bluuebunny/crossref_metadata_2025 huggingface dataset:
Alveolar macrophages and airway hyperresponsiveness associated with respiratory syncytial virus infection
Authors: Wang Yuxin , Zheng Junwen , Wang Xia , Yang Pu , Zhao Dongchi
Published: October 2022

Respiratory syncytial virus (RSV) is a ubiquitous pathogen of viral bronchiolitis and pneumonia in children younger than 2 years of age, which is closely associated with recurrent wheezing and airway hyperresponsiveness (AHR). Alveolar macrophages (AMs) located on the surface of the alveoli cavity are the important innate immune barrier in the respiratory tract. AMs are recognized as recruited airspace macrophages (RecAMs) and resident airspace macrophages (RAMs) based on their origins and roaming traits. AMs are polarized in the case of RSV infection, forming two macrophage phenotypes termed as M1-like and M2-like macrophages. Both M1 macrophages and M2 macrophages are involved in the modulation of inflammatory responses, among which M1 macrophages are capable of pro-inflammatory responses and M2 macrophages are capable of anti-proinflammatory responses and repair damaged tissues in the acute and convalescent phases of RSV infection. Polarized AMs affect disease progression through the alteration of immune cell surface phenotypes as well as participate in the regulation of T lymphocyte differentiation and the type of inflammatory response, which are closely associated with long-term AHR. In recent years, some progress have been made in the regulatory mechanism of AM polarization caused by RSV infection, which participates in acute respiratory inflammatory response and mediating AHR in infants. Here we summarized the role of RSV-infection-mediated AM polarization associated with AHR in infants.
Immunotherapeutic progress and application of bispecific antibody in cancer
Authors: Kang Jingyue , Sun Tonglin , Zhang Yan
Published: October 2022

Bispecific antibodies (bsAbs) are artificial antibodies with two distinct antigen-binding sites that can bind to different antigens or different epitopes on the same antigen. Based on a variety of technology platforms currently developed, bsAbs can exhibit different formats and mechanisms of action. The upgrading of antibody technology has promoted the development of bsAbs, which has been effectively used in the treatment of tumors. So far, 7 bsAbs have been approved for marketing in the world, and more than 200 bsAbs are in clinical and preclinical research stages. Here, we summarize the development process of bsAbs, application in tumor treatment and look forward to the challenges in future development.
Comprehensive characterization of TNFSF14/LIGHT with implications in prognosis and immunotherapy of human gliomas
Authors: Han Mingzhi , Sun Yanfei , Zhao Wenbo , Xiang Guo , Wang Xu , Jiang Zheng , Xue Zhiwei , Zhou Wei
Published: October 2022

Glioblastoma multiforme (GBM) is a common central neural system malignant tumor among adults. Alongside its microscopic spread, immunosuppression in the tumor microenvironment also induces its refractoriness, which makes immunotherapy for GBM particularly important. Unfortunately, traditional immune checkpoint inhibitors (ICIs) often show limited therapeutic effects in GBM clinical trials, and new therapeutic strategies or targets are urgently needed. TNFSF14/LIGHT is a novel immune checkpoint molecule that plays essential roles in both innate and acquired immunity. Despite recent advances in our understanding of the function of TNFSF14/LIGHT in a variety of cancer types, the clinical and immunological importance of TNFSF14/LIGHT in human gliomas has not been fully explained. Here, we employed a comprehensive in silico analysis with publicly available data to analyze the molecular and immune characteristics of TNFSF14/LIGHT to explore its feasibility as an immunotherapy target. Totally, 2215 glioma cases were enrolled in the current study. Immunohistochemistry staining based on patient tissues (n = 34) was performed for the validation. TNFSF14/LIGHT was expressed higher in higher-WHO-grade gliomas and mesenchymal subtypes, and it was sensitive as a prognostic marker in GBM and low-grade glioma (LGG). A nomogram prognostic model was established based on TNFSF14/LIGHT expression together with other risk factors. Additionally, Gene Ontology and pathway analysis revealed that TNFSF14/LIGHT participated in T-cell activities and inflammatory processes. Moreover, analysis based on the structure and interactions of TNFSF14/LIGHT revealed its mutation sites in tumors as well as crucial interacting proteins. Analysis of IMvigor210 indicated the role of TNFSF14/LIGHT in immunotherapy. Altogether, our results reveal an underlying role of TNFSF14/LIGHT as an immunotherapy target in GBM.
Downregulation of the vitamin D receptor expression during acute gastrointestinal graft versus host disease is associated with poor outcome after allogeneic stem cell transplantation
Authors: Matos Carina , Mamilos Andreas , Shah Pranali N. , Meedt Elisabeth , Weber Daniela , Ghimire Saroj , Hiergeist Andreas , Gessner André , Dickinson Anne , Dressel Ralf , Walter Lutz , Stark Klaus , Heid Iris M. , Poeck Hendrik , Edinger Matthias , Wolff Daniel , Herr Wolfgang , Holler Ernst , Kreutz Marina , Ghimire Sakhila
Published: October 2022

The vitamin D receptor (VDR) is critical in regulating intestinal homeostasis and emerging evidence demonstrates that VDR deficiency is a critical factor in inflammatory bowel disease pathology. However, no clinical data exist regarding the intestinal expression of VDR in patients after allogeneic haematopoietic stem cell transplantation (HSCT). Analyzing intestinal biopsies from 90 patients undergoing HSCT with mortality follow-up, we demonstrated that patients with severe acute gastrointestinal graft versus host disease (GI-GvHD) showed significant downregulation of VDR gene expression compared to mild or no acute GI-GvHD patients (p = 0.007). Reduced VDR expression was already detectable at acute GI-GvHD onset compared to GvHD-free patients (p = 0.01). These results were confirmed by immunohistochemistry (IHC) where patients with severe acute GI-GvHD showed fewer VDR+ cells (p = 0.03) and a reduced VDR staining score (p = 0.02) as compared to mild or no acute GI-GvHD patients. Accordingly, low VDR gene expression was associated with a higher cumulative incidence of treatment-related mortality (TRM) (p = 1.6x10-6) but not with relapse-related mortality (RRM). A multivariate Cox regression analysis identified low VDR as an independent risk factor for TRM (p = 0.001, hazard ratio 4.14, 95% CI 1.78-9.63). Furthermore, VDR gene expression significantly correlated with anti-microbial peptides (AMPs) gene expression (DEFA5: r = 0.637, p = 7x10-5, DEFA6: r 0 0.546, p = 0.001). In conclusion, our findings suggest an essential role of the VDR in the pathogenesis of gut GvHD and the prognosis of patients undergoing HSCT.
Managing the TME to improve the efficacy of cancer therapy
Authors: Bilotta Maria Teresa , Antignani Antonella , Fitzgerald David J.
Published: October 2022

The tumor microenvironment (TME) influences tumor growth, metastatic spread and response to treatment. Often immunosuppression, mediated by the TME, impairs a beneficial response. The complexity of the tumor composition challenges our abilities to design new and more effective therapies. Going forward we will need to ‘manage’ the content and or functionality of the TME to improve treatment outcomes. Currently, several different kinds of treatments are available to patients with cancer: there are the traditional approaches of chemotherapy, radiation and surgery; there are targeted agents that inhibit kinases associated with oncogenic pathways; there are monoclonal antibodies that target surface antigens often delivering toxic payloads or cells and finally there are antibodies and biologics that seek to overcome the immunosuppression caused by elements within the TME. How each of these therapies interact with the TME is currently under intense and widespread investigation. In this review we describe how the TME and its immunosuppressive components can influence both tumor progression and response to treatment focusing on three particular tumor types, classic Hodgkin Lymphoma (cHL), Pancreatic Ductal Adenocarcinoma (PDAC) and Glioblastoma Multiforme (GBM). And, finally, we offer five approaches to manipulate or manage the TME to improve outcomes for cancer patients.
The immune factors have complex causal regulation effects on bone mineral density
Authors: Cao Rong-Rong , Yu Xing-Hao , Xiong Meng-Fei , Li Xue-Ting , Deng Fei-Yan , Lei Shu-Feng
Published: October 2022

Recent evidence has gradually recognized that the immune and skeletal systems are two closely correlated systems, but the specific immune factors on bone mineral density (BMD) are largely unknown. Based on the summary-level data of genome-wide association studies (GWASs), we performed a series of analyses including two-sample Mendelian randomization (MR) analysis to test potential causal links between 731 immune traits [including median fluorescence intensities (MFIs), absolute cell (AC) counts, relative cell (RC) counts, and morphological parameters (MP)] and BMD. After false discovery rate (FDR) correction, 9 MFI-BMD, 16 AC-BMD, 22 RC-BMD, and 5 MP-BMD pairs reached the level of significance (FDR-adjusted p< 0.05). For MFI traits, the T- and B-cell panels had the largest number of significant immune trait pairs than other panels. CD40, as a molecule expressed by four subsets of monocytes, was highlighted due to its consistently positive correlation with BMD at four sites. For both AC and RC traits, immune traits from the T-cell panel were also highlighted, with CD39-positive T-cell subsets being the most frequently observed feature. For MP traits, the most significant association immune trait with BMD was SSC-A on CD14+ monocyte. Sensitivity analyses suggested that the identified immune factors were robust to pleiotropy. Multivariable MR analysis confirmed the independent causal effect of several immune traits on BMD. Mediation analyses showed that CD40 on monocytes could mediate multiple immune traits, especially the suggestive associations of CD27 on several memory B cells with BMD mediated by CD40 on CD14+ CD16− monocyte. Our study represents the first comprehensive evaluation of the causal effects of immune traits on the risk of osteoporosis. The findings highlighted the complex and important role of immune-derived factors in the pathogenesis of osteoporosis.
Immunophenotyping of pulmonary sarcomatoid carcinoma
Authors: Ma Yu , Li Wensheng , Li Zhenzhen , Chen Jie , Wang Hongtao , Jiang Tao , Zhu Jianfei
Published: October 2022

Background

Previous studies have suggested that patients with pulmonary sarcomatoid carcinoma (PSC)may benefit from immune checkpoint inhibitors (ICIs); however, relevant data are lacking. This study aimed to establish the immunophenotype of PSC by assessing PD-L1 and CD8+ T-cell infiltration.

Methods

A retrospective analysis of pathologically confirmed PSC cases from two centers was performed from January 2009 to May 2021. According to the infiltration of CD8+ T cells in different spatial regions, patients were classified into three types: immune-inflamed, immune-excluded, and immune desert. PD-L1 staining was also performed on the intratumoral region and the tumor proportion score (TPS) was used for scoring. Combined with CD8+ T-cell infiltration and PD-L1 expression in the intratumoral region, immunophenotyping can be divided into four types: type I (PD-L1+/CD8+, adaptive immune resistance), type II (PD-L1-/CD8-, immunologic ignorance), type III (PD-L1+/CD8-, intrinsic induction), and type IV (PD-L1-/CD8+, tolerance). Finally, correlation analysis was performed on the immunophenotype, clinicopathological characteristics, and outcomes of the patients.

Results

A total of 32 patients with PSC were included in the final analysis. Of these patients, 65.6% (21/32), 15.6% (5/32), and 18.8% (6/32) were classified as immune-inflamed, immune-excluded, and immune-desert, respectively. Notably, the immune-inflamed type is predominantly observed in pleomorphic carcinomas (PC, 66.7%). Moreover, among these participants, 19 (59.4%) were classified as PD-L1 positive according to the TPS score. In particular, 11 (34.4%) patients had PD-L1 TPS scores >50%. Next, we immunophenotyped patients with PSC based on CD8+ T cell infiltration and tumor cell PD-L1 expression (types I–IV). Type I (PD-L1+/CD8+, adaptive immune resistance) was the most prevalent subtype, accounting for 46.9% (15/32), followed by type II (PD-L1-/CD8-, immunological ignorance) (21.9%), type IV (PD-L1-/CD8+, tolerance) (18.7%), and type III (PD-L1+/CD8-, intrinsic induction) (12.5%). Finally, we performed a survival analysis and found that neither immunophenotype was a predictor of prognosis in patients with PSC. Multivariate analysis showed that pneumonectomy increased the risk of death by four times compared with lobectomy (RR: 4.1; 95% CI:1.3-12.4, P=0.014).

Conclusion

Patients with PSC are characterized by immune-inflamed type and type I (PD-L1+/CD8+, adaptive immune resistance), explaining the intrinsic reasons for their high response rate to immunotherapy.
Comprehensive analysis of cuproptosis-related genes and tumor microenvironment infiltration characterization in breast cancer
Authors: Song Shaoran , Zhang Miao , Xie Peiling , Wang Shuhong , Wang Yaochun
Published: October 2022

Background

Cuproptosis is a newly discovered programmed cell death dependent on overload copper-induced mitochondrial respiration dysregulation. The positive response to immunotherapy, one of the most important treatments for invasive breast cancer, depends on the dynamic balance between tumor cells and infiltrating lymphocytes in the tumor microenvironment (TME). However, cuproptosis-related genes (CRGs) in clinical prognosis, immune cell infiltration, and immunotherapy response remain unclear in breast cancer progression.

Methods

The expression and mutation patterns of 12 cuproptosis-related genes were systematically evaluated in the BRCA training group. Through unsupervised clustering analysis and developing a cuproptosis-related scoring system, we further explored the relationship between cuproptosis and breast cancer progression, prognosis, immune cell infiltration, and immunotherapy.

Results

We identified two distinct CuproptosisClusters, which were correlated with the different patterns between clinicopathological features, prognosis, and immune cell infiltration. Moreover, the differences of the three cuproptosis-related gene subtypes were evaluated based on the CuproptosisCluster-related DEGs. Then, a cuproptosis-related gene signature (PGK1, SLC52A2, SEC14L2, RAD23B, SLC16A6, CCL5, and MAL2) and the scoring system were constructed to quantify the cuproptosis pattern of BRCA patients in the training cohort, and the testing cohorts validated them. Specifically, patients from the low-CRG_score group were characterized by higher immune cell infiltration, immune checkpoint expression, immune checkpoint inhibitor (ICI) scores, and greater sensitivity to immunotherapy. Finally, we screened out RAD23B as a favorable target and indicated its expression was associated with breast cancer progression, drug resistance, and poor prognosis in BRCA patients by performing real-time RT-PCR, cell viability, and IC50 assay.

Conclusions

Our results confirmed the essential function of cuproptosis in regulating the progression, prognosis, immune cell infiltration, and response to breast cancer immunotherapy. Quantifying cuproptosis patterns and constructing a CRG_score could help explore the potential molecular mechanisms of cuproptosis regulating BRCA advancement and provide more effective immunotherapy and chemotherapy targets.
Chimeric immune checkpoint protein vaccines inhibit the tumorigenesis and growth of rat cholangiocarcinoma
Authors: Pan Yi-Ru , Wu Chiao-En , Huang Wen-Kuan , Chen Ming-Huang , Lan Keng-Hsueh , Yeh Chun-Nan
Published: October 2022

Cholangiocarcinoma (CCA) is the second most common primary liver malignancy and carries a dismal prognosis due to difficulties in achieving an optimal resection, and poor response to current standard-of-care systemic therapies. We previously devised a CTLA4-PD-L1 DNA cancer vaccine (DNA vaccine) and demonstrated its therapeutic effects on reducing tumor growth in a thioacetamide (TAA)-induced rat intrahepatic CCA (iCCA) model. Here, we developed a CTLA4-PD-L1 chimeric protein vaccine (Protein vaccine), and examined its effects in the rat iCCA model. In a therapeutic setting, iCCA-bearing rats received either DNA plus Protein vaccines or Protein vaccine alone, resulting in increased PD-L1 and CTLA-4 antibody titers, and reduced iCCA tumor burden as verified by animal positron emission tomography (PET) scans. Treating iCCA-bearing rats with Protein vaccine alone led to the increase of CTAL4 antibody titers that correlated with the decrease of tumor SUV ratio, indicating regressed tumor burden, along with increased CD8 and granzyme A (GZMA) expression, and decreased PD-L1 expression on tumor cells. In a preventive setting, DNA or Protein vaccines were injected in rats before the induction of iCCA by TAA. Protein vaccines induced a more sustained PD-L1 and CTLA-4 antibody titers compared with DNA vaccines, and was more potent in preventing iCCA tumorigenesis. Correspondingly, Protein vaccines, but not DNA vaccines, downregulated PD-L1 gene expression and hindered the carcinogenesis of iCCA. Taken together, the CTLA4-PD-L1 chimeric protein vaccine may function both as a therapeutic cancer vaccine and as a preventive cancer vaccine in the TAA-induced iCCA rat model.
Solute carrier nutrient transporters in rheumatoid arthritis fibroblast-like synoviocytes
Authors: Torres Alyssa , Pedersen Brian , Guma Monica
Published: October 2022

Metabolomic studies show that rheumatoid arthritis (RA) is associated with metabolic disruption. Metabolic changes in fibroblast-like synoviocytes (FLS) likely contribute to FLS abnormal response and strongly contribute to joint destruction. These changes often involve increased expression of nutrient transporters to meet a high demand for energy or biomolecules. The solute carrier (SLC) transporter families are nutrient transporters and serve as ‘metabolic gates’ for cells by mediating the transport of several different nutrients such as glucose, amino acids, vitamins, neurotransmitters, and inorganic/metal ions. In RA FLS SLC-mediated transmembrane transport was one pathway associated with different epigenetic landscape between RA and osteoarthritis (OA) FLS. These highlight that transporters from the SLC family offer unique targets for further research and offer the promise of future therapeutic targets for RA.
Identification and validation of a tyrosine metabolism-related prognostic prediction model and characterization of the tumor microenvironment infiltration in hepatocellular carcinoma
Authors: Zhou Yangying , Li Xuanxuan , Long Guo , Tao Yongguang , Zhou Ledu , Tang Jianing
Published: October 2022

Background

Hepatocellular carcinoma (HCC) is an aggressive and heterogeneous disease characterized by high morbidity and mortality. The liver is the vital organ that participates in tyrosine catabolism, and abnormal tyrosine metabolism could cause various diseases, including HCC. Besides, the tumor immune microenvironment is involved in carcinogenesis and can influence the patients’ clinical outcomes. However, the potential role of tyrosine metabolism pattern and immune molecular signature is poorly understood in HCC.

Methods

Gene expression, somatic mutations, copy number variation data, and clinicopathological information of HCC were downloaded from The Cancer Genome Atlas (TCGA) database. GSE14520 from the Gene Expression Omnibus (GEO) databases was used as a validation dataset. We performed unsupervised consensus clustering of tyrosine metabolism-related genes (TRGs) and classified patients into distinct molecular subtypes. We used ESTIMATE algorithms to evaluate the immune infiltration. We then applied LASSO Cox regression to establish the TRGs risk model and validated its predictive performance.

Results

In this study, we first described the alterations of 42 TRGs in HCC cohorts and characterized the clinicopathological characteristics and tumor microenvironmental landscape of the two distinct subtypes. We then established a tyrosine metabolism-related scoring system and identified five TRGs, which were highly correlated with prognosis and representative of this gene set, namely METTL6, GSTZ1, ADH4, ADH1A, and LCMT1. Patients in the high-risk group had an inferior prognosis. Univariate and multivariate Cox proportional hazards regression analysis also showed that the tyrosine metabolism-related signature was an independent prognostic indicator. Besides, receiver operating characteristic curve (ROC) analysis demonstrated the predictive accuracy of the TRGs signature that could reliably predict 1-, 3-, and 5-year survival in both TCGA and GEO cohorts. We also got consistent results by performing clone formation and invasion analysis, and immunohistochemical (IHC) assays. Moreover, we also discovered that the TRGs signature was significantly associated with the different immune landscapes and therapeutic drug sensitivity.

Conclusion

Our comprehensive analysis revealed the potential molecular signature and clinical utilities of TRGs in HCC. The model based on five TRGs can accurately predict the survival outcomes of HCC, improving our knowledge of TRGs in HCC and paving a new path for guiding risk stratification and treatment strategy development for HCC patients.
Standardized in-vitro evaluation of CAR-T cells using acellular artificial target particles
Authors: Harari-Steinfeld Rona , Abhinav Ayyadevara V. S. S. , Cuevas Lizette , Marincola Francesco , Roh Kyung-Ho
Published: October 2022

The horizon of immunotherapy using CAR-T cells is continuously extending to treat solid tumors beyond the success in the treatment of liquid tumors. Precise in-vitro evaluations of CAR-T cells for their phenotypes, quantity and quality of activation in various tumor microenvironments including different antigen densities, and the resulting effector functions are critical for the successful development of CAR-T therapies and safe translation to clinics. Unfortunately, the development of methods and tools to accommodate these needs have been lagging behind. Here, we developed a novel biomaterial platform, acellular artificial target particles (aaTPs) against CAR-T cells, using magnetic microbeads that are already widely employed in the manufacturing of T cell products. By devising a simple and standardized procedure, we precisely controlled the antigen surface densities presented on the aaTPs for a wide range. By co-incubation of aaTPs with CAR-T cells followed by flow cytometry and cytokine assays, we quantitatively determined the antigen-specific and dose-dependent activation of anti-HER2 CAR-T cells. We also demonstrated that the aaTP can serve as a clean target cell in in-vitro assays to prove the proposed mechanism of action of a next-generation CAR-T product. Overall, the simple, inexpensive, modular and precisely controllable synthetic nature of aaTPs enables the development of clean and standardized in-vitro assays for CAR-T cells, which provides critical advantages over the conventional assays using target cell lines. The design of aaTPs can be extended to include other tumor antigens and relevant surface molecules of physiological target cells. Thus, the aaTP platform has great potential as a standardized tool for the development and evaluation of both conventional and new CAR-T products in the context of approval from regulatory agencies and clinical translation.
Theory, practice, and design criteria for utilizing artificial reefs to increase production of marine fishes
Authors: Pondella Daniel J. , Claisse Jeremy T. , Williams Chelsea M.
Published: October 2022

Increasing the production of marine fishes is a tractable goal with wide socioeconomic and ecological appeal. Ecosystem restoration projects that increase the amount of suitable habitat in an area and/or habitat quality enhance both fishery production and ecosystem services. Fortuitously, there are a wealth of studies documenting the specific examples of restoring these services from successful artificial reef deployments. Considering the need to create future structures in a variety of scenarios and locations, it is salient to summarize the mechanisms through which increased secondary production occurs and the design considerations. To achieve this objective maximizing ecological processes including the provisioning of planktonic and epibenthic food resources and related trophic pathways, and those associated with life-stage specific habitat use (e.g., recruitment, juvenile survival, reproductive output) are critical mechanisms of productive reefs. We synthesized this information by addressing the structural and ecological theory of artificial reef design based upon physical attributes such as complexity, vertical relief, habitat heterogeneity, and spatial scale. Within this framework we summarized the mechanisms that may be used to increase secondary fish production and propose a general theory for optimization of these variables.
Improving the tensile strength of non-keyhole friction stir lap welding joint of 2024-T4 Al alloy by radial basis function neural network and improved particle swarm optimization algorithm
Authors: Li Yuting , Sun Zelin , Qi Xin , Gong Peng , Ji Shude , Wang Baoguang , Zhang Zhiqing , Zhang Jiaqi
Published: October 2022

The non-keyhole friction stir lap welding (N-KFSLW) technology assisted by the outer stationary shoulder and the inner upper half-thread rotating pin was proposed to obtain the welding joint without keyhole through one-time process. Choosing 2024 aluminum alloys as the research object, the formation, microhardness and tensile strength of N-KFSLW joint were investigated. The improved particle swarm optimization (IPSO) algorithm was newly developed and had the advantages of large convergence speed and strong search ability, by which the radial basis function (RBF) neural network was optimized to enhance its prediction accuracy. After that, the RBF and IPSO (IPSO-RBF) system was used to predict the joint strength and optimize the process parameters combination. The results showed that the lap joint had not only the SZ with the thickness almost equal to the thickness of upper sheet but also the cold lap with a very small height, thereby leading to the high tensile strength of joint. The optimized parameters of welding speed, rotating speed and pin type by the IPSO-RBF system were respectively 612 rpm, 80 mm/min, and upper half-thread pin, and the tensile strength of lap joint reached 11.88 kN/mm. The N-KFSLW technology assisted by upper half-thread pin provides an effective way to obtain the lap joint with high performance, and the IPSO-RBF system can be used to maximize the strength of welding joint.
Practice patterns and adherence to society guidelines for suspected choledocholithiasis: A comparison of academic and community settings from a large US healthcare system
Authors: Rashtak Shahrooz , Goyal Hemant , Chandran Aswathi , Dedania Bhavtosh , Patil Prithvi , Wadhwa Vaibhav , Guha Sushovan , Davee Tomas , Ramireddy Srinivas , Thosani Nirav
Published: October 2022

Background

The American Society of Gastrointestinal Endoscopy (ASGE) has proposed practice guidelines for evaluating patients with suspected choledocholithiasis. This study aims to assess and compare practice patterns for following ASGE guidelines for choledocholithiasis in a large academic vs. community hospital setting.

Methods

A total of one thousand ER indicated for choledocholithiasis were randomly selected. Patients’ demographics, total bilirubin, imaging studies including magnetic resonance cholangiopancreatography (MRCP), intraoperative cholangiogram (IOC), endoscopic ultrasound (EUS), and ERCP results were retrospectively collected. Patients with prior sphincterotomy were excluded. We examined the following practice deviations from the current ASGE guidelines; (1) ERCP was potentially delayed in high probability cases while awaiting additional imaging studies, (2) ERCP was performed without additional imaging studies in cases of low/intermediate-risk, or (3) ERCP was performed in low/intermediate-risk cases when additional imaging studies were negative.

Results

A total of 640 patients with native papilla who underwent ERCP were included in the final analysis. Overall, the management of 43% (275) of patients was deviated from the applicable ASGE guidelines. Academic and community provider rates of non-adherence were 32 vs. 45%, respectively (p-value: < 0.01). Of 381 high-risk cases, 54.1% had additional imaging before ERCP. (Academic vs. community; 11.7 vs. 88.3%, p-value: < 0.01). In 26.7% (69/258) of low/intermediate risk cases, ERCP was performed without additional studies; academic (14.5%) vs. community (85.5%) (p-value: < 0.01). Finally, in 11.2% (19/170) of patients, ERCP was performed despite intermediate/low probability and negative imaging; academic (26.3%) vs. community (73.7%) (p-value: 0.02).

Conclusion

Our study results show that providers do not adhere to ASGE practice guidelines in 43% of suspected choledocholithiasis cases. The rate of non-adherence was significantly higher in community settings. It could be due to various reasons, including lack/delays for alternate studies (i.e., MRCP, EUS), concern regarding the length of stay, patient preference, or lack of awareness/understanding of the guidelines. Increased availability of alternate imaging and educational strategies may be needed to increase the adoption of practice guidelines across academic and community settings to improve patient outcomes and save healthcare dollars.
Application of Jiawei Maxing Shigan Tang in the treatment of COVID-19: An observational study
Authors: Wu Jia , Tang Feng , Zhang Xiao-Qiang , Fu Zai-Lin , Fu Shui
Published: October 2022

Objective

To explore the clinical efficacy and adverse reactions of Jiawei Maxing Shigan Tang (JMST; a modified decoction of ephedra, apricot kernel, gypsum, and licorice) combined with western medicine in the symptomatic treatment of COVID-19.

Methods

In this study, we retrospectively collected the basic data of 48 patients with COVID-19 who were discharged from our hospital between January 20 and February 28, 2020. Besides, the blood routines, biochemical indexes, nucleic acid detection results, clinical symptoms, lung imaging improvements, adverse reactions, and other clinical data of these patients before and after treatment were recorded. Finally, we drew comparisons between the outcomes and adverse reactions of patients in the combined treatment group (therapeutic regimen recommended by authoritative guidelines and supplemented by JMST) and the conventional treatment group (therapeutic regimen recommended by authoritative guidelines).

Results

There were no significant differences in age, gender, clinical classification, and underlying medical conditions between the combined treatment group (28 cases) and the conventional treatment group (20 cases). However, the combined treatment group presented superior results to the conventional treatment group in several key areas. For instance, patients produced negative nasal/throat swab-based nucleic acid detection results in a shorter time, clinical symptoms were more effectively alleviated, and the absorption time of lung exudation was shorter (P < 0.05). Furthermore, the combined treatment group had a shorter length of stay (LOS) and faster lymphocyte recovery duration than the conventional treatment group, although the differences were not statistically significant. Moreover, there were no significant differences concerning gastrointestinal reaction, hepatic injury, renal impairment, myocardial injury, and other adverse reactions between the two groups.

Conclusion

The results of this study indicate that JMST combined with the recommended therapeutic regimen enhances the recovery of COVID-19 patients without increasing the risk of adverse reactions. Therefore, this therapy promotes positive outcomes for COVID-19 patients.
An overview of bats microbiota and its implication in transmissible diseases
Authors: Federici Luca , Masulli Michele , De Laurenzi Vincenzo , Allocati Nerino
Published: October 2022

Recent pandemic events have raised the attention of the public on the interactions between human and environment, with particular regard to the more and more feasible transmission to humans of micro-organisms hosted by wild-type species, due to the increasing interspecies contacts originating from human’s activities. Bats, due to their being flying mammals and their increasing promiscuity with humans, have been recognized as hosts frequently capable of transmitting disease-causing microorganisms. Therefore, it is of considerable interest and importance to have a picture as clear as possible of the microorganisms that are hosted by bats. Here we focus on our current knowledge on bats microbiota. We review the most recent literature on this subject, also in view of the bat’s body compartments, their dietary preferences and their habitat. Several pathogenic bacteria, including many carrying multidrug resistance, are indeed common guests of these small mammals, underlining the importance of preserving their habitat, not only to protect them from anthropogenic activities, but also to minimize the spreading of infectious diseases.
Paraburkholderia phytofirmans PsJN delays Botrytis cinerea development on grapevine inflorescences
Authors: Miotto Vilanova Lidiane Carla , Rondeau Marine , Robineau Mathilde , Guise Jean François , Lavire Céline , Vial Ludovic , Fontaine Florence , Clément Christophe , Jacquard Cédric , Esmaeel Qassim , Aït Barka Essaïd , Sanchez Lisa
Published: October 2022

Grapevine flowering is an important stage in the epidemiology of Botrytis cinerea, the causal agent of gray mold disease. To prevent infection and to minimize postharvest losses, the control of this necrotrophic fungus is mainly based on chemical fungicides application. However, there is a growing interest in other control alternatives. Among them, the use of beneficial microorganisms appears as an eco-friendly strategy. This study aims to investigate the effect of Paraburkholderia phytofirmans PsJN, root-inoculated or directly sprayed on fruiting cuttings inflorescences to control B. cinerea growth. For this purpose, quantification by real time PCR of Botrytis development, direct effect of PsJN on fungal spore germination and chemotaxis were assayed. Our results showed a significant protective effect of PsJN only by direct spraying on inflorescences. Moreover, we demonstrated an inhibition exerted by PsJN on Botrytis spore germination, effective when there was a direct contact between the two microorganisms. This study showed that PsJN is positively attracted by the pathogenic fungus B. cinerea and forms a biofilm around the fungal hyphae in liquid co-culture. Finally, microscopic observations on fruit cuttings revealed a co-localization of both beneficial and pathogenic microorganisms on grapevine receptacle and stigma that might be correlated with the protective effect induced by PsJN against B. cinerea via a direct antimicrobial effect. Taking together, our findings allowed us to propose PsJN as a biofungicide to control grapevine gray mold disease.
Prognostic value, immune signature and molecular mechanisms of the APOBEC family members APOBEC1, APOBEC3A, APOBEC3G and APOBEC3H in pancreatic adenocarcinoma
Authors: Duan Yunjie , Du Yongxing , Gu Zongting , Zheng Xiaohao , Wang Chengfeng
Published: October 2022

Background: Increasing evidence supports that the APOBEC family is associated with development of a variety of cancers. However, the function of APOBEC1/3A/3G/3H in pancreatic adenocarcinoma (PAAD) is still unclear.

Methods: Comprehensive bioinformatic analysis using R (version 3.6.3), TISIDB, Metascape etc. were performed to study the clinicopathological characteristics, prognostic value, immune features and functional mechanisms of the APOBEC1/3A/3G/3H in PAAD.

Results: APOBEC1/3A/3G/3H showed significantly elevated expression in PAAD than para-cancerous or normal tissues. Their high expression or amplification were significantly correlated with worse clinicopathological characteristics and prognosis in PAAD patients. In addition, the role of APOBEC1/3A/3G/3H in the immune regulation is diverse and complex, the high expression of APOBEC1 may inhibit the infiltration level of many kinds of immunoreactive tumor-infiltrating cells, which may be an important factor leading to immune escape of PAAD cells. Mechanistically, APOBEC1/3A/3G/3H played an activating role in multiple oncogenic pathways, including the EMT, RAS/MAPK and TSC/mTOR pathways. Moreover, we found that the expression level of APOBEC3G was positively correlated with the sensitivity of gemcitabine and doxorubicin.

Conclusion: APOBEC1/3A/3G/3H play an oncogenic role in the development of PAAD and might serve as new biomarkers or therapeutic targets.
The influence of 17q21.31 and APOE genetic ancestry on neurodegenerative disease risk
Authors: Harerimana Nadia V. , Goate Alison M. , Bowles Kathryn R.
Published: October 2022

Advances in genomic research over the last two decades have greatly enhanced our knowledge concerning the genetic landscape and pathophysiological processes involved in multiple neurodegenerative diseases. However, current insights arise almost exclusively from studies on individuals of European ancestry. Despite this, studies have revealed that genetic variation differentially impacts risk for, and clinical presentation of neurodegenerative disease in non-European populations, conveying the importance of ancestry in predicting disease risk and understanding the biological mechanisms contributing to neurodegeneration. We review the genetic influence of two important disease-associated loci, 17q21.31 (the “MAPT locus”) and APOE, to neurodegenerative disease risk in non-European populations, touching on global population differences and evolutionary genetics by ancestry that may underlie some of these differences. We conclude there is a need to increase representation of non-European ancestry individuals in genome-wide association studies (GWAS) and biomarker analyses in order to help resolve existing disparities in understanding risk for, diagnosis of, and treatment for neurodegenerative diseases in diverse populations.
Exploring the mediating effects of negative and positive religious coping between resilience and mental well-being
Authors: Surzykiewicz Janusz , Skalski Sebastian Binyamin , Niesiobędzka Małgorzata , Konaszewski Karol
Published: October 2022

Background:

The purpose of the study was to examine more thoroughly the relationship between trait resilience and mental well-being. Although research demonstrates that this relationship is partially mediated by stress-related variables, no study has taken into account the mediating role of religious coping. We examined the mediating role of both variants of religious coping, positive and negative, along with specific strategies within the scope of religious coping strategies in a group of practicing Catholics.

Method:

Participants were 317 people aged 19–60 years (M = 24.34; SD = 6.30). The respondents indicated their gender and age, and then completed the RS-14 (trait resilience), RCOPE (religious coping), and WEMWBS (mental well-being) scales.

Results:

The results displayed a significant relationship between resilience and mental well-being (r = 0.67; p < 0.001). The relationship between resilience and positive religious coping was negligible (r = 0.09; p = 0.74), contrary to the relationship between resilience and negative coping that was significant but weak (r = −0.29; p < 0.001). Although the relationships between overall negative and positive religious coping with mental well-being were irrelevant, we found significant relationships between some strategies and mental well-being. The mediation analysis has demonstrated that the general negative religious coping and the strategies of demonic reappraisal, passive religious deferral, and spiritual discontent have enhanced the positive relationship between resilience and mental well-being. Contrary to expectation, positive strategies did not mediate the relationship between resilience and mental well-being, except religious practices (c′path totaled β = 0.66; t = 15.74, p < 0.001). The insignificant mediation effect can stem from the fact that the relationship between positive religious coping and stress is noticeable only in the long term. We controlled age and sex as statistically significant covariates so that the mediation effects obtained were devoid of the influence of those critical variables on the models.

Conclusion:

This is the first study to investigate the role of religious coping as a mediator in the relationship between resilience and mental well-being.
Outcomes in older kidney recipients from older donors: A propensity score analysis
Authors: Cuadrado-Payán Elena , Montagud-Marrahi Enrique , Casals-Urquiza Joaquim , del Risco-Zevallos Jimena , Rodríguez-Espinosa Diana , Cacho Judit , Arana Carolt , Cucchiari David , Ventura-Aguiar Pedro , Revuelta Ignacio , Piñeiro Gaston J. , Esforzado Nuria , Cofan Frederic , Bañon-Maneus Elisenda , Campistol Josep M. , Oppenheimer Federico , Torregrosa Josep-Vicens , Diekmann Fritz
Published: October 2022

Background

The age of patients referred for kidney transplantation has increased progressively. However, the precise influence of age on transplant outcomes is controversial.

Methods

Etrospective study in which graft and recipient survival were assessed in a cohort of ≥75 years old kidney recipients and compared with a contemporary younger one aged 60-65 years through a propensity score analysis.

Results

We included 106 recipients between 60-65 and 57 patients of ≥75 years old with a median follow-up of 31 [13-54] months. Unadjusted one- and five-year recipient survival did not significantly differ between the older (91% and 74%) and the younger group (95% and 82%, P=0.06). In the IPTW weighted Cox regression analysis, recipient age was not associated with an increased risk of death (HR 1.88 95%CI [0.81-4.37], P=0.14). Unadjusted one- and five-year death-censored graft survival did not significantly differ between both groups (96% and 83% for the older and 99% and 89% for the younger group, respectively, P=0.08). After IPTW weighted Cox Regression analysis, recipient age ≥75 years was no associated with an increased risk of graft loss (HR 1.95, 95%CI [0.65-5.82], P=0.23).

Conclusions

These results suggest that recipient age should not be considered itself as an absolute contraindication for kidney transplant
Quantitative susceptibility mapping (QSM) and R2* of silent cerebral infarcts in sickle cell anemia
Authors: Murdoch Russell , Stotesbury Hanne , Kawadler Jamie M. , Saunders Dawn E. , Kirkham Fenella J. , Shmueli Karin
Published: October 2022

Silent cerebral infarction (SCI) is the most commonly reported radiological abnormality in patients with sickle cell anemia (SCA) and is associated with future clinical stroke risk. To date, there have been few histological and quantitative MRI studies of SCI and multiple radiological definitions exist. As a result, the tissue characteristics and composition of SCI remain elusive. The objective of this work was therefore to investigate the composition of segmented SCI lesions using quantitative MRI for R2* and quantitative magnetic susceptibility mapping (QSM). 211 SCI lesions were segmented from 32 participants with SCA and 6 controls. SCI were segmented according to two definitions (FLAIR+/–T1w-based threshold) using a semi-automated pipeline. Magnetic susceptibility (χ) and R2* maps were calculated from a multi-echo gradient echo sequence and mean SCI values were compared to an equivalent region of interest in normal appearing white matter (NAWM). SCI χ and R2* were investigated as a function of SCI definition, patient demographics, anatomical location, and cognition. Compared to NAWM, SCI were significantly less diamagnetic (χ = –0.0067 ppm vs. –0.0153 ppm, p < 0.001) and had significantly lower R2* (16.7 s−1 vs. 19.2 s−1, p < 0.001). SCI definition had a significant effect on the mean SCI χ and R2*, with lesions becoming significantly less diamagnetic and having significantly lower R2* after the application of a more stringent T1w-based threshold. SCI-NAWM R2* decrease was significantly greater in patients with SCA compared with controls (–2.84 s−1 vs. –0.64 s−1, p < 0.0001). No significant association was observed between mean SCI–NAWM χ or R2* differences and subject age, lesion anatomical location, or cognition. The increased χ and decreased R2* in SCI relative to NAWM observed in both patients and controls is indicative of lower myelin or increased water content within the segmented lesions. The significant SCI–NAWM R2* differences observed between SCI in patients with SCA and controls suggests there may be differences in tissue composition relative to NAWM in SCI in the two populations. Quantitative MRI techniques such as QSM and R2* mapping can be used to enhance our understanding of the pathophysiology and composition of SCI in patients with SCA as well as controls.
Case report: Expanding the phenotype of ARHGEF17 mutations from increased intracranial aneurysm risk to a neurodevelopmental disease
Authors: Ravindran Ethiraj , Ullah Noor , Mani Shyamala , Chew Elaine Guo Yan , Tandiono Moses , Foo Jia Nee , Khor Chiea Chuen , Kaindl Angela M. , Siddiqi Saima
Published: October 2022

RhoGTPase regulators play a key role in the development of the nervous system, and their dysfunction can result in brain malformation and associated disorders. Several guanine nucleotide exchange factors (GEF) have been linked to neurodevelopmental disorders. In line with this, ARHGEF17 has been recently linked as a risk gene to intracranial aneurysms. Here we report siblings of a consanguineous Pakistani family with biallelic variants in the ARHGEF17 gene associated with a neurodevelopmental disorder with intellectual disability, speech delay and motor dysfunction but not aneurysms. Cranial MRI performed in one patient revealed generalized brain atrophy with an enlarged ventricular system, thin corpus callosum and microcephaly. Whole exome sequencing followed by Sanger sequencing in two of the affected individuals revealed a homozygous missense variant (g.11:73021307, c.1624C>T (NM_014786.4), p.R542W) in the ARHGEF17 gene. This variant is in a highly conserved DCLK1 phosphorylation consensus site (I/L/V/F/M]RRXX[pS/pT][I/L/M/V/F) of the protein. Our report expands the phenotypic spectrum of ARHGEF17 variants from increased intracranial aneurysm risk to neurodevelopmental disease and thereby add ARHGEF17 to the list of GEF genes involved in neurodevelopmental disorders.