoagulant therapy in patients with atrial fibrillation with prior gastrointestinal bleeding: A systematic review and meta-analysis
Authors: Zhao Jie , Wu Xiaojuan , Li Siyuan , Gu Qiuping
Published: July 2022

Background

Gastrointestinal bleeding (GIB) commonly complicates anticoagulant therapy for patients with atrial fibrillation (AF). However, AF patients with prior GIB were excluded from most randomized controlled trials on anticoagulation therapy. Therefore, we conducted a systematic review and meta-analysis to assess the effect of oral anticoagulant (OAC) therapy in this specific population.

Methods

Randomized trials and observational studies reporting the data about the resumption of OAC therapy among AF patients with prior GIB were included. The search was performed in the PubMed and Embase databasesup to March 2022. The adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled by a random-effects model with an inverse variance method.

Results

A total of 7 studies involving 57,623 patients were included. Compared with no anticoagulant therapy, OAC therapy was associated with decreased risks of stroke or systemic embolism (HR = 0.71, 95% CI: 0.59–0.84) and all-cause death (HR = 0.66, 95% CI: 0.60–0.72), but there was no significant difference in the risk of recurrent GIB (HR = 1.22, 95% CI: 0.94–1.59). Compared with vitamin K antagonists, non-vitamin K antagonist oral anticoagulants (NOACs) were associated with reduced risks of stroke or systemic embolism (HR = 0.61, 95% CI: 0.54–0.68), all-cause mortality (HR = 0.86, 95% CI: 0.75–0.99), major bleeding (HR = 0.75, 95% CI: 0.66–0.84), and GIB recurrence (HR = 0.83, 95% CI: 0.72–0.96).

Conclusions

In AF patients with prior GIB, OAC therapy (especially NOACs) demonstrated superior effectiveness compared with no anticoagulant therapy.
Non-vitamin K antagonist oral anticoagulants versus warfarin in atrial fibrillation patients with heart failure and preserved, mildly reduced, and reduced ejection fraction: A systemic review and meta-analysis
Authors: Wulamiding Kaisaier , Xu Zixuan , Chen Yili , He Jiangui , Wu Zexuan
Published: July 2022

Background

Patient prevalence of atrial fibrillation (AF) and heart failure (HF) is increasing, and anticoagulation for patients from heterogeneous backgrounds with both conditions remains controversial. In this meta-analysis, we are aiming to compare the effectiveness and safety of the non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin in AF patients with HF and preserved (HFpEF), mildly reduced (HFmrEF), and reduced (HFrEF) ejection fraction.

Methods and results

We systematically searched the PubMed, Cochrane, and Embase databases until January 2022. The primary effectiveness and safety outcomes were stroke or systemic embolism (SSE) and major bleeding, respectively. We abstracted risk ratios (RR) and 95% confidence intervals (CIs) and compiled them using a random-effects model. We analyzed data of 266,291 patients from 10 studies. By comparing NOACs with warfarin, patients with AF and HF have reduced the risk of SSE (RR: 0.83, 95% CI 0.76–0.91), all-cause mortality (RR: 0.85, 95% CI 0.80–0.91), major bleeding (RR: 0.79, 95% CI 0.69–0.90), and intracranial hemorrhage (RR: 0.54, 95% CI 0.46–0.63). Further analyses based on the HF subtypes showed that NOACs reduced the chances of SSE (RR: 0.71, 95% CI 0.53–0.94) in the HFrEF group and major bleeding (RR: 0.74, 95% CI 0.57–0.95) in HFmrEF and HFpEF groups. There were no differences regarding SSE (RR: 0.91, 95% CI 0.76–1.09) in HFmrEF and HFpEF groups and major bleeding (RR: 0.99, 95% CI 0.79–1.23) in the HFrEF group.

Conclusion

For patients with AF and HF, NOACs have better or similar effectiveness and safety than warfarin, but the stroke prevention superiority of NOACs over warfarin varies in different HF subtypes.
Deploying machine learning with messy, real world data in low- and middle-income countries: Developing a global health use case
Authors: Finnegan Amy , Potenziani David D. , Karutu Caroline , Wanyana Irene , Matsiko Nicholas , Elahi Cyrus , Mijumbi Nobert , Stanley Richard , Vota Wayan
Published: July 2022

The rapid emergence of machine learning in the form of large-scale computational statistics and accumulation of data offers global health implementing partners an opportunity to adopt, adapt, and apply these techniques and technologies to low- and middle-income country (LMIC) contexts where we work. These benefits reside just out of the reach of many implementing partners because they lack the experience and specific skills to use them. Yet the growth of available analytical systems and exponential growth of data require the global digital health community to become conversant in this technology to continue to make contributions to help fulfill our missions. In this community case study, we describe the approach we took at IntraHealth International to inform the use case for machine learning in global health and development. We found that the data needed to take advantage of machine learning were plentiful and that an international, interdisciplinary team can be formed to collect, clean, and analyze the data at hand using cloud-based (e.g., Dropbox, Google Drive) and open source tools (e.g., R). We organized our work as a “sprint” lasting roughly 10 weeks in length so that we could rapidly prototype these approaches in order to achieve institutional buy in. Our initial sprint resulted in two requests in subsequent workplans for analytics using the data we compiled and directly impacted program implementation.
The different structure-function correlation as measured by OCT and octopus perimetry cluster analysis in intracranial tumor and glaucoma patients
Authors: Li Xiaochun , Qin Jiayin , Cao Xiaoguang , Ren Zeqin , Cui Ting , Bao Yongzhen
Published: July 2022

Background

To explore the correlation between visual field (VF) defect values and retinal nerve fiber layer (RNFL) thickness for intracranial tumor and glaucoma patients.

Methods

Retrospective analysis is performed for the intracranial and glaucoma patients, whose VF defect values were measured with Octopus perimeter cluster analysis, RNFL thickness, ganglion cell layer (GCL) thickness, and optic disk parameters measured with swept-source OCT. The differences between VF and RNFL (including the data of optic disc) are calculated. The correlation between VF defect values and RNFL and GCL thickness are explored.

Results

In total 43 eyes of 29 patients with intracranial tumor and 31 eyes of 19 patients with glaucoma were enrolled. The thickness of RNFL not only for the whole (360°), but also for the four quadrants was thinner in the glaucoma group than those of the intracranial tumor group (p<0.05), and similar to the thickness of GCL without significance (p>). There is no significant difference in VF for those two groups except glaucoma having lower sLV (p<0.05). A stronger correlation for mean deviations (MD)s of VF ten clusters and RNFL thickness of OCT twelve sectors is found in the glaucoma patients, but few in the intracranial tumor patients. Logistic regression also shows the loss of RNFL or increasing of vertical CDR and cup volume tending to the diagnosis of glaucoma and the irregular VF damage is inclined to the diagnosis of intracranial tumor.

Conclusions

Intracranial tumor has a weak correlation between the RNFL thickness and Octopus VF MD, compared with that of glaucoma. OCT and Octopus VF might provide more helpful information for the differential diagnosis of intracranial tumor and glaucoma.
Safety and efficacy of ultrasound-guided thermal ablation in treating T1aN0M0 and T1bN0M0 papillary thyroid carcinoma: A meta-analysis
Authors: Wang Mei-Huan , Liu Xiao , Wang Qian , Zhang Hua-Wei
Published: July 2022

Background

Papillary thyroid cancer (PTC) is the most common thyroid tumor, and early diagnosis and treatment can effectively improve prognosis. Many controversies surround the treatment method of T1N0M0 PTC. Recently, thermal ablation (TA) has shown some benefits in the treatment of PTC patients, but the safety and efficacy of its treatment remain controversial. This article performs a meta-analysis of TA in patients with T1aN0M0 and T1bN0M0 PTC.

Methods

The PubMed, Embase, Web of Science, and Cochrane Library databases were systematically searched for retrospective or prospective studies of TA for treating patients with T1N0M0 PTC from the database establishment to May 1, 2022. Data on volume reduction rate (VRR), disease progress, and complication rate were collected. In addition, a meta-analysis was performed using the Stata 12.0 and Review Manager 5.3.

Results

A total of 9 eligible studies were included. Our study demonstrated the effectiveness of VRR and disease progress. The VRR was reduced after 3 months (−75.90%; 95% CI [−118.46–33.34%]), 6 months (34.33%; 95% CI [15.01–53.65%]), 12 months (78.69%; 95% CI [71.69–85.68%]), and 24 months (89.97%; 95% CI [84.00–95.94%]). The disease progress was 1.9% (95% CI [1.1–3.0]). Safety is justified by the complication rate, which was 6.5% (95% CI [3.5–10.2]). Pain and hoarseness were the most common complications, and no life-threatening complications were reported. Egger’s test demonstrated that publication bias was acceptable.

Conclusions

TA is an effective and safe method for managing T1aN0M0 and T1bN0M0 papillary thyroid nodules.
The Properties and Functions of Glial Cell Types of the Hypothalamic Median Eminence
Authors: Clayton Richard W. , Lovell-Badge Robin , Galichet Christophe
Published: July 2022

The median eminence (ME) is part of the neuroendocrine system (NES) that functions as a crucial interface between the hypothalamus and pituitary gland. The ME contains many non-neuronal cell types, including oligodendrocytes, oligodendrocyte precursor cells (OPCs), tanycytes, astrocytes, pericytes, microglia and other immune cells, which may be involved in the regulation of NES function. For example, in mice, ablation of tanycytes (a special class of ependymal glia with stem cell-like functions) results in weight gain, feeding, insulin insensitivity and increased visceral adipose, consistent with the demonstrated ability of these cells to sense and transport both glucose and leptin, and to differentiate into neurons that control feeding and metabolism in the hypothalamus. To give a further example, OPCs in the ME of mice have been shown to rapidly respond to dietary signals, in turn controlling composition of the extracellular matrix in the ME, derived from oligodendrocyte-lineage cells, which may contribute to the previously described role of these cells in actively maintaining leptin-receptor-expressing dendrites in the ME. In this review, we explore and discuss recent advances such as these, that have developed our understanding of how the various cell types of the ME contribute to its function in the NES as the interface between the hypothalamus and pituitary gland. We also highlight avenues of future research which promise to uncover additional functions of the ME and the glia, stem and progenitor cells it contains.
Wild Panax plants adapt to their thermal environment by harboring abundant beneficial seed endophytic bacteria
Authors: Liu Dong , Lin Liang , Zhang Tie , Xu Qian , Wang Mulan , Gao Minghai , Bhople Parag , Pritchard Hugh W. , Yang Xiangyun , Yu Fuqiang
Published: July 2022

The seed microbiome of crop wild relatives is a potential reservoir of beneficial traits that potentially improve their host plant resilience to fluctuating environments and pathogenic threats. Herein, we studied the seed microbiome of three species of the medicinal genus Panax (P. vietnamensis, P. japonicas, and P. stipuleanatus) collected from seven locations in Southwest China. We used qPCR and metabarcoding high-throughput sequencing to target both endophytic bacteria and fungi. Seed bacterial absolute abundance (1.1 × 109∼1.0 × 107 gene copy numbers per gram seed) was substantially higher than that of fungi (7.6 × 105∼3.7 × 102). Host plant genotype was the main driver of seed microbiome composition for both bacteria and fungi. Panax growing hypothermal environments significantly shaped their seed endophytic bacterial but not fungal microbiota. The three Panax species’ seeds harbored unique microbes [averaged ∼150 amplicon sequence variants (ASVs)], sharing only 12 bacterial ASVs (half affiliated to Halomonas) and four fungal ASVs. Network analysis showed that the Panax seed endophytic bacteria tend to form inter-weaved functional modules that are majorly connected by core members from the genus Halomonas, Pseudomonas, and Pantoea. These genera have been associated with nutrient cycling, plant, disease suppression, and tolerance to environmental fluctuation. Together, these novel insights may shade light on the ecological strategies of wild Panax plants adaptation to their thermal environment by possessing abundant beneficial seed endophytic bacteria.
A Simple-to-Perform ifn-γ mRNA Gene Expression Assay on Whole Blood Accurately Appraises Varicella Zoster Virus-Specific Cell-Mediated Immunity After Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Boccard Mathilde , Conrad Anne , Mouton William , Valour Florent , Roure-Sobas Chantal , Frobert Emilie , Rohmer Barbara , Alcazer Vincent , Labussière-Wallet Hélène , Ghesquières Hervé , Venet Fabienne , Brengel-Pesce Karen , Trouillet-Assant Sophie , Ader Florence
Published: July 2022

Herpes zoster, which is due to the reactivation of Varicella zoster virus (VZV), is a leading cause of morbidity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). While cell-mediated immunity (CMI) is critical to inhibiting VZV reactivation, CMI is not routinely assessed due to a lack of reliable tests. In this study, we aimed to evaluate VZV-specific CMI among allo-HSCT recipients (n = 60) and healthy individuals (HI, n = 17) through a panel of three immune functional assays after ex vivo stimulation by VZV antigen: quantification of (i) IFN-γ release in the supernatants, (ii) T-cell proliferation after a 7-day stimulation of peripheral blood mononuclear cells (PBMC), and (iii) measurement of the ifn-γ mRNA gene expression level after 24 h of stimulation of a whole-blood sample. VZV responsiveness was defined according to IFN-γ release from VZV-stimulated PBMC. Upon VZV stimulation, we found that allo-HSCT recipients at a median time of 6 [5-8] months post-transplant had lower IFN-γ release (median [IQR], 0.34 [0.12–8.56] vs. 409.5 [143.9–910.2] pg/ml, P <.0001) and fewer proliferating T cells (0.05 [0.01–0.57] % vs. 8.74 [3.12–15.05] %, P <.0001) than HI. A subset of allo-HSCT recipients (VZV-responders, n = 15/57, 26%) distinguished themselves from VZV-non-responders (n = 42/57, 74%; missing data, n = 3) by higher IFN-γ release (80.45 [54.3–312.8] vs. 0.22 [0.12–0.42] pg/ml, P <.0001) and T-cell proliferation (2.22 [1.18–7.56] % vs. 0.002 [0.001–0.11] %, P <.0001), suggesting recovery of VZV-specific CMI. Interestingly, VZV responders had a significant fold increase in ifn-γ gene expression, whereas ifn-γ mRNA was not detected in whole blood of VZV-non-responders (P <.0001). This study is the first to suggest that measurement of ifn-γ gene expression in 24-h-stimulated whole blood could be an accurate test of VZV-specific CMI. The routine use of this immune functional assay to guide antiviral prophylaxis at an individual level remains to be evaluated.
Volatile organic compounds: A proinflammatory activator in autoimmune diseases
Authors: Ogbodo John Onyebuchi , Arazu Amarachukwu Vivan , Iguh Tochukwu Chisom , Onwodi Ngozichukwuka Julie , Ezike Tobechukwu Christian
Published: July 2022

The etiopathogenesis of inflammatory and autoimmune diseases, including pulmonary disease, atherosclerosis, and rheumatoid arthritis, has been linked to human exposure to volatile organic compounds (VOC) present in the environment. Chronic inflammation due to immune breakdown and malfunctioning of the immune system has been projected to play a major role in the initiation and progression of autoimmune disorders. Macrophages, major phagocytes involved in the regulation of chronic inflammation, are a major target of VOC. Excessive and prolonged activation of immune cells (T and B lymphocytes) and overexpression of the master pro-inflammatory constituents [cytokine and tumor necrosis factor-alpha, together with other mediators (interleukin-6, interleukin-1, and interferon-gamma)] have been shown to play a central role in the pathogenesis of autoimmune inflammatory responses. The function and efficiency of the immune system resulting in immunostimulation and immunosuppression are a result of exogenous and endogenous factors. An autoimmune disorder is a by-product of the overproduction of these inflammatory mediators. Additionally, an excess of these toxicants helps in promoting autoimmunity through alterations in DNA methylation in CD4 T cells. The purpose of this review is to shed light on the possible role of VOC exposure in the onset and progression of autoimmune diseases.
Proposed clinical phases for the improvement of personalized treatment of checkpoint inhibitor–related pneumonitis
Authors: Zhou Chengzhi , Yang Yilin , Lin Xinqing , Fang Nianxin , Chen Likun , Jiang Juhong , Deng Haiyi , Deng Yu , Wan Minghui , Qiu Guihuan , Sun Ni , Wu Di , Long Xiang , Zhong Changhao , Xie Xiaohong , Xie Zhanhong , Liu Ming , Ouyang Ming , Qin Yinyin , Petrella Francesco , Fiorelli Alfonso , Bravaccini Sara , Kataoka Yuki , Watanabe Satoshi , Goto Taichiro , Solli Piergiorgio , Igai Hitoshi , Saito Yuichi , Tsoukalas Nikolaos , Nakada Takeo , Li Shiyue , Chen Rongchang
Published: July 2022

Background

Checkpoint inhibitor–related pneumonitis (CIP) is a lethal immune-related adverse event. However, the development process of CIP, which may provide insight into more effective management, has not been extensively examined.

Methods

We conducted a multicenter retrospective analysis of 56 patients who developed CIP. Clinical characteristics, radiological features, histologic features, and laboratory tests were analyzed. After a comprehensive analysis, we proposed acute, subacute, and chronic phases of CIP and summarized each phase’s characteristics.

Results

There were 51 patients in the acute phase, 22 in the subacute phase, and 11 in the chronic phase. The median interval time from the beginning of CIP to the different phases was calculated (acute phase: ≤4.9 weeks; subacute phase: 4.9~13.1 weeks; and chronic phase: ≥13.1 weeks). The symptoms relieved from the acute phase to the chronic phase, and the CIP grade and Performance Status score decreased (P<0.05). The main change in radiologic features was the absorption of the lesions, and 3 (3/11) patients in the chronic phase had persistent traction bronchiectasis. For histologic features, most patients had acute fibrinous pneumonitis in the acute phase (5/8), and most had organizing pneumonia in the subacute phase (5/6). Other histologic changes advanced over time, with the lesions entering a state of fibrosis. Moreover, the levels of interleukin-6, interleukin-10 and high-sensitivity C-reactive protein (hsCRP) increased in the acute phase and decreased as CIP progressed (IL-6: 17.9 vs. 9.8 vs. 5.7, P=0.018; IL-10: 4.6 vs 3.0 vs. 2.0, P=0.041; hsCRP: 88.2 vs. 19.4 vs. 14.4, P=0.005).

Conclusions

The general development process of CIP can be divided into acute, subacute, and chronic phases, upon which a better management strategy might be based devised.
Snowflake: A deep learning-based human leukocyte antigen matching algorithm considering allele-specific surface accessibility
Authors: Niemann Matthias , Matern Benedict M. , Spierings Eric
Published: July 2022

Histocompatibility in solid-organ transplantation has a strong impact on long-term graft survival. Although recent advances in matching of both B-cell epitopes and T-cell epitopes have improved understanding of allorecognition, the immunogenic determinants are still not fully understood. We hypothesized that HLA solvent accessibility is allele-specific, thus supporting refinement of HLA B-cell epitope prediction. We developed a computational pipeline named Snowflake to calculate solvent accessibility of HLA Class I proteins for deposited HLA crystal structures, supplemented by constructed HLA structures through the AlphaFold protein folding predictor and peptide binding predictions of the APE-Gen docking framework. This dataset trained a four-layer long short-term memory bidirectional recurrent neural network, which in turn inferred solvent accessibility of all known HLA Class I proteins. We extracted 676 HLA Class-I experimental structures from the Protein Data Bank and supplemented it by 37 Class-I alleles for which structures were predicted. For each of the predicted structures, 10 known binding peptides as reported by the Immune Epitope DataBase were rendered into the binding groove. Although HLA Class I proteins predominantly are folded similarly, we found higher variation in root mean square difference of solvent accessibility between experimental structures of different HLAs compared to structures with identical amino acid sequence, suggesting HLA’s solvent accessible surface is protein specific. Hence, residues may be surface-accessible on e.g. HLA-A*02:01, but not on HLA-A*01:01. Mapping these data to antibody-verified epitopes as defined by the HLA Epitope Registry reveals patterns of (1) consistently accessible residues, (2) only subsets of an epitope’s residues being consistently accessible and (3) varying surface accessibility of residues of epitopes. Our data suggest B-cell epitope definitions can be refined by considering allele-specific solvent-accessibility, rather than aggregating HLA protein surface maps by HLA class or locus. To support studies on epitope analyses in organ transplantation, the calculation of donor-allele-specific solvent-accessible amino acid mismatches was implemented as a cloud-based web service.
Identification and characterization of four immune-related signatures in keloid
Authors: Wang Xiaoxiang , Liang Bo , Li Jiehua , Pi Xiaobing , Zhang Peng , Zhou Xinzhu , Chen Xiaodong , Zhou Sitong , Yang Ronghua
Published: July 2022

A keloid is a fibroproliferative disorder of unknown etiopathogenesis that requires ill-defined treatment. Existing evidence indicates that the immune system plays an important role in the occurrence and development of keloid. However, there is still a lack of research on the immune-related signatures of keloid. Here we identified immune-related signatures in keloid and explored their pathological mechanisms. Transcriptomic datasets (GSE7890, GSE92566, and GSE44270) of keloid and normal skin tissues were obtained from the Gene Expression Omnibus database. The overlap of differentially expressed genes and immune-related genes was considered as differentially expressed immune-related genes (DEIGs). Functional analysis, expression, and distribution were applied to explore the function and characteristics of DEIGs, and the expression of these DEIGs in keloid and normal skin tissues was verified by immunohistochemistry. Finally, we conducted interactive network analysis and immune infiltration analysis to determine the therapeutic potential and immune correlation. We identified four DEIGs (LGR5, PTN, JAG1, and DKK1). In these datasets, only GSE7890 met the screening criteria. In the GSE7890 dataset, DKK1 and PTN were downregulated in keloid, whereas JAG1 and LGR5 were upregulated in keloid. In addition, we obtained the same conclusion through immunohistochemistry. Functional analysis indicated that these four DEIGs were mainly involved in stem cell, cell cycle, UV response, and therapy resistance. Through interactive network analysis, we found that these DEIGs were associated with drugs currently used to treat keloid, such as hydrocortisone, androstanolone, irinotecan, oxaliplatin, BHQ-880, and lecoleucovorin. Finally, many immune cells, including CD8+ T cells, resting memory CD4+ T cells, and M1 macrophages, were obtained by immune infiltration analysis. In conclusion, we identified four immune signaling molecules associated with keloid (LGR5, PTN, JAG1, and DKK1). These immune-related signaling molecules may be important modules in the pathogenesis of keloid. Additionally, we developed novel therapeutic targets for the treatment of this challenging disease.
Atopic dermatitis: Is innate or adaptive immunity in control? A clinical perspective
Authors: Ong Peck Y.
Published: July 2022

Atopic dermatitis (AD) is a chronic inflammatory skin disease with barrier defects and immune dysregulations. The pathogenesis of AD involves the physical barrier as well as epithelial cells, which are considered a vital part of the innate immunity of the skin. The importance of filaggrin mutations in the pathogenesis of AD has also been well-established with reproducible results around the world in multiple studies and ethnic groups. This protein plays an important role in skin barrier functions and further reaffirms barrier defects as one of the primary causes of AD. The main epithelial cells, keratinocytes, function as a major sentinel for the skin in detecting danger signals or microbial pathogens, and trigger downstream immune responses. In AD, these cells express TSLP, IL-33 and IL-25, which lead to downstream systemic production of type 2 cytokines. In spite of major advances in our understanding of the innate immunity of AD, recent success in the systemic therapeutics of AD have focused on targeting the products of the adaptive immunity, particularly cytokines produced by T cells. In addition to type 2 cytokines, type 17 cytokines have also been implicated in the pathogenesis of AD. The current review examines the implications of these cytokines in AD from clinical perspectives.
Monoclonal antibodies targeting the influenza virus N6 neuraminidase
Authors: Strohmeier Shirin , Amanat Fatima , Carreño Juan Manuel , Krammer Florian
Published: July 2022

Influenza A viruses are a diverse species that include 16 true hemagglutinin (HA) subtypes and 9 true neuraminidase (NA) subtypes. While the antigenicity of many HA subtypes is reasonably well studied, less is known about NA antigenicity, especially when it comes to non-human subtypes that only circulate in animal reservoirs. The N6 subtype NAs are mostly found in viruses infecting birds. However, they have also been identified in viruses that infect mammals, such as swine and seals. More recently, highly pathogenic H5N6 subtype viruses have caused rare infections and mortality in humans. Here, we generated murine mAbs to the N6 NA, characterized their breadth and antiviral properties in vitro and in vivo and mapped their epitopes by generating escape mutant viruses. We found that the antibodies had broad reactivity across the American and Eurasian N6 lineages, but relatively little binding to the H5N6 NA. Several of the antibodies exhibited strong NA inhibition activity and some also showed activity in the antibody dependent cellular cytotoxicity reporter assay and neutralization assay. In addition, we generated escape mutant viruses for six monoclonal antibodies and found mutations on the lateral ridge of the NA. Lastly, we observed variable protection in H4N6 mouse challenge models when the antibodies were given prophylactically.
Balancing B cell responses to the allograft: implications for vaccination
Authors: Crane Clarkson , Loop Lauren , Anterasian Christine , Geng Bob , Ingulli Elizabeth
Published: July 2022

Balancing enough immunosuppression to prevent allograft rejection and yet maintaining an intact immune system to respond to vaccinations, eliminate invading pathogens or cancer cells is an ongoing challenge to transplant physicians. Antibody mediated allograft rejection remains problematic in kidney transplantation and is the most common cause of graft loss despite current immunosuppressive therapies. The goal of immunosuppressive therapies is to prevent graft rejection; however, they prevent optimal vaccine responses as well. At the center of acute and chronic antibody mediated rejection and vaccine responses is the B lymphocyte. This review will highlight the role of B cells in alloimmune responses including the dependency on T cells for antibody production. We will discuss the need to improve vaccination rates in transplant recipients and present data on B cell populations and SARS-CoV-2 vaccine response rates in pediatric kidney transplant recipients.
IFNAR2 relevance in the clinical outcome of individuals with severe COVID-19
Authors: Fricke-Galindo Ingrid , Martínez-Morales Alfonso , Chávez-Galán Leslie , Ocaña-Guzmán Ranferi , Buendía-Roldán Ivette , Pérez-Rubio Gloria , Hernández-Zenteno Rafael de Jesus , Verónica-Aguilar Abigail , Alarcón-Dionet Aimé , Aguilar-Duran Hiram , Gutiérrez-Pérez Ilse Adriana , Zaragoza-García Oscar , Alanis-Ponce Jesús , Camarena Angel , Bautista-Becerril Brandon , Nava-Quiroz Karol J. , Mejía Mayra , Guzmán-Guzmán Iris Paola , Falfán-Valencia Ramcés
Published: July 2022

Interferons (IFNs) are a group of cytokines with antiviral, antiproliferative, antiangiogenic, and immunomodulatory activities. Type I IFNs amplify and propagate the antiviral response by interacting with their receptors, IFNAR1 and IFNAR2. In COVID-19, the IFNAR2 (interferon alpha and beta receptor subunit 2) gene has been associated with the severity of the disease, but the soluble receptor (sIFNAR2) levels have not been investigated. We aimed to evaluate the association of IFNAR2 variants (rs2236757, rs1051393, rs3153, rs2834158, and rs2229207) with COVID-19 mortality and to assess if there was a relation between the genetic variants and/or the clinical outcome, with the levels of sIFNAR2 in plasma samples from hospitalized individuals with severe COVID-19. We included 1,202 subjects with severe COVID-19. The genetic variants were determined by employing Taqman® assays. The levels of sIFNAR2 were determined with ELISA in plasma samples from a subgroup of 351 individuals. The rs2236757, rs3153, rs1051393, and rs2834158 variants were associated with mortality risk among patients with severe COVID-19. Higher levels of sIFNAR2 were observed in survivors of COVID-19 compared to the group of non-survivors, which was not related to the studied IFNAR2 genetic variants. IFNAR2, both gene, and soluble protein, are relevant in the clinical outcome of patients hospitalized with severe COVID-19.
Interleukin 6-regulated macrophage polarization controls atherosclerosis-associated vascular intimal hyperplasia
Authors: Chen Jiaquan , Wang Weilun , Ni Qihong , Zhang Lan , Guo Xiangjiang
Published: July 2022

Vascular intimal hyperplasia (VIH) is an important stage of atherosclerosis (AS), in which macrophages not only play a critical role in local inflammation, but also transform into foam cells to participate into plaque formation, where they appear to be heterogeneous. Recently, it was shown that CD11c+ macrophages were more associated with active plaque progression. However, the molecular regulation of phenotypic changes of plaque macrophages during VIH has not been clarified and thus addressed in the current study. Since CD11c- cells were M2a-polarized anti-inflammatory macrophages, while CD11c+ cells were M1/M2b-polarized pro-inflammatory macrophages, we used bioinformatics tools to analyze the CD11c+ versus CD11c- plaque macrophages, aiming to detect the differential genes associated with M1/M2 macrophage polarization. We obtained 122 differential genes that were significantly altered in CD11c+ versus CD11c- plaque macrophages, regardless of CD11b expression. Next, hub genes were predicted in these 122 genes, from which we detected 3 candidates, interleukin 6 (Il6), Decorin (Dcn) and Tissue inhibitor matrix metalloproteinase 1 (Timp1). The effects of these 3 genes on CD11c expression as well as on the macrophage polarization were assessed in vitro, showing that only expression of Il6, but not expression of Dcn or Timp1, induced M1/M2b-like polarization in M2a macrophages. Moreover, only suppression of Il6, but not suppression of either of Dcn or Timp1, induced M2a-like polarization in M1/M2b macrophages. Furthermore, pharmaceutical suppression of Il6 attenuated VIH formation and progression of AS in a mouse model that co-applied apolipoprotein E-knockout and high-fat diet. Together, our data suggest that formation of VIH can be controlled through modulating macrophage polarization, as a promising therapeutic approach for prevent AS.
CD8+ T cell trajectory subtypes decode tumor heterogeneity and provide treatment recommendations for hepatocellular carcinoma
Authors: Liu Long , Liu Zaoqu , Gao Jie , Liu Xudong , Weng Siyuan , Guo Chunguang , Hu Bowen , Wang Zhihui , Zhang Jiakai , Shi Jihua , Guo Wenzhi , Zhang Shuijun
Published: July 2022

Introduction

Mounting evidence has revealed that the interactions and dynamic alterations among immune cells are critical in shaping the tumor microenvironment and ultimately map onto heterogeneous clinical outcomes. Currently, the underlying clinical significance of immune cell evolutions remains largely unexplored in hepatocellular carcinoma (HCC).

Methods

A total of 3,817 immune cells and 1,750 HCC patients of 15 independent public datasets were retrieved. The Seurat and Monocle algorithms were used to depict T cell evolution, and nonnegative matrix factorization (NMF) was further applied to identify the molecular classification. Subsequently, the prognosis, biological characteristics, genomic variations, and immune landscape among distinct clusters were decoded. The clinical efficacy of multiple treatment approaches was further investigated.

Results

According to trajectory gene expression, three heterogeneous clusters with different clinical outcomes were identified. C2, with a more advanced pathological stage, presented the most dismal prognosis relative to C1 and C3. Eight independent external cohorts validated the robustness and reproducibility of the three clusters. Further explorations elucidated C1 to be characterized as lipid metabolic HCC, and C2 was referred to as cell-proliferative HCC, whereas C3 was defined as immune inflammatory HCC. Moreover, C2 also displayed the most conspicuous genomic instability, and C3 was deemed as “immune-hot”, having abundant immune cells and an elevated expression of immune checkpoints. The assessments of therapeutic intervention suggested that patients in C1 were suitable for transcatheter arterial chemoembolization treatment, and patients in C2 were sensitive to tyrosine kinase inhibitors, while patients in C3 were more responsive to immunotherapy. We also identified numerous underlying therapeutic agents, which might be conducive to clinical transformation in the future.

Conclusions

Our study developed three clusters with distinct characteristics based on immune cell evolutions. For specifically stratified patients, we proposed individualized treatment strategies to improve the clinical outcomes and facilitate the clinical management.
Serial negative response after standard and third (Booster) dose of COVID-19 inactivated vaccine is associated with low vitamin D levels in patients with solid cancers
Authors: Ma Yifei , Zhu Pengfei , Zhong Guanqing , Wang Dao , Cao Lu , Bai Shenrui , Wang Youlong , Zhang Ao , Wang Xinjia
Published: July 2022

Introduction

The response is poorly understood to the third dose in patients with cancer who failed the standard dose of inactivated SARS-CoV-2 vaccines (CoronaVac). We aim to assess the immune response to the third dose and identify whether vitamin D deficiency is associated with serial serologic failure in patients with cancer.

Methods

Solid cancer patients (SCP-N) and healthy controls (HCs) who were seronegative after the standard-dose vaccines in our previous study were prospectively recruited, from October 2021 to February 2022, to receive the third dose vaccines and anti-SARS-CoV-2S antibodies were measured. SCP-N who failed the third dose (serial seronegative group, SSG) were matched by propensity scores with the historical standard-dose positive cancer patient group (robust response group, RRG). An exploratory analysis was carried out to validate the role of vitamin D on the serology response.

Results

The multi-center study recruited 97 SCP-N with 279 positive controls as RRG and 82 negative controls as HC group. The seroconversion rate after third-dose vaccination was higher in SCP-N than in HC (70.6% vs. 29.4%, p < 0.01). The matched comparison showed that patients in SSG had a significantly lower level of vitamin D and consumption rate than RRG or RRG-B (RRG with third-dose positive) (all p < 0.01). None had serious (over grade II) adverse events after the third dose.

Conclusion

Solid cancer patients with second-dose vaccine failure may have a relatively poor humoral response to the third dose of COVID-19 vaccines as compared with the seronegative HC group. The consecutively poor humoral response could be associated with poor vitamin D levels and intake. Vitamin D status and cancer-related immune compromise may jointly affect the humoral response following booster vaccination.
Androgen receptor signaling and spatial chromatin organization in castration-resistant prostate cancer
Authors: Zhou Tianyi , Feng Qin
Published: July 2022

Prostate cancer is one of the leading causes of cancer death and affects millions of men in the world. The American Cancer Society estimated about 34,500 deaths from prostate cancer in the United States in year 2022. The Androgen receptor (AR) signaling is a major pathway that sustains local and metastatic prostate tumor growth. Androgen-deprivation therapy (ADT) is the standard of care for metastatic prostate cancer patient and can suppress the tumor growth for a median of 2–3 years. Unfortunately, the malignancy inevitably progresses to castration-resistant prostate cancer (CRPC) which is more aggressive and no longer responsive to ADT. Surprisingly, for most of the CPRC patients, cancer growth still depends on androgen receptor signaling. Accumulating evidence suggests that CRPC cells have rewired their transcriptional program to retain AR signaling in the absence of androgens. Besides AR, other transcription factors also contribute to the resistance mechanism through multiple pathways including enhancing AR signaling pathway and activating other complementary signaling pathways for the favor of AR downstream genes expression. More recent studies have shown the role of transcription factors in reconfiguring chromatin 3D structure and regulating topologically associating domains (TADs). Pioneer factors, transcription factors and coactivators form liquid-liquid phase separation compartment that can modulate transcriptional events along with configuring TADs. The role of AR and other transcription factors on chromatin structure change and formation of condensate compartment in prostate cancer cells has only been recently investigated and appreciated. This review intends to provide an overview of transcription factors that contribute to AR signaling through activation of gene expression, governing 3D chromatin structure and establishing phase to phase separation. A more detailed understanding of the spatial role of transcription factors in CRPC might provide novel therapeutic targets for the treatment of CRPC.