bluuebunny/crossref_metadata_2025 huggingface dataset:
Specific classification and new therapeutic targets for neuroendocrine prostate cancer: A patient-based, diagnostic study
Authors: Wang YouZhi , Wu Ning , Wang KeKe , Liao YiHao , Guo JiaNing , Zhong BoQiang , Guo Tao , Liang JiaMing , Jiang Ning
Published: September 2022

Objective: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer (PC) that may arise de novo or in patients previously treated with hormonal therapies for prostate adenocarcinoma as a mechanism of resistance. In our investigation, there appeared to be a strong correlation between neuroendocrine differentiation prostate cancer (NEDPC) and NEPC. The objectives of this study included exploring whether NEDPC is an intermediate stage in the progression of high-risk prostate cancer (HRPC) to NEPC and identifying risk factors and new targets associated with survival in the treatment of NEPC.

Methods: The selected prostate cancer patients were progressed to high-risk and characterized by neuroendocrine. We collected the clinical data and characteristics of patients with three types of cancer: the incidence of metastasis, site and time of metastasis, recurrence rate, related treatment methods, etc. The similarity and differences of the three groups were compared through experiment and database.

Results: By analyzing the clinical data and immunohistochemical results, we found that there seems to be a clinical feature of neuroendocrine differentiation (NED) status in between when patients progress from PC to NEPC. Finding novel treatment targets would therefore be beneficial by taking into account NEDPC as the stage of PC progression prior to NEPC. The metastasis-free survival curve and the immunohistochemical results are informing us that NEDPC can be a pre-state for diagnosing NEPC.

Conclusion: NEPC is a late PC symptom that is frequently disregarded and has a bad prognosis. Finding novel treatment targets would therefore be beneficial by taking into account NEDPC as the stage of PC progression prior to NEPC.
Identification of potential key genes for immune infiltration in childhood asthma by data mining and biological validation
Authors: Wang Zhili , He Yu , Cun Yupeng , Li Qinyuan , Zhao Yan , Luo Zhengxiu
Published: September 2022

Asthma is the most common chronic condition among children; however, the underlying molecular mechanism remains unclear. Dysregulated immune response and different infiltration states of immune cells are critical for asthma pathogenesis. Here, three childhood asthma gene expression datasets were used to detect key genes, immune cells, and pathways involved in childhood asthma. From these datasets, 33 common differentially expressed genes (DEGs) were identified, which showed enrichment in the T helper 1 (Th1) and T helper 2 (Th2) cell differentiation pathway and the T helper 17 (Th17) cell differentiation pathway. Using the weighted gene co-expression network analysis (WGCNA), CD3D and CD3G were identified as key genes closely correlated with childhood asthma. Upregulation of CD3D and CD3G was further validated in bronchoalveolar lavage cells from childhood asthmatics with control individuals by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The immune cell infiltration analysis indicated that CD3D and CD3G were negatively correlated with increased resting mast cells and eosinophils, and highly correlated with several cell markers of Th1, Th2, and Th17 cells. In addition, we found that CD3D and CD3G were closely related to the Th1 and Th2 cell differentiation pathway and the Th17 cell differentiation pathway. Our results reveal the important roles of two key genes and immune infiltration in the pathogenesis of childhood asthma. Thus, this study provides a new perspective for exploring potential molecular targets for childhood asthma treatment.
Paraoxonase 1 gene polymorphisms in lipid oxidation and atherosclerosis development
Authors: Vavlukis Marija , Vavlukis Ana , Krsteva Katerina , Topuzovska Sonja
Published: September 2022

Paraoxonase 1 (PON1) is calcium-dependent aryldialkylphosphatase, thought to possess; anti-oxidant, anti-adhesion, anti-inflammatory, anti-thrombosis and anti-apoptosis effects, as well as lipid-modifying properties. Numerous clinical studies have shown associations between different PON1 polymorphisms and different cardiovascular pathologies. The rs622 (c.575A > G) and the rs854560 (c.163A > T) are the most studied PON1 SNPs in the coding region, with rs705381 (− 162A/G), rs854572 (− 909G/C) and rs705379 (− 108C/T) being the most studied SNPs in the regulatory PON1 gene region. The three major PON1 activities are aryldialkylphosphatase, arylesterase and lactonase activity. The different SNPs affect PON1 serum concentrations and enzyme activity, thus leading to pro-/anti-atherogenic effects. In that setting, it is very difficult to establish as to whether the genotype or phenotype of PON1 is primarily associated with cardiovascular risk. Given the current scientific evidence, PON1 genotyping might be reasonable in patients with high and very high cardiovascular risk.
Ultrasound radiomics features predicting the dosimetry for focused ultrasound surgery of benign breast tumor: A retrospective study
Authors: Liang Mengdi , Zhang Cai , Xia Tiansong , Chen Rui , Wang Xinyang , Weng Miaomiao , Xie Hui , Chen Lin , Liu Xiaoan , Wang Shui
Published: September 2022

Purpose: To investigate the correlation between pre-ablation ultrasound radiomics features and the sonication energy for focused ultrasound surgery (FUS) of benign breast tumors.

Method: 53 benign breast tumors of 28 patients treated by ultrasound-guided focused ultrasound surgery (USgFUS) were included in this study. The sonication energy per unit volume of each tumor was calculated. Three-quarter point was chosen as the cut-off to divide the 53 included tumors into high sonication energy (HSE, n = 14) and low sonication energy (LSE, n = 39) groups. For each tumor, the region of interest (ROI) of both the tumor itself (tROI) and the near field tissue (nfROI) were delineated and analyzed separately using ImageJ software. Pearson correlation coefficient and multiple linear regression analysis were used for radiomics feature selection. To explore the diagnostic performance of different ultrasound radiomics features, a receiver operating characteristic (ROC) curve analysis was performed.

Results: In total of 68 radiomics features were extracted from pre-ablation ultrasound images of each tumor. Of all radiomics features, BX in tROI (p < 0.001), BX (p = 0.001) and Circ (p = 0.019) in nfROI were independently predictive features of sonication energy per unit volume. The ROC curves showed that the area under the curve (AUC) values of BX in tROI, BX, and Circ in nfROI were 0.797, 0.787 and 0.822, respectively.

Conclusion: This study provided three radiomics features of pre-ablation ultrasound image as predictors of sonication dose for FUS in benign breast tumors. Further clinical trials are needed to confirm the predictive effect of these radiomics features.
Ferroptosis regulators related scoring system by Gaussian finite mixture model to predict prognosis and immunotherapy efficacy in nasopharyngeal carcinoma
Authors: Liu Zijian , He Jinlan , Hu Xiaolin
Published: September 2022

The role of ferroptosis in tumor progression and metastasis has been demonstrated. Nonetheless, potential biological function of ferroptosis regulatory pattern in nasopharyngeal carcinoma (NPC) remains unknown. Ferroptosis regulatory patterns of nasopharyngeal carcinoma samples were evaluated based on 113 ferroptosis regulators and three distinct ferroptosis subtypes were determined by unsupervised clustering. The ferroptosis score (FEP score) was identified to quantify ferroptosis patterns within individual tumors by Gaussian finite mixture model and systematically correlated with representative tumor characteristics. Subtype 1 and subtype 3 were consistent with immune activated phenotype, while subtype 2 was consistent with immune suppressed phenotype. High ferroptosis score, characterized by immune activation and suppression of mRNA based stemness index (mRNAsi) and Epstein-Barr virus (EBV) genes, indicated an immune activated tumor microenvironment (TME) phenotype, with better progression free survival (PFS) and lower risk of recurrence and metastasis. Low ferroptosis score, characterized by activation of Wnt and NF-κB signaling pathways and lack of effective immune infiltration, indicated an immune suppressed tumor microenvironment phenotype and poorer survival. High ferroptosis score was also correlated to enhanced response to immunotherapy, and was confirmed to correlate with therapeutic advantages and clinical benefits in an anti-programmed cell death 1 ligand 1 (PD-L1) immunotherapy cohort. As ferroptosis played a crucial role in the tumor microenvironment’s diversity, assessing the ferroptosis pattern within individual tumor with ferroptosis score could enhance our understanding of tumor microenvironment infiltration characterization and help develop more effective immunotherapy.
A novel hypoxia-driven gene signature that can predict the prognosis and drug resistance of gliomas
Authors: Ren Peng , Wang Jing-Ya , Zeng Zhi-Rui , Li Nan-Xi , Chen Hong-Lei , Peng Xin-Ge , Bhawal Ujjal K. , Guo Wen-Zhi
Published: September 2022

Hypoxia spontaneously forms in the interior of glioma tissues and regulates the expression of various genes. However, the status of hypoxia-driven genes in glioma tissues is not completely known. In the current study, RNA-seq data of 695 glioma tissues in The Cancer Genome Atlas (TCGA) were set as a discovery cohort and were used to identify hypoxia-driven genes and construct a novel gene signature. The prognostic values of that signature were verified in data from the TCGA and the Chinese Glioma Genome Atlas (CGGA). The expression and diagnostic values of hypoxia-driven genes were analyzed using immunohistochemistry and receiver operator characteristic curves. Finally, the effects of hypoxia-driven genes on temozolomide (TMZ) resistance were analyzed by western blot, CCK-8 and colony formation assay. A total of 169 hypoxia-driven genes were identified, which were associated with a poor outcome in glioma patients. Among them, 22 genes had a degree score ≥10 and 6 genes (WT1, HOXA2, HOXC6, MMP9, SHOX2 and MYOD1) were selected to construct a signature to classify glioma patients into low- or high-risk groups. That signature had a remarkable prognostic value for glioma patients in TCGA and CGGA. The expression of HOXC6, MMP9, SHOX2 and MYOD1 was associated with hypoxia degree in glioma tissues and in recurrent cases, had a remarkable diagnostic value and a significant relationship with disease free survival in glioma patients. Moreover, SHOX2 was highly expressed in glioma tissues with O-6-methylguanine-DNA methyltransferase (MGMT)-unmethylation and temozolomide (TMZ) resistant glioma cell lines, and associated with MGMT expression. Knockdown the expression of SHOX2 significantly reduced the TMZ-resistance induced by hypoxia in glioma cells. Ultimately, we identified six novel hypoxia-driven genes for reliable prognostic prediction in gliomas and found that SHOX2 might be a potential target to overcome the TMZ resistance induced by hypoxia.
A novel gene signature unveils three distinct immune-metabolic rewiring patterns conserved across diverse tumor types and associated with outcomes
Authors: Pedrosa Leire , Foguet Carles , Oliveres Helena , Archilla Iván , de Herreros Marta García , Rodríguez Adela , Postigo Antonio , Benítez-Ribas Daniel , Camps Jordi , Cuatrecasas Miriam , Castells Antoni , Prat Aleix , Thomson Timothy M. , Maurel Joan , Cascante Marta
Published: September 2022

Existing immune signatures and tumor mutational burden have only modest predictive capacity for the efficacy of immune check point inhibitors. In this study, we developed an immune-metabolic signature suitable for personalized ICI therapies. A classifier using an immune-metabolic signature (IMMETCOLS) was developed on a training set of 77 metastatic colorectal cancer (mCRC) samples and validated on 4,200 tumors from the TCGA database belonging to 11 types. Here, we reveal that the IMMETCOLS signature classifies tumors into three distinct immune-metabolic clusters. Cluster 1 displays markers of enhanced glycolisis, hexosamine byosinthesis and epithelial-to-mesenchymal transition. On multivariate analysis, cluster 1 tumors were enriched in pro-immune signature but not in immunophenoscore and were associated with the poorest median survival. Its predicted tumor metabolic features suggest an acidic-lactate-rich tumor microenvironment (TME) geared to an immunosuppressive setting, enriched in fibroblasts. Cluster 2 displays features of gluconeogenesis ability, which is needed for glucose-independent survival and preferential use of alternative carbon sources, including glutamine and lipid uptake/β-oxidation. Its metabolic features suggest a hypoxic and hypoglycemic TME, associated with poor tumor-associated antigen presentation. Finally, cluster 3 is highly glycolytic but also has a solid mitochondrial function, with concomitant upregulation of glutamine and essential amino acid transporters and the pentose phosphate pathway leading to glucose exhaustion in the TME and immunosuppression. Together, these findings suggest that the IMMETCOLS signature provides a classifier of tumors from diverse origins, yielding three clusters with distinct immune-metabolic profiles, representing a new predictive tool for patient selection for specific immune-metabolic therapeutic approaches.
Prototheca bovis induces autophagy in bovine mammary epithelial cells via the HIF-1α and AMPKα/ULK1 pathway
Authors: Zhao Wenpeng , Xu Maolin , Barkema Herman W. , Xie Xiaochen , Lin Yushan , Khan Sohrab , Kastelic John P. , Wang Dong , Deng Zhaoju , Han Bo
Published: September 2022

Prototheca bovis, a highly contagious pathogen, causes bovine mastitis, resulting in premature culling of affected cows and severe economic losses. Infection with P. bovis caused oxidative stress and apoptosis in bovine mammary epithelial cells (bMECs); however, mechanisms underlying P. bovis-induced autophagy remain unclear. Therefore, the autophagy flux induced by P. bovis in bMECs was analyzed by Western blot and laser scanning confocal microscopy. Expression levels of proteins in the HIF-1α and AMPKα/ULK1 pathway, including HIF-1α, AMPKα, p-AMPKα, ULK1, p-ULK1, mTOR, and p-mTOR, plus expression of autophagy-related genes including SQSTM1/p62, Atg5, Beclin1, and LC3II/LC3I, were quantified with Western blot. Infection with P. bovis induced autophagosomes and LC3 puncta in bMECs that were detected using transmission electron microscopy and laser scanning confocal microscopy, respectively. In addition, lysosome-associated proteins Rab7 and LAMP2a, and lysosomal activity were measured with Western blot and laser scanning confocal microscopy. Infection with P. bovis induced an unobstructed autophagic flux, increased protein expression of LC3II/LC3I, and decreased SQSTM1/p62 protein expression at 6 hpi. Furthermore, P. bovis upregulated protein expression in the HIF-1α and AMPKα/ULK1 pathway and increased the ratio of LC3II/LC3I, implying autophagy was activated in bMECs. However, deletion of AMPKα or ULK1 decreased LC3II/LC3I expression levels and LC3 puncta numbers, suggesting that autophagy was inhibited in bMECs. Additionally, deficiency of HIF-1α decreased protein expression of AMPKα and ULK1 as well as LC3 puncta numbers, and autophagy induced by P. bovis was also inhibited in bMECs. At 6 hpi, lysosome-associated protein Rab7 was decreased and LAMP2a was increased, indicating normal autophagy. In contrast, at 12 hpi, expression of Rab7 and LAMP2a proteins indicated that autophagy was inhibited in bMECs at that time. Therefore, we confirmed that P. bovis infection induced autophagy in bMECs via the HIF-1α and AMPKα/ULK1 pathway, with involvement of lysosome-associated protein Rab7 and LAMP2a.
Deciphering the immune landscape dominated by cancer-associated fibroblasts to investigate their potential in indicating prognosis and guiding therapeutic regimens in high grade serous ovarian carcinoma
Authors: Li Yimin , Tian Ruotong , Liu Jiaxin , Li Juanni , Tan Hong , Wu Qihui , Fu Xiaodan
Published: September 2022

Limited immunotherapeutic effect in high-grade serous ovarian carcinoma (HGSOC) propels exploration of the mechanics behind this resistance, which may be partly elucidated by investigating characters of cancer-associated fibroblasts (CAFs), a significant population in HGSOC involved in shaping tumor immune microenvironment. Herein, leveraging gene expression data of HGSOC samples from The Cancer Genome Atlas and Gene Expression Omnibus datasets, we suggested that CAFs detrimentally affected the outcomes of HGSOC patients. Subsequently, we performed weighted gene co-expression network analysis (WGCNA) to identify a CAFs-related module and screened out seven hub genes from this module, all of which were positively correlated with the infiltration of immunosuppressive macrophages. As one of the hub genes, the expression of fibrillin 1 (FBN1) and its relevance to CD206 were further verified by immunohistochemistry staining in HGSOC samples. Meanwhile, we extracted genes that correlated well with CAF signatures to construct a CAFscore. The capacity of the CAFscore as an independent prognostic factor was validated by Cox regression analyses, and its relevance to components as well as signals in the tumor immune microenvironment was also investigated. Under the evaluation by the CAFscore, HGSOC patients with relatively high CAFscore had worse outcomes, activated mesenchymal signaling pathways, and immune checkpoint blockade (ICB) resistance signatures, which was consistent with the fact that non-responders in anti-PD-1 treatment cohorts tended to have higher CAFscore. Besides, the possibility of CAFscore to guide the selection of sensitive chemotherapeutic agents was explored. In conclusion, individualized assessment of the CAFscore could uncover the extent of stroma activation and immunosuppression and inform therapeutic strategies to improve the benefit of therapies.
Lyl1-deficiency promotes inflammatory responses and increases mycobacterial burden in response to Mycobacterium tuberculosis infection in mice
Authors: Jones Shelby-Sara , Ozturk Mumin , Kieswetter Nathan Scott , Poswayo Sibongiseni K. L. , Hazra Rudranil , Tamgue Ousman , Parihar Suraj P. , Suzuki Harukazu , Brombacher Frank , Guler Reto
Published: September 2022

Lymphoblastic leukemia 1 (Lyl1) is a well-studied transcription factor known to exhibit oncogenic potential in various forms of leukemia with pivotal roles in hematopoietic stem cell biology. While its role in early hematopoiesis is well established, its function in mature innate cells is less explored. Here, we identified Lyl1 as a drastically perturbed gene in theMycobacterium tuberculosis(Mtb) infected mouse macrophage transcriptome. We report that Lyl1 downregulation upon immune stimulation is a host-driven process regulated by NFκB and MAP kinase pathways. Interestingly, Lyl1-deficient macrophages have decreased bacterial killing potential with reduced nitric oxide (NO) levels while expressing increased levels of pro-inflammatory interleukin-1 and CXCL1. Lyl1-deficient mice show reduced survival toMtbHN878 infection with increased bacterial burden and exacerbated inflammatory responses in chronic stages. We observed that increased susceptibility to infection was accompanied by increased neutrophil recruitment and IL-1, CXCL1, and CXCL5 levels in the lung homogenates. Collectively, these results suggest that Lyl1 controlsMtbgrowth, reduces neutrophilic inflammation and reveals an underappreciated role for Lyl1 in innate immune responses.
Targeting immunometabolism mediated by the IDO1 Pathway: A new mechanism of immune resistance in endometrial cancer
Authors: Passarelli Anna , Pisano Carmela , Cecere Sabrina Chiara , Di Napoli Marilena , Rossetti Sabrina , Tambaro Rosa , Ventriglia Jole , Gherardi Federica , Iannacone Eva , Venanzio Sergio Setola , Fiore Francesco , Bartoletti Michele , Scognamiglio Giosuè , Califano Daniela , Pignata Sandro
Published: September 2022

Immunotherapy is acquiring a primary role in treating endometrial cancer (EC) with a relevant benefit for many patients. Regardless, patients progressing during immunotherapy or those who are resistant represent an unmet need. The mechanisms of immune resistance and escape need to be better investigated. Here, we review the major mechanisms of immune escape activated by the indolamine 2,3-dioxygenase 1 (IDO1) pathway in EC and focus on potential therapeutic strategies based on IDO1 signaling pathway control. IDO1 catalyzes the first rate-limiting step of the so-called “kynurenine (Kyn) pathway”, which converts the essential amino acid l-tryptophan into the immunosuppressive metabolite l-kynurenine. Functionally, IDO1 has played a pivotal role in cancer immune escape by catalyzing the initial step of the Kyn pathway. The overexpression of IDO1 is also associated with poor prognosis in EC. These findings can lead to advantages in immunotherapy-based approaches as a rationale for overcoming the immune escape. Indeed, besides immune checkpoints, other mechanisms, including the IDO enzymes, contribute to the EC progression due to the immunosuppression induced by the tumor milieu. On the other hand, the IDO1 enzyme has recently emerged as both a promising therapeutic target and an unfavorable prognostic biomarker. This evidence provides the basis for translational strategies of immune combination, whereas IDO1 expression would serve as a potential prognostic biomarker in metastatic EC.
Integrated analysis of immune parameters, miRNA-mRNA interaction, and immune genes expression in the liver of rainbow trout following infectious hematopoietic necrosis virus infection
Authors: Wu Shenji , Huang Jinqiang , Li Yongjuan , Lei Mingquan , Zhao Lu , Liu Zhe
Published: September 2022

Rainbow trout (Oncorhynchus mykiss) is an important economical cold-water fish worldwide. However, infection with infectious hematopoietic necrosis virus (IHNV) has severely restricted the development of aquaculture and caused huge economic losses. Currently, little is known about the immune defense mechanisms of rainbow trout against IHNV. In this study, we detected the changes of immune parameters over different post-infection periods (6-, 12-, 24-, 48-, 72-, 96-, 120-, and 144 hours post-infection (hpi)), mRNA and miRNA expression profiles under 48 hpi (T48L) compared to control (C48L), and key immune-related genes expression patterns in rainbow trout liver following IHNV challenge through biochemical methods, RNA-seq, and qRT-PCR, and the function of miR-330-y was verified by overexpression and silencing in vitro and in vivo. The results revealed that alkaline phosphatase (AKP), alanine aminotransferase (ALT), catalase (CAT), and total superoxide dismutase (T-SOD) activities, and lysozyme (LZM) content showed significant peaks at 48 hpi, whereas malondialdehyde (MDA) content and aspartate aminotransferase (AST) activity decreased continuously during infection, and acid phosphatase (ACP) activity varied slightly. From RNA-seq, a total of 6844 genes and 86 miRNAs were differentially expressed, and numerous immune-related differentially expressed genes (DEGs) involved in RIG-I-like receptor signaling pathway, Toll-like receptor signaling pathway, NOD-like receptor signaling pathway, cytokine-cytokine receptor interaction, and antigen processing and presentation were significantly upregulated in T48Lm group, including IFIH1, DHX58, MAVS, TRAF3, IRF3, IRF7, MX1, TLR3, TLR8, MYD88, NOD1, NOD2, IL-8, CXCR1, CD209, CD83, and TAP1. Integrated analysis identified seven miRNAs (miR-425-x, miR-185-x, miR-338-x, miR-330-y, miR-361-x, miR-505-y, and miR-191-x) that target at least three key immune-related DEGs. Expression analysis showed that IFIH1, DHX58, IRF3, IRF7, MX1, TLR3, TLR8, and MYD88 showed a marked increase after 24 hpi during infection. Further research confirmed TAP1 as one of the targets of miR-330-y, overexpression of miR-330-y with mimics or agomir significantly reduced the expression levels of TAP1, IRF3, and IFN, and the opposite effects were obtained by inhibitor. These results facilitate in-depth understanding of the immune mechanisms in rainbow trout against IHNV.
Research advance of natural products in tumor immunotherapy
Authors: Huo Jin-Ling , Fu Wen-Jia , Liu Zheng-Han , Lu Nan , Jia Xiang-Qian , Liu Zhang-Suo
Published: September 2022

Cancer immunotherapy has emerged as a novel anti-tumor treatment. Despite significant breakthroughs, cancer immunotherapy remains focused on several types of tumors that are sensitive to the immune system. Therefore, effective strategies to expand its indications and improve its efficacy become key factors for the further development of cancer immunotherapy. In recent decades, the anticancer activities of natural products are reported to have this effect on cancer immunotherapy. And the mechanism is largely attributed to the remodeling of the tumor immunosuppressive microenvironment. The compelling data highlight that natural products offer an alternative method option to improve immune function in the tumor microenvironment (TME). Currently, more attention is being paid to the discovery of new potential modulators of tumor immunotherapy from natural products. In this review, we describe current advances in employing natural products and natural small-molecule drugs targeting immune cells to avoid tumor immune escape, which may bring some insight for guiding tumor treatment.
Immunotherapy resistance in esophageal cancer: Possible mechanisms and clinical implications
Authors: Fang Pinhao , Zhou Jianfeng , Liang Zhiwen , Yang Yushang , Luan Siyuan , Xiao Xin , Li Xiaokun , Zhang Hanlu , Shang Qixin , Zeng Xiaoxi , Yuan Yong
Published: September 2022

Esophageal cancer (EC) is a common malignant gastrointestinal (GI) cancer in adults. Although surgical technology combined with neoadjuvant chemoradiotherapy has advanced rapidly, patients with EC are often diagnosed at an advanced stage and the five-year survival rate remains unsatisfactory. The poor prognosis and high mortality in patients with EC indicate that effective and validated therapy is of great necessity. Recently, immunotherapy has been successfully used in the clinic as a novel therapy for treating solid tumors, bringing new hope to cancer patients. Several immunotherapies, such as immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell therapy, and tumor vaccines, have achieved significant breakthroughs in EC treatment. However, the overall response rate (ORR) of immunotherapy in patients with EC is lower than 30%, and most patients initially treated with immunotherapy are likely to develop acquired resistance (AR) over time. Immunosuppression greatly weakens the durability and efficiency of immunotherapy. Because of the heterogeneity within the immune microenvironment and the highly disparate oncological characteristics in different EC individuals, the exact mechanism of immunotherapy resistance in EC remains elusive. In this review, we provide an overview of immunotherapy resistance in EC, mainly focusing on current immunotherapies and potential molecular mechanisms underlying immunosuppression and drug resistance in immunotherapy. Additionally, we discuss prospective biomarkers and novel methods for enhancing the effect of immunotherapy to provide a clear insight into EC immunotherapy.
The efficacy and safety of tacrolimus on top of glucocorticoids in the management of IIM-ILD: A retrospective and prospective study
Authors: Chen Yuxue , Bai Zhiqian , Zhang Ziyun , Hu Qiongjie , Zhong Jixin , Dong Lingli
Published: September 2022

Objective

To examine the efficacy of tacrolimus on top of glucocorticoids (GCs) in the management of idiopathic inflammatory myopathies-associated interstitial lung disease (IIM-ILD) and further assess the therapeutic benefit and safety of low-dose pirfenidone followed above treatments.

Methods

The retrospective study comprised 250 patients with IIM-ILD hospitalized in Tongji Hospital from 2014 to 2020. Demographic data, survival outcomes, and recurrence rates over the 1-year follow-up period were retrospectively analyzed. These patients were divided into two groups based on treatment with tacrolimus alone or other conventional immunosuppressants. Endpoints were compared by adjusted Cox regression model using inverse probability of treatment weighting to minimize treatment bias and potential confounders. For the prospective study, IIM-ILD patients treated with tacrolimus alone or tacrolimus combined with low-dose pirfenidone were enrolled from 2018 to 2020. Clinical characteristics, survival outcomes and multifarious assessment scales were followed up at baseline, 3, 6 and 12 months. The primary endpoint was 12-month survival rate and the secondary endpoints included respiratory-related events, adverse events, exacerbation in HRCT findings and laboratory parameters during therapy courses, and changes in respiratory function.

Results

For the retrospective study, tacrolimus group (n=93) had a significantly higher survival rate (weighted HR=0.330, p=0.002) and a lower relapse rate (weighted HR=0.548, p=0.003) compared with patients treated with other types of immunosuppressant (n=157) after adjustment. The prospectively enrolled 34 IIM-ILD patients were treated with tacrolimus (n=12) or tacrolimus combined with low-dose pirfenidone (n=22). After 12 months of treatment with tacrolimus, patients in the prospective cohort showed significant improvements in cardio-pulmonary function, disease activity, muscle strength, and mental scale from baseline. Subgroup analysis indicated that patients with tacrolimus and pirfenidone combination therapy showed lower chest HRCT scores (p=0.021) and lower respiratory-related relapse rates than those in tacrolimus monotherapy group (log-rank p=0.0029). The incidence rate of drug-associated adverse events (AEs) was comparable between two groups and none of the patients discontinued the treatment due to severe AEs.

Conclusion

Tacrolimus is well-tolerated and effective in the treatment of IIM-ILD. Furthermore, low-dose pirfenidone add-on treatment seems result in favorable improvements in pulmonary involvements for IIM-ILD patients.

Clinical Trial Registration

http://www.chictr.org.cn, identifier ChiCTR2100043595.
The role of the different CD3γ domains in TCR expression and signaling
Authors: Garcillán Beatriz , Megino Rebeca F. , Herrero-Alonso Marta , Guardo Alberto C. , Perez-Flores Veronica , Juraske Claudia , Idstein Vincent , Martin-Fernandez Jose M. , Geisler Carsten , Schamel Wolfgang W. A. , Marin Ana V. , Regueiro Jose R.
Published: September 2022

The CD3 subunits of the T-cell antigen receptor (TCR) play a central role in regulation of surface TCR expression levels. Humans who lack CD3γ (γ—) show reduced surface TCR expression levels and abolished phorbol ester (PMA)-induced TCR down-regulation. The response to PMA is mediated by a double leucine motif in the intracellular (IC) domain of CD3γ. However, the molecular cause of the reduced TCR surface expression in γ—lymphocytes is still not known. We used retroviral vectors carrying wild type CD3γ or CD3δ or the following chimeras (EC-extracellular, TM-transmembrane and IC): δECγTMγIC(δγγ for short), γγδ, γδδ and γγ-. Expression of γγγ, γγδ, γδδ or γγ- in the γ—T cell line JGN, which lacks surface TCR, demonstrated that cell surface TCR levels in JGN were dependent on the EC domain of CD3γ and could not be replaced by the one of CD3δ. In JGN and primary γ—patient T cells, the tested chimeras confirmed that the response to PMA maps to the IC domain of CD3γ. Since protein homology explains these results better than domain structure, we conclude that CD3γ contributes conformational cues that improve surface TCR expression, likely at the assembly or membrane transport steps. In JGN cells all chimeric TCRs were signalling competent. However, an IC domain at CD3γ was required for TCR-induced IL-2 and TNF-α production and CD69 expression, indicating that a TCR without a CD3γ IC domain has altered signalling capabilities.
Humoral antimalaria immune response in Nigerian children exposed to helminth and malaria parasites
Authors: Adukpo Selorme , Adedoja Ayodele , Esen Meral , Theisen Michael , Ntoumi Francine , Ojurongbe Olusola
Published: September 2022

Background

Malaria and helminthic parasites are endemic in tropical countries, and co-infections might influence host-parasite interactions. In this community-based cross-sectional study, the effect that the presence of soil-transmitted helminths (STH) (Hookworm, Hymenolepis nana) and Schistosoma haematobium infections could have on the immunoglobulin (Ig) candidate protein of the malaria vaccine GMZ2 levels was evaluated.

Methods

Blood, stool, and urine samples were collected from 5-15-year-old children to diagnose P. falciparum (Pf), STH, and Schistosoma haematobium, respectively. Identification and quantification of the parasite load of STH and S. haematobium were achieved by light microscopy. A polymerase chain reaction was carried out to detect submicroscopic infections of P. falciparum. Plasma levels of GMZ2 specific IgG and its subclasses were quantified by ELISA.

Results

The median level of total IgG in individuals with co-infection with Pf/H. nana was significantly lower in the mono-infected group with Pf (p = 0.0121) or study participants without infection (p=0.0217). Similarly, the median level of IgG1 was statistically lower in Pf/H. nana group compared to Pf-group (p=0.0137). Equally, the Pf/H. nana infected individuals posted a lower level of IgG1 compared to Pf-group (p=0.0137) and IgG4 compared to the Pf-group (p=0.0144). Spearman rank correlation analyses indicated positive relationships between the densities of H. nana (ρ=0.25, p=0.015) and S. haematobium (ρ=0.36, p<0.0001).

Conclusions

Hookworm and H. nana infections are associated with reduced GMZ2 specific IgG levels. This study shows the possible manipulation of immune responses by helminths for their survival and transmission, which may have serious implications for vaccine development and deployment in helminth-endemic regions.
The potential roles of interleukin-25 in infectious diseases
Authors: Wu Jing , Zhang Fang , Tao Hongji , Nawaz Waqas , Chen Deyan , Wu Zhiwei
Published: September 2022

Interleukin-25 (IL-25), also known as IL-17E, is a recently identified cytokine of the IL-17 family. Numerous studies illustrated that the expression of IL-25 is regulated by multiple pathogens, including parasitic, viral, and bacterial infections. IL-25 has a dual function in infectious diseases. On the one hand, IL-25 activates type 2 immunity via the relevant cytokines, including IL-4, IL-5, and IL-13, which are associated with the development of pathogenic infection-related allergic diseases. On the other hand, IL-25 involves in the recruitment of group 2 innate lymphoid cells (ILC2) to enhanced T helper 2 (Th2) cell differentiation, which are important to the clearance of pathogens. However, the precise roles of IL-25 in infectious diseases remain largely unknown. Thus, the current review will shed light on the pivotal roles of IL-25 in infectious diseases.
Characterizing location of spotted lanternfly egg masses in wooded habitat during early invasion stages
Authors: Madalinska Katarzyna , McDougall Robert , Nielsen Anne L.
Published: September 2022

The spotted lanternfly, Lycorma delicatula (Hemiptera: Fulgoridae), is an invasive planthopper from Asia that is estimated to have spread 17 km/yr since it's initial detection in Pennsylvania in 2014. Lycorma delicatula is a pest to the agricultural and forestry industries in the Mid-Atlantic region of the United States, in part due to its highly polyphagous nature. Current detection relies on visual observations, unbaited traps, or eDNA surveillance in its primary hosts, including grape and hardwoods. These approaches narrow the surveillance area by concentrating on known host plants but could be further refined to narrow the search parameters from the 100+ known host plants. Because L. delicatula appears to have a strong population buildup in wooded areas, we evaluated the relationship between egg mass presence and habitat characteristics in wooded habitats adjacent to vineyards in New Jersey at six farms within the first two years of L. delicatula detection. Habitat characteristics included distance from wood edge, and presence of a critical host plant Ailanthus altissima, and presence of Vitis spp. within 4.5 m. We identified a significant relationship between egg mass presence and Vitis spp. with an 88% probability of finding an egg mass close to a wild grapevine, dropping to 9% where grapes were absent. During the early invasion stages when this research was conducted, a two-year delay from initial detection in wooded habitats to nymphal presence in the vineyard was observed.
Evaluating the stock status of 10 croaker species landed along the north-eastern Arabian Sea using the length-based Bayesian biomass approach
Authors: Rahangdale Shikha , Zacharia Pariyappanal Ulahannan , Kumar Rajan , Vase Vinayakumar
Published: September 2022

India accounts for nearly 60% of the croakers caught in the Indian Ocean. The north-west (NW) coast of India is the most productive fishing ground for croakers and contributes almost half of the nation’s croaker catch. Lesser sciaenids (small- and medium-sized croakers) are the multi-species complex landed by commercial trawlers along the NW coast of India. Despite several notable changes in the fishing pattern in the region, such as the emergence of multi-day fishing and increasing dominance of pelagic trawling, there is no recent assessment of this major demersal fishery group. The present study evaluates the stock status of 10 species of lesser sciaenids forming the commercial fishery in the region using length frequency data collected during 2020–2021. The assessment was made using the length-based Bayesian biomass (LBB) estimation method. The indicators of relative biomass (B/B0 and B/BMSY) showed that most of the species (seven) are fully exploited, whereas two and one species were found under- and over-exploited, respectively. Excessive juveniles (Lmean/Lopt and Lc/Lc_opt< 0.90) in catches were observed in the case of Paranibea semiluctuosa. A sufficient number of larger individuals (L95th/Linf< 0.90) in the population were lacking in the case of Johnius belangerii and Otoithes ruber. However, the study indicated a gradual improvement in stock status for most of the species over previous estimates, which can be attributed to the diversion of trawl fishing efforts towards the pelagic realm.
Ecological environmental quality assessment of Chinese estuarine wetlands during 2000–2020 based on a remote sensing ecological index
Authors: Zhang Zhen , Cai Zongcai , Yang Junhua , Guo Xiaohui
Published: September 2022

Coastal estuarine wetlands are important transition zones between rivers and oceans and are extremely rich in biodiversity. In recent years in China, large-scale reclamation and development of coastal cities have imposed serious pressures on coastal ecosystems. Thus, assessing the ecological quality of estuarine wetlands is extremely important for sustainable development. Our study focuses on four typical estuarine wetlands at the mouths of the Yangtze, Yellow, Liaohe and PearRivers. Their ecological quality between 2000 and 2020 was assessed using a remote sensing ecological index (RSEI), which was derived from several remote sensing indexes processed via the online Google Earth Engine platform. From 2000 to 2020, the RSEIs of coastal wetland increased from 0.42 to 0.63 in the Liao River estuary, 0.27 to 0.45 in the Pearl River estuary and from 0.47 to 0.54 in the Yangtze River estuary, and decreased from 0.56 to 0.49 in the Yellow River estuary. The spatial distribution in ecological environmental quality was significantly clustered. High-high clusters occurred mainly in areas of lush vegetation, while low-low clusters were mostly found in built-up areas or coastal zones. Aquacultural and built-up areas had negative impacts on the ecological environment, while vegetation cover had a positive influence. The quality of the ecological environment within these wetlands has gradually improved due to the environmental management policies of national and local governments. This approach to evaluating the ecological quality of estuarine wetlands using the RSEI and Google Earth Engine provides critical information to inform sustainable development policy.
Frequency and gender differences in the use of professional home care in late life. Findings from three German old-age cohorts
Authors: Buczak-Stec Elżbieta W. , Hajek André , Pabst Alexander , Brettschneider Christian , van den Bussche Hendrik , Wiese Birgitt , Weyerer Siegfried , Werle Jochen , Hoell Andreas , Pentzek Michael , Fuchs Angela , Luppa Melanie , Löbner Margit , Stein Janine , Förster Franziska , Weeg Dagmar , Mösch Edelgard , Heser Kathrin , Scherer Martin , Maier Wolfgang , Angermeyer Matthias C. , Wagner Michael , Riedel-Heller Steffi G. , König Hans-Helmut
Published: September 2022

Aim

The aim of this study was to investigate the frequency of and the gender differences in the use of professional home care in Germany.

Methods

We used harmonized data from three large cohort studies from Germany (“Healthy Aging: Gender-specific trajectories into the latest life”; AgeDifferent.de Platform). Data were available for 5,393 older individuals (75 years and older). Mean age was 80.2 years (SD: 4.1 years), 66.6% were female. Professional homecare outcome variables were use of outpatient nursing care, paid household assistance, and meals on wheels' services. Logistic regression models were used, adjusting for important sociodemographic variables.

Results

Altogether 5.2% of older individuals used outpatient nursing care (6.2% women and 3.2% men; p < 0.001), 24.2% used paid household assistance (26.1% women and 20.5% men; p < 0.001) and 4.4% used meals on wheels' services (4.5% women and 4.0% men; p = 0.49). Regression analysis revealed that women had higher odds of using paid household assistance than men (OR = 1.48, 95% CI: [1.24–1.76]; p < 0.001), whereas they had lower odds of using meals on wheels' services (OR = 0.64, 95% CI: [0.42–0.97]; p < 0.05). No statistically significant differences in using outpatient nursing care between women and men were found (OR = 1.26, 95% CI: [0.87–1.81]; p = 0.225). Further, the use of home care was mainly associated with health-related variables (e.g., stroke, Parkinson's disease) and walking impairments.

Conclusions

Our study showed that gender differences exist in using paid household assistance and in culinary dependency. For example, meals on wheels' services are of great importance (e.g., for individuals living alone or for individuals with low social support). Gender differences were not identified regarding outpatient nursing care. Use of professional home care services may contribute to maintaining autonomy and independence in old age.
Responses of soil enzyme activities and bacterial community structure to different hydrological regimes during peatland restoration in the Changbai Mountain, northeast China
Authors: Wang Ming , Xu Shangqi , Wang Shengzhong , Chen Cong , Wang Yuting , Liu Lei
Published: September 2022

Appropriate hydrological management is critical for peatland restoration. An important prerequisite for peatland restoration is a recovery of soil biological processes. However, little is known about the effects of different hydrological management practices on soil biological processes during peatland restoration. In this study, the variations in soil properties, enzyme activities, and bacterial communities across different peatlands, namely natural peatland (NP), peatland restored under high water level (HR), peatland restored under alternating high-low water level (HLR), peatland restored under low water level (LR), and degraded peatland (DP), in the Changbai Mountains were investigated. Results showed that soil organic carbon, soil water content, and total nitrogen in NP were significantly higher than those in restored and degraded peatlands, and these soil properties in restored peatlands increased with the water level. The activities of soil hydrolases including β-1, 4-glucosidase, β-1, 4-n-acetylglucosidase, and acid phosphatase in NP were higher than in restored and degraded peatlands, while the activity of polyphenol oxidase in NP was the lowest. In restored peatlands, all measured enzyme activities decreased with the decline in water level. Both bacterial diversity and richness in NP were the lowest, while the highest diversity and richness were observed in HR. Redundancy analysis indicated that soil organic carbon, water level, soil water content, total nitrogen, and pH were the most important factors that affected the soil enzyme activities and bacterial community. Our findings give insight into the effects of different hydrological regimes on soil biological processes during peatland restoration. Maintaining a high water level early in the restoration process is more beneficial to restoring the ecological functions of peatlands than other hydrological regimes.
Identification of ophiostomatalean fungi associated with Tomicus pilifer infesting Pinus koraiensis in Northeastern China
Authors: Wang Huimin , Liu Caixia , Yue Fangzheng , Yan Dong-Hui , Lu Quan
Published: September 2022

Ophiostomatalean fungi usually facilitate bark beetles to infest tree hosts and seriously endanger the health of coniferous forests. Tomicus pilifer Spessivtsev is a common endemic bark beetle in Asia and primarily threatens Pinus koraiensis. Tomicus species have similar morphology; however, they can be differentiated by their genetic characteristics through phylogenetic analyses. To date, the 28S rDNA sequence of T. pilifer and the diversity of ophiostomatalean fungi associated with T. pilifer have not been reported. In this study, we aimed to clarify the taxonomic status of T. pilifer and identify ophiostomatalean fungi associated with T. pilifer infesting P. koraiensis in northeastern China. In total, 315 ophiostomatalean fungal strains were isolated from 62 adults of T. pilifer and 220 tissue samples from T. pilifer galleries in Jilin Province. Thirty-five representative strains were further identified by comparing their morphological and physiological characteristics and conducting the phylogenetic analysis of ITS, ITS2-LSU, TUB2, and TEF1-α. We identified nine species of ophiostomatalean fungi belonging to four genera, which included six novel species (Ceratocystiopsis changbaiensis sp. nov., Leptographium linjiangense sp. nov., Leptographium qieshaoense sp. nov., Ophiostoma piliferi sp. nov., Ophiostoma tonghuaense sp. nov., and Ophiostoma yaluense sp. nov.), two previously described species (Graphilbum interstitiale and Ophiostoma fuscum), and one undefined specie (Ceratocystiopsis sp. 1). To the best of our knowledge, this is the first report of G. interstitiale and O. fuscum in China and the fungal diversity of ophiostomatalean in T. pilifer. The dominant species were O. piliferi and L. qieshaoense, representing 39.37% and 35.87% of the isolates, respectively. The results of this study provide valuable information on the symbiotic relationship between bark beetles and ophiostomatalean fungi.