bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk factors and diagnostic prediction models for papillary thyroid carcinoma
Authors: Zhang Xiaowen , Ze Yuyang , Sang Jianfeng , Shi Xianbiao , Bi Yan , Shen Shanmei , Zhang Xinlin , Zhu Dalong
Published: September 2022

Thyroid nodules (TNs) represent a common scenario. More accurate pre-operative diagnosis of malignancy has become an overriding concern. This study incorporated demographic, serological, ultrasound, and biopsy data and aimed to compare a new diagnostic prediction model based on Back Propagation Neural Network (BPNN) with multivariate logistic regression model, to guide the decision of surgery. Records of 2,090 patients with TNs who underwent thyroid surgery were retrospectively reviewed. Multivariate logistic regression analysis indicated that Bethesda category (OR=1.90, P<0.001), TIRADS (OR=2.55, P<0.001), age (OR=0.97, P=0.002), nodule size (OR=0.53, P<0.001), and serum levels of Tg (OR=0.994, P=0.004) and HDL-C (OR=0.23, P=0.001) were statistically significant independent differentiators for patients with PTC and benign nodules. Both BPNN and regression models showed good accuracy in differentiating PTC from benign nodules (area under the curve [AUC], 0.948 and 0.924, respectively). Notably, the BPNN model showed a higher specificity (88.3% vs. 73.9%) and negative predictive value (83.7% vs. 45.8%) than the regression model, while the sensitivity (93.1% vs. 93.9%) was similar between two models. Stratified analysis based on Bethesda indeterminate cytology categories showed similar findings. Therefore, BPNN and regression models based on a combination of demographic, serological, ultrasound, and biopsy data, all of which were readily available in routine clinical practice, might help guide the decision of surgery for TNs.
It is not worth postponing frozen embryo transfers after oocyte pickup: A retrospective cohort study based on propensity score matching
Authors: Ji Mengxia , Jin Bihui , Guo Xiaoyan , Wu Ruifang , Jiang Yunqing , Zhang Ling , Shu Jing
Published: September 2022

This study was to explore whether postponing frozen embryo transfers (FET) after oocyte pickup (OPU) improves clinical and neonatal outcomes. From May 2018 to Dec 2020, a total of 1109 patients underwent their first OPU cycles adopting a non-selective freeze-all policy were included in this retrospective cohort study. In the immediate group (n=219), patients underwent FET in the first menstrual cycle after OPU, and patients in the postponed group (n=890) waited for more than 1 menstrual cycle after OPU to perform FET. A propensity score matching (PSM) model was used to evaluate the clinical outcomes and neonatal outcomes between the two groups. There were 209 patients in the immediate group and 499 patients in the postponed one after PSM. Patients waited for a significantly shorter period for FET in the immediate group (30.74 ± 3.85 days) compared with the postponed group (80.39 ± 26.25 days, P<0.01). The clinical pregnancy rate (CPR) and live birth rate (LBR) in the immediate group were 58.4% and 48.3%, respectively, which were comparable to those of the postponed one (58.1%, 49.7%, P > 0.05). No statistical significance was found in the average birth weight (3088.82 ± 565.35 g vs 3038.64 ± 625.78 g, P > 0.05) and height (49.08 ± 1.87 cm vs 49.30 ± 2.52 cm) of neonates between the two groups. The gender ratio, the incidence of macrosomia and low birth weight did not differ significantly between the two groups. In conclusion, postponing FET does not improve clinical and neonatal outcomes. If patients have no contraindications, FETs should be carried out immediately after OPU.
Edge intelligence enabled optimal scheduling with distributed price-responsive load for regenerative electric boilers
Authors: Fan Dongchuan , Wang Ruizhe , Qi Haonan , Deng Xiaoyun , Chen Yongdong , Liu Tingjian , Liu Youbo
Published: September 2022

Heat supply accounts for a substantial amount of terminal energy usage. However, along with price rises in primary energy, there is an urgent need to reduce the average cost of energy consumption during the purchasing of thermal services. Electric heating, an electricity-fed heating production and delivery technology, has been suggested as a promising method for improving heating efficiency, due to the ease of scheduling. However, the traditional centralized operating methods of electricity purchasing rely on explicit physical modeling of every detail, and accurate future predictions, the implementation of which are rarely practical in reality. To facilitate model-free decisions in the field of electricity purchasing, heat storage, and supply management, aimed at cost saving in a real-time price environment, this study proposes a scheduling framework based on deep reinforcement learning (DRL) and the existence of responsive users. First, the structure of a distributed heating system fed by regenerative electric boilers (REBs), which facilitate shiftable heat-load control, is introduced. A terminal heat demand response model based on thermal sensation vote (TSV), characterizing the consumption flexibility of responsive users, is also proposed. Second, due to thermal system inertia, the sequential decision problem of electric heating load scheduling is transformed into a specific Markov decision process (MDP). Finally, the edge intelligence (EI) deployed on the demand side uses a twin delayed deterministic policy gradient (TD-3) algorithm to address the action space continuity of electric heating devices. The combination of a DRL strategy and the computing power of EI enables real-time optimal scheduling. Unlike the traditional method, the trained intelligent agent makes adaptive control strategies according to the currently observed state space, thus avoiding prediction uncertainty. The simulation results validate that the intelligent agent responds positively to changes in electricity prices and weather conditions, reducing electricity consumption costs while maintaining user comfort. The adaptability and generalization of the proposed approach to different conditions is also demonstrated.
Performance evaluation of renewable-based sustainable micro-grid under predictive management control strategy: A case study of Gado refugee camp in Cameroon
Authors: Same Noel Ngando , Yakub Abdulfatai Olatunji , Kigha Nsafon Benyoh Emmanuel , Owolabi Abdulhameed Babatunde , Mih Thomas Attia , Suh Dongjun , Huh Jeung-Soo
Published: September 2022

The recent use of hybrid renewable energy systems (HRESs) is considered one of the most reliable ways to improve energy access to decentralized communities because of their techno-economic and environmental benefits. Many distant locales, such as camps in war-torn nations, lack basic necessities like power. This study proposes a remedy for power outages in these areas; by designing an HRES and a control system for monitoring, distributing, and managing the electrical power from sustainable energy sources to supply the load. Hence, providing affordable, reliable, and clean energy for all (Sustainable Development Goal 7). In this study, the feasibility and techno-economic performance of an HRES for a refugee camp was evaluated under load following (LF), cycle charging (CC), and predictive control strategy (PS). The optimization results revealed that the PS was the most suitable, as it had the lowest cost and was more eco-friendly and energy-efficient. The predictive control strategy had a 48-h foresight of the load demand and resource potential and hence could effectively manage the HRES. The total net present cost (NPC) for the electrification of this refugee camp was $3,809,822.54, and the cost of electricity generated for every kWh is $0.2018. Additionally, 991,240.32 kg of emissions can be avoided annually through the hybridization of the diesel generator under the PS.
Nexus between uncertainty, remittances, and households consumption: Evidence from dynamic SUR application
Authors: Yin Ying , Qamruzzaman Md. , Xiao He , Mehta Ahmed Muneeb , Naqvi Farah Naz , Baig Imran Ali
Published: September 2022

Household consumption induces aggregated economic activities by pushing market demand, capital accumulation and financial growth in the economy; on the other hand, instability in household consumption adversely affects the overall economic progress. Thus, exploring the key determinants responsible for household consumption instability is essential. The motivation of the study is to gauge the role of pandemic uncertainties and remittance inflow on household consumption in lower, Lower-middle, and Upper-Middle-income Countries for the period 1996 to 2020. The study employed several econometrical tools, including a panel cointegration test with the error correction term, dynamic SUR. The panel unit root test following CADF and CIPS documented variables are stationary after the first difference, and long-run associations are confirmed with the panel cointegration test. The coefficient of Dynamic Seemingly Unrelated Regression exposed pandemic uncertainties and has a negative impact on household consumption in all three-panel estimations; however, the coefficient of PUI is more prominent with COVID-19 effects. Remittances’ role in household consumption was positive and statistically significant, suggesting migrant remittances encourage additional consumption among households. On the policy aspect, the study proposed that the government should undertake macro policies to manage policy uncertainties so that the normal course of consumption level should not be interrupted because household consumption volatility creates discomfort in aggregated development. Moreover, efficient reallocation and remittance channels should be ensured in the economy; therefore, efficient institutional development has to be confirmed.
Cytological alterations and oxidative stress induced by Cerium and Neodymium in lentil seedlings and onion bulbs
Authors: Gjata Isidora , Tommasi Franca , De Leonardis Silvana , Dipierro Nunzio , Paciolla Costantino
Published: September 2022

Rare earth elements (REEs) are a group of 15 elements, the lanthanides and Yttrium and Scandium, with similar chemical and physical properties. Their use for many advanced technological applications remarkably increased in the last decades, and it was associated with an intensive extraction of such elements from their ores. Consequently, increasing amounts of either REE-containing by-products, deriving from the extraction process, and REE-containing wastes, deriving from the disposal of REE-containing devices, are reaching the environmental systems both at the local and global levels, as never in the past. Few data in the literature concern the effect (beneficial or toxic) induced by REEs application in terrestrial plant species and at different physiological stages. A set of experiments with exposure to two REEs was performed on some plants to evaluate this. Data of investigations focused on the exposure of lentil (Lens culinaris Medik.) seedlings and onion (Allium cepa L.) bulbs to cerium chloride (CeCl3) and neodymium chloride (NdCl3) at different concentrations for 72 h. Results showed alteration of the growth rate and the levels of some parameters considered as biomarkers of stress (reactive oxygen species and antioxidant systems). An increase in some mitotic aberrations was also observed in the root tissues of both species. The results indicate that the sensitivity of lentil in this bioassay is higher for lower concentrations compared to onion. Also, lower concentrations of these REEs had a positive effect on the growth rate of lentils underlining the complex interaction occurring between REEs and different plant organisms.
An overview of the contribution of the textiles sector to climate change
Authors: Leal Filho Walter , Perry Patsy , Heim Hilde , Dinis Maria Alzira Pimenta , Moda Haruna , Ebhuoma Eromose , Paço Arminda
Published: September 2022

The textile industry is responsible for a significant amount of global CO2 emissions, exceeding those from several other sectors such as international aviation and shipping. This article outlines the reasons for the textile industry’s contribution to climate change along with an overview of current trends. Finally, it outlines several measures to reduce its carbon footprint.
Investigation of the transability of dietary small non-coding RNAs to animals
Authors: Norouzi Milad , Bakhtiarizadeh Mohammad Reza , Salehi Abdolreza
Published: September 2022

Our daily diet not only provides essential nutrients needed for survival and growth but also supplies bioactive ingredients to promote health and prevent disease. Recent studies have shown that exogenous microRNAs (miRNAs), xenomiRs, may enter the consumer’s body through dietary intake and regulate gene expression. This fascinating phenomenon suggests that xenomiRs can act as a new class of bioactive substances associated with mammalian systems. In contrast, several studies have failed to detect xenomiRs in consumers and reported that the observed diet-derived miRNAs in the previous studies can be related to the false positive effects of experiments. This discrepancy can be attributed to the potential artifacts related to the process of experiments, small sample size, and inefficient bioinformatics pipeline. Since this hypothesis is not generally accepted yet, more studies are required. Here, a stringent and reliable bioinformatics pipeline was used to analyze 133 miRNA sequencing data from seven different studies to investigate this phenomenon. Generally, our results do not support the transfer of diet-derived miRNAs into the animal/human tissues in every situation. Briefly, xenomiRs were absent from most samples, and also, their expressions were very low in the samples where they were present, which is unlikely to be sufficient to regulate cell transcripts. Furthermore, this study showed that the possibility of miRNAs being absorbed through animals’ diets and thus influencing gene expression during specific periods of biological development is not inconceivable. In this context, our results were in agreement with the theory of the transfer of small RNAs under certain conditions and periods as xenomiRs were found in colostrum which may modulate infants’ immune systems via post-transcriptional regulation. These findings provide evidence for the selective absorption of diet-derived small RNAs, which need to be investigated in future studies to shed light on the mechanisms underlying the transference of diet-derived miRNAs.
Immune cell infiltration-related clinical diagnostic model for Ankylosing Spondylitis
Authors: Zhou Chenxing , Liang Tuo , Jiang Jie , Zhang Zide , Chen Jiarui , Chen Tianyou , Chen Liyi , Sun Xuhua , Huang ShengSheng , Zhu Jichong , Wu Shaofeng , Zhan Xinli , Liu Chong
Published: September 2022

Background: The pathogenesis and diagnosis of Ankylosing Spondylitis (AS) has remained uncertain due to several reasons, including the lack of studies on the local and systemic immune response in AS. To construct a clinical diagnostic model, this study identified the micro RNA-messenger RNA (miRNA-mRNA) interaction network and immune cell infiltration-related hub genes associated with AS.

Materials and Methods: Total RNA was extracted and purified from the interspinous ligament tissue samples of three patients with AS and three patients without AS; miRNA and mRNA microarrays were constructed using the extracted RNA. Bioinformatic tools were used to construct an miRNA-mRNA network, identify hub genes, and analyze immune infiltration associated with AS. Next, we collected the blood samples and clinical characteristics of 359 patients (197 with AS and 162 without AS). On the basis of the clinical characteristics and results of the routine blood tests, we selected immune-related cells whose numbers were significantly different in patients with AS and patients without AS. Univariate and multivariate logistic regression analysis was performed to construct a nomogram. Immunohistochemistry staining analysis was utilized to verify the differentially expression of LYN in AS and controls.

Results: A total of 225 differentially expressed miRNAs (DE miRNAs) and 406 differentially expressed mRNAs (DE mRNAs) were identified from the microarray. We selected 15 DE miRNAs and 38 DE mRNAs to construct a miRNA-mRNA network. The expression of LYN, an immune-related gene, correlated with the counts of monocytes, neutrophils, and dendritic cells. Based on the independent predictive factors of sex, age, and counts of monocytes, neutrophils, and white blood cells, a nomogram was established. Receiver operating characteristic (ROC) analysis was performed to evaluate the nomogram, with a C-index of 0.835 and AUC of 0.855.

Conclusion:LYN, an immune-related hub gene, correlated with immune cell infiltration in patients with AS. In addition, the counts of monocytes and neutrophils were the independent diagnostic factors for AS. If verified in future studies, a diagnostic model based on these findings may be used to predict AS effectively.
Multi-trait genome prediction of new environments with partial least squares
Authors: Montesinos-López Osval A. , Montesinos-López Abelardo , Bernal Sandoval David Alejandro , Mosqueda-Gonzalez Brandon Alejandro , Valenzo-Jiménez Marco Alberto , Crossa José
Published: September 2022

The genomic selection (GS) methodology proposed over 20 years ago by Meuwissen et al. (Genetics, 2001) has revolutionized plant breeding. A predictive methodology that trains statistical machine learning algorithms with phenotypic and genotypic data of a reference population and makes predictions for genotyped candidate lines, GS saves significant resources in the selection of candidate individuals. However, its practical implementation is still challenging when the plant breeder is interested in the prediction of future seasons or new locations and/or environments, which is called the “leave one environment out” issue. Furthermore, because the distributions of the training and testing set do not match, most statistical machine learning methods struggle to produce moderate or reasonable prediction accuracies. For this reason, the main objective of this study was to explore the use of the multi-trait partial least square (MT-PLS) regression methodology for this specific task, benchmarking its performance with the Bayesian Multi-trait Genomic Best Linear Unbiased Predictor (MT-GBLUP) method. The benchmarking process was performed with five actual data sets. We found that in all data sets the MT-PLS method outperformed the popular MT-GBLUP method by 349.8% (under predictor E + G), 484.4% (under predictor E + G + GE; where E denotes environments, G genotypes and GE the genotype by environment interaction) and 15.9% (under predictor G + GE) across traits. Our results provide empirical evidence of the power of the MT-PLS methodology for the prediction of future seasons or new environments. Furthermore, the comparison between single univariate-trait (UT) versus MT for GBLUP and PLS gave an increase in prediction accuracy of MT-GBLUP versus UT-GBLUP, but not for MT-PLS versus UT-PLS.
An integrated metabolome and transcriptome analysis of the Hibiscus syriacus L. petals reveal the molecular mechanisms of anthocyanin accumulation
Authors: Wang Xiaohong , Li Lihua , Liu Caixian , Zhang Minhuan , Wen Yafeng
Published: September 2022

Hibiscus syriacus L. var. Shigyoku is a new double-flowered bluish-purple variety in China that changes color during flower development from bluish-purple to light purple. There is limited information on the anthocyanin accumulation patterns and associated transcriptome signatures in Shigyoku from D1 (bud) to open flower (D3). Here, we employed a combined transcriptome and metabolome approach to understanding the mechanism of this color change. Our results demonstrate that cyanidins, pelargonidins, delphinidins, petunidins, peonidins, and malvidins were differentially accumulated in Shigyoku petals. The anthocyanin biosynthesis started in D1, was significantly upregulated in D2 (semi-open flower), and reduced in D3. However, malvidins, pelargonidins, and peonidins could be associated with the bluish-purple coloration on D2. Their reduced accumulation in D3 imparted the light purple coloration to Shigyoku petals on D3. Significant contributions in the color change could be associated with the expression changes in anthocyanin biosynthesis genes i.e., LARs, ANSs, DFRs, UGT79B1, C3’Hs, 3ATs, and BZ1s. The UFGTs were associated with the higher accumulation of glycosylated anthocyanins in D2 and D3. Furthermore, the changes in the expressions of the MYB and bHLH transcription factors were consistent with the anthocyanin accumulation. Finally, we discussed the possible roles of Jasmonic acid, auxin, and gibberellic acid signaling in regulating the MBW complex. Taken together, we conclude that H. syriacus petal coloration is associated with anthocyanin biosynthesis genes, the MBW complex, and phytohormone signaling.
Maternal self-conception and mental wellbeing during the first wave of the COVID-19 pandemic. A qualitative interview study through the lens of “intensive mothering” and “ideal worker” ideology
Authors: Batram-Zantvoort Stephanie , Wandschneider Lisa , Niehues Vera , Razum Oliver , Miani Céline
Published: September 2022

Mothers tended to be responsible for most of the (additional) caregiving and domestic tasks during the COVID-19 pandemic while simultaneously having to pursue their work duties. Increased role conflicts, parenting stress, and exhaustion predict adverse mental health. We aimed to examine how women referred to and made sense of dominant gender norms in their arrangements of pandemic daily life and how these beliefs impacted their maternal self-conception. Qualitative interviews with 17 women were analyzed through the lens of “intensive mothering” ideology and “ideal workers” norms, emphasizing notions of maternal guilt rising from a perceived mismatch between the ideal and actual maternal self-conception. We found that mothers' notions of guilt and their decreases in health link to dominant discourses on motherhood and intersect with “ideal worker” norms. As such, these norms amplify the burden of gendered health inequalities.
The role of tumor-associated macrophages and soluble mediators in pulmonary metastatic melanoma
Authors: Xiong Kaifen , Qi Min , Stoeger Tobias , Zhang Jianglin , Chen Shanze
Published: September 2022

Skin malignant melanoma is a highly aggressive skin tumor, which is also a major cause of skin cancer-related mortality. It can spread from a relatively small primary tumor and metastasize to multiple locations, including lymph nodes, lungs, liver, bone, and brain. What’s more metastatic melanoma is the main cause of its high mortality. Among all organs, the lung is one of the most common distant metastatic sites of melanoma, and the mortality rate of melanoma lung metastasis is also very high. Elucidating the mechanisms involved in the pulmonary metastasis of cutaneous melanoma will not only help to provide possible explanations for its etiology and progression but may also help to provide potential new therapeutic targets for its treatment. Increasing evidence suggests that tumor-associated macrophages (TAMs) play an important regulatory role in the migration and metastasis of various malignant tumors. Tumor-targeted therapy, targeting tumor-associated macrophages is thus attracting attention, particularly for advanced tumors and metastatic tumors. However, the relevant role of tumor-associated macrophages in cutaneous melanoma lung metastasis is still unclear. This review will present an overview of the origin, classification, polarization, recruitment, regulation and targeting treatment of tumor-associated macrophages, as well as the soluble mediators involved in these processes and a summary of their possible role in lung metastasis from cutaneous malignant melanoma. This review particularly aims to provide insight into mechanisms and potential therapeutic targets to readers, interested in pulmonary metastasis melanoma.
Cardiac alterations following experimental hip fracture - inflammaging as independent risk factor
Authors: Lackner Ina , Weber Birte , Pressmar Jochen , Odwarka Anna , Lam Charles , Haffner-Luntzer Melanie , Marcucio Ralph , Miclau Theodore , Kalbitz Miriam
Published: September 2022

Background

Cardiac injuries following trauma are associated with a worse clinical outcome. So-called trauma-induced secondary cardiac injuries have been recently described after experimental long bone fracture even in absence of direct heart damage. With the progressive aging of our society, the number of elderly trauma victims rises and therefore the incidence of hip fractures increases. Hip fractures were previously shown to be associated with adverse cardiac events in elderly individuals, which have mainly been attributed to pre-conditioned cardiac diseases. The aim of the present study was to investigate the effect of hip fractures on the heart in healthy young and middle-aged mice.

Materials and Methods

Young (12-week-old) and middle-aged (52-week-old) female C57BL/6 mice either received an intramedullary stabilized proximal femur fracture or sham treatment. The observation time points included 6 and 24 h. Systemic levels of pro-inflammatory mediators as well as local inflammation and alterations in myocardial structure, metabolism and calcium homeostasis in left ventricular tissue was analyzed following hip fracture by multiplex analysis, RT-qPCR and immunohistochemistry.

Results

After hip fracture young and middle-aged mice showed increased systemic IL-6 and KC levels, which were significantly elevated in the middle-aged animals. Furthermore, the middle-aged mice showed enhanced myocardial expression of HMGB1, TLR2/4, TNF, IL1β and NLRP3 as well as considerable alterations in the myocardial expression of glucose- and fatty acid transporters (HFABP, GLUT4), calcium homeostasis proteins (SERCA) and cardiac structure proteins (desmin, troponin I) compared to the young animals following hip fracture.

Conclusion

Young and middle-aged mice showed local myocardial alterations, which might predispose for the development of secondary cardiac injury following hip fracture. Age and the age-associated phenomenon of ‘inflammaging’ seemed to be an independent risk factor aggravating and accelerating cardiac alterations following hip fracture.
Impact of hypertension on long-term humoral and cellular response to SARS-CoV-2 infection
Authors: Chu Chang , Schönbrunn Anne , Klemm Kristin , von Baehr Volker , Krämer Bernhard K. , Elitok Saban , Hocher Berthold
Published: September 2022

It was shown that hypertension delays SARS CoV-2 viral clearance and exacerbates airway hyperinflammation in the respiratory tract. However, it is unknown whether hypertension determines the long-term cellular and humoral response to SARS Cov2. Health care workers (HCWs) after an outbreak of SARS Cov-2 infections were analyzed. Infected HCWs were not vaccinated before blood collection. 5-14 months (median 7 months) after detection of SARS CoV-2 infection, blood was taken to analyze humoral response (S1 IgG and SARS CoV-2 neutralizing antibodies) and cellular (T cell responses to SARS-CoV-2 with Lymphocyte Transformation Test). To identify clinical factors that determine the immune response, a multivariate regression analysis was done considering age, BMI, sex, diabetes, hypertension, smoking, COPD, asthma and time between PCR positivity and blood collection as confounding factors. Infected hypertensive HCWs more often needed to be hospitalized than non-hypertensive HCWs, but were less likely to develop anosmia and myalgia. The long-term humoral and cellular immune response was significantly strengthened in hypertensive versus normotensive infected HCWs. Multivariate regression analysis revealed that hypertension was independently associated with the humoral response to SARS CoV-2 infection. Multivariate regression analysis using same confounding factors for the humoral response showed a clear trend for an association with the cellular response to SARS CoV-2 infection as well. In conclusion, SARS CoV-2 infection strengthened immune response to SARS CoV-2 infection in hypertensive HCWs independent of other risk factors.
Targeting lipid metabolism reprogramming of immunocytes in response to the tumor microenvironment stressor: A potential approach for tumor therapy
Authors: Zhang Ming , Wei Tingju , Zhang Xiaodan , Guo Danfeng
Published: September 2022

The tumor microenvironment (TME) has become a major research focus in recent years. The TME differs from the normal extracellular environment in parameters such as nutrient supply, pH value, oxygen content, and metabolite abundance. Such changes may promote the initiation, growth, invasion, and metastasis of tumor cells, in addition to causing the malfunction of tumor-infiltrating immunocytes. As the neoplasm develops and nutrients become scarce, tumor cells transform their metabolic patterns by reprogramming glucose, lipid, and amino acid metabolism in response to various environmental stressors. Research on carcinoma metabolism reprogramming suggests that like tumor cells, immunocytes also switch their metabolic pathways, named “immunometabolism”, a phenomenon that has drawn increasing attention in the academic community. In this review, we focus on the recent progress in the study of lipid metabolism reprogramming in immunocytes within the TME and highlight the potential target molecules, pathways, and genes implicated. In addition, we discuss hypoxia, one of the vital altered components of the TME that partially contribute to the initiation of abnormal lipid metabolism in immune cells. Finally, we present the current immunotherapies that orchestrate a potent antitumor immune response by mediating the lipid metabolism of immunocytes, highlight the lipid metabolism reprogramming capacity of various immunocytes in the TME, and propose promising new strategies for use in cancer therapy.
Case report: Persistence of residual antigen and RNA of the SARS-CoV-2 virus in tissues of two patients with long COVID
Authors: Goh Denise , Lim Jeffrey Chun Tatt , Fernaíndez Sonia Bilbao , Joseph Craig Ryan , Edwards Sara Gil , Neo Zhen Wei , Lee Justina Nadia , Caballero Sílvia Guerrero , Lau Mai Chan , Yeong Joe Poh Sheng
Published: September 2022

The World Health Organization has defined long COVID-19 (LC) as a condition that occurs in individuals with a history of SARS-CoV-2 infection who exhibit persistent symptoms after its acute phase that last for at least two months and cannot be explained by an alternative diagnosis. Since we had previously reported residual viral antigens in tissues of convalescent patients, we aimed to assess the presence of such antigens in long COVID tissues. Here, we established the presence of the residual virus in the appendix, skin, and breast tissues of 2 patients who exhibited LC symptoms 163 and 426 days after symptom onset. With multiplex immunohistochemistry, we detected viral nucleocapsid protein in all three tissues. The nucleocapsid protein was further observed to colocalize with macrophage marker CD68, suggesting that immune cells were direct targets of SARS-CoV-2. Additionally, using RNAscope, the presence of viral RNA was also detected. Our positive finding in the breast tissue is corroborated by the recent reports of immunocompromised patients experiencing LC symptoms and persistent viral replication. Overall, our findings and emerging LC studies raise the possibility that the gastrointestinal tract may function as a reservoir for SARS-CoV-2.
Intratumoral CD73: An immune checkpoint shaping an inhibitory tumor microenvironment and implicating poor prognosis in Chinese melanoma cohorts
Authors: Gao Zixu , Wang Lu , Song Zhengqing , Ren Ming , Yang Yang , Li Jianrui , Shen Kangjie , Li Yinlam , Ding Yiteng , Yang Yanwen , Zhou Yuhong , Wei Chuanyuan , Gu Jianying
Published: September 2022

Background

As a novel immune checkpoint, CD73 has been reported to play prominent roles in several malignancies. However, the significance of CD73 in melanoma remains ambiguous. This study sought to reveal the impact of CD73 on the tumor microenvironment (TME) and patients’ prognosis, and to investigate whether CD73 could be a therapeutic target in Chinese melanomas, which were dominated by acral and mucosal subtypes.

Methods

Two independent Chinese cohorts of 194 patients with melanoma were enrolled. CD73 and PD-L1 expression as well as CD8+ and CD56+ cell infiltrations were evaluated by immunohistochemistry in 194 resected melanoma samples. Clinical outcomes of patients were assessed utilizing the Kaplan-Meier plotter and Cox proportional hazard analysis. RNA-seq data was obtained from TCGA database. Gene set functional annotations were performed based on GO, KEGG and GSEA analysis. CIBERSORT, ssGSEA and TIMER were used to explore the association between CD73 and immune infiltration. These findings were validated by establishing tumor xenograft model, and functions of tumor-infiltrating immune cells were examined by flow cytometry and immunofluorescence.

Results

High CD73 expression showed poorer clinical outcomes and was identified as an independent prognostic indicator for survival in two cohorts. Expression of CD73 was more prevalent than PD-L1 in Chinese melanoma cohorts (54.6% vs 23.2%). Co-expression of both immune checkpoints was infrequent (12.9%) in melanoma, and 54.4% of PD-L1 negative cases showed elevated expression of CD73. CD73high tumors showed a microenvironment with fewer CD8+ T cells and CD56+ NK cells infiltration, which displayed a dysfunctional phenotype. With the treatment of CD73 inhibitor APCP, the amount of CD8+ T cells and CD56+ NK cells infiltrated in tumors was elevated and the immunosuppressive effect of CD73 was eliminated.

Conclusions

High CD73 expression was associated with an inhibitory TME and adverse clinical outcomes of melanoma. In comparison to PD-L1, CD73 was more prevalent and possessed more definite prognostic significance. Therefore, it may serve as a prognostic indicator and immunotherapeutic target next to PD-L1 in melanoma for Chinese population.
Single cell RNA sequencing reveals hemocyte heterogeneity in Biomphalaria glabrata: Plasticity over diversity
Authors: Pichon Rémi , Pinaud Silvain , Vignal Emmanuel , Chaparro Cristian , Pratlong Marine , Portet Anaïs , Duval David , Galinier Richard , Gourbal Benjamin
Published: September 2022

The freshwater snail Biomphalaria glabrata is an intermediate host of Schistosoma mansoni, the agent of human intestinal schistosomiasis. However, much is to be discovered about its innate immune system that appears as a complex black box, in which the immune cells (called hemocytes) play a major role in both cellular and humoral response towards pathogens. Until now, hemocyte classification has been based exclusively on cell morphology and ultrastructural description and depending on the authors considered from 2 to 5 hemocyte populations have been described. In this study, we proposed to evaluate the hemocyte heterogeneity at the transcriptomic level. To accomplish this objective, we used single cell RNA sequencing (scRNAseq) technology coupled to a droplet-based system to separate hemocytes and analyze their transcriptome at a unique cell level in naive Biomphalaria glabrata snails. We were able to demonstrate the presence of 7 hemocyte transcriptomic populations defined by the expression of specific marker genes. As a result, scRNAseq approach showed a high heterogeneity within hemocytes, but provides a detailed description of the different hemocyte transcriptomic populations in B. glabrata supported by distinct cellular functions and lineage trajectory. As a main result, scRNAseq revealed the 3 main population as a super-group of hemocyte diversity but, on the contrary, a great hemocytes plasticity with a probable capacity of hemocytes to engage to different activation pathways. This work opens a new field of research to understand the role of hemocytes particularly in response to pathogens, and towards S. mansoni parasites.
Clinical application status and prospect of the combined anti-tumor strategy of ablation and immunotherapy
Authors: Yin Li , Li Xing-yu , Zhu Lin-lin , Chen Gui-lai , Xiang Zhuo , Wang Qing-qing , Bi Jing-wang , Wang Qiang
Published: September 2022

Image-guided tumor ablation eliminates tumor cells by physical or chemical stimulation, which shows less invasive and more precise in local tumor treatment. Tumor ablation provides a treatment option for medically inoperable patients. Currently, clinical ablation techniques are widely used in clinical practice, including cryoablation, radiofrequency ablation (RFA), and microwave ablation (MWA). Previous clinical studies indicated that ablation treatment activated immune responses besides killing tumor cells directly, such as short-term anti-tumor response, immunosuppression reduction, specific and non-specific immune enhancement, and the reduction or disappearance of distant tumor foci. However, tumor ablation transiently induced immune response. The combination of ablation and immunotherapy is expected to achieve better therapeutic results in clinical application. In this paper, we provided a summary of the principle, clinical application status, and immune effects of tumor ablation technologies for tumor treatment. Moreover, we discussed the clinical application of different combination of ablation techniques with immunotherapy and proposed possible solutions for the challenges encountered by combined therapy. It is hoped to provide a new idea and reference for the clinical application of combinate treatment of tumor ablation and immunotherapy.
Adaptive transcriptomic and immune infiltrate responses in the tumor immune microenvironment following neoadjuvant chemotherapy in high grade serous ovarian cancer reveal novel prognostic associations and activation of pro-tumorigenic pathways
Authors: James Nicole E. , Woodman Morgan , De La Cruz Payton , Eurich Katrin , Ozsoy Melih Arda , Schorl Christoph , Hanley Linda C. , Ribeiro Jennifer R.
Published: September 2022

The high rate of ovarian cancer recurrence and chemoresistance necessitates further research into how chemotherapy affects the tumor immune microenvironment (TIME). While studies have shown that immune infiltrate increases following neoadjuvant (NACT) chemotherapy, there lacks a comprehensive understanding of chemotherapy-induced effects on immunotranscriptomics and cancer-related pathways and their relationship with immune infiltrate and patient responses. In this study, we performed NanoString nCounter® PanCancer IO360 analysis of 31 high grade serous ovarian cancer (HGSOC) patients with matched pre-treatment biopsy and post-NACT tumor. We observed increases in pro-tumorigenic and immunoregulatory pathways and immune infiltrate following NACT, with striking increases in a cohort of genes centered on the transcription factors ATF3 and EGR1. Using quantitative PCR, we analyzed several of the top upregulated genes in HGSOC cell lines, noting that two of them, ATF3 and AREG, were consistently upregulated with chemotherapy exposure and significantly increased in platinum resistant cells compared to their sensitive counterparts. Furthermore, we observed that pre-NACT immune infiltrate and pathway scores were not strikingly related to platinum free interval (PFI), but post-NACT immune infiltrate, pathway scores, and gene expression were. Finally, we found that higher levels of a cohort of proliferative and DNA damage-related genes was related to shorter PFI. This study underscores the complex alterations in the ovarian TIME following chemotherapy exposure and begins to untangle how immunologic factors are involved in mediating chemotherapy response, which will allow for the future development of novel immunologic therapies to combat chemoresistance.
Early-life stress and dietary fatty acids impact the brain lipid/oxylipin profile into adulthood, basally and in response to LPS
Authors: Reemst Kitty , Broos Jelle Y. , Abbink Maralinde R. , Cimetti Chiara , Giera Martin , Kooij Gijs , Korosi Aniko
Published: September 2022

Brain lipid dysregulation is a hallmark of depression and Alzheimer’s disease, also marked by chronic inflammation. Early-life stress (ELS) and dietary intake of polyunsaturated fatty acids (PUFAs) are risk factors for these pathologies and are known to impact inflammatory processes. However, if these early-life factors alter brain lipid homeostasis on the long-term and thereby contribute to this risk remains to be elucidated. We have recently shown that an early diet enriched in omega(ω)-3 PUFAs protected against the long-term negative effects of ELS on cognition and neuroinflammation. Here, we aim to understand if modulation of brain lipid and oxylipin profiles contributes to the detrimental effects of ELS and the protective ones of the diet. We therefore studied if and how ELS and early dietary PUFAs modulate the brain lipid and oxylipin profile, basally as well as in response to an inflammatory challenge, to unmask possible latent effects. Male mice were exposed to ELS via the limited bedding and nesting paradigm, received an early diet with high or low ω6/ω3 ratio (HRD and LRD) and were injected with saline or lipopolysaccharide (LPS) in adulthood. Twenty-four hours later plasma cytokines (Multiplex) and hypothalamic lipids and oxylipins (liquid chromatography tandem mass spectrometry) were measured. ELS exacerbated the LPS-induced increase in IL-6, CXCL1 and CCL2. Both ELS and diet affected the lipid/oxylipin profile long-term. For example, ELS increased diacylglycerol and LRD reduced triacylglycerol, free fatty acids and ceramides. Importantly, the ELS-induced alterations were strongly influenced by the early diet. For example, the ELS-induced decrease in eicosapentaenoic acid was reversed when fed LRD. Similarly, the majority of the LPS-induced alterations were distinct for control and ELS exposed mice and unique for mice fed with LRD or HRD. LPS decreased ceramides and lysophosphotidylcholine, increased hexosylceramides and prostaglandin E2, reduced triacylglycerol species and ω6-derived oxylipins only in mice fed LRD and ELS reduced the LPS-induced increase in phosphatidylcholine. These data give further insights into the alterations in brain lipids and oxylipins that might contribute to the detrimental effects of ELS, to the protective ones of LRD and the possible early-origin of brain lipid dyshomeostasis characterizing ELS-related psychopathologies.
The cuproptosis-associated 13 gene signature as a robust predictor for outcome and response to immune- and targeted-therapies in clear cell renal cell carcinoma
Authors: Yuan Huiyang , Qin Xin , Wang Jing , Yang Qingya , Fan Yidong , Xu Dawei
Published: September 2022

Cuproptosis, the newly identified form of regulatory cell death (RCD), results from mitochondrial proteotoxic stress mediated by copper and FDX1. Little is known about significances of cuproptosis in oncogenesis. Here we determined clinical implications of cuproptosis in clear cell renal cell carcinoma (ccRCC). Based on the correlation and survival analyses of cuproptosis-correlated genes in TCGA ccRCC cohort, we constructed a cuproptosis-associated 13 gene signature (CuAGS-13) score system. In both TCGA training and two validation cohorts, when patients were categorized into high- and low-risk groups according to a median score as the cutoff, the CuAGS-13 high-risk group was significantly associated with shorter overall survival (OS) and/or progression-free survival (PFS) independently (P<0.001 for all). The CuAGS-13 score assessment could also predict recurrence and recurrence-free survival of patients at stage I – III with a high accuracy, which outperformed the ccAccB/ClearCode34 model, a well-established molecular predictor for ccRCC prognosis. Moreover, patients treated with immune checkpoint inhibitors (ICIs) acquired complete/partial remissions up to 3-time higher coupled with significantly longer PFS in the CuAGS-13 low- than high-risk groups in both training and validation cohorts of ccRCCs (7.2 – 14.1 vs. 2.1 – 3.0 months, P<0.001). The combination of ICI with anti-angiogenic agent Bevacizumab doubled remission rates in CuAGS-13 high-risk patients while did not improve the efficacy in the low-risk group. Further analyses showed a positive correlation between CuAGS-13 and TIDE scores. We also observed that the CuAGS-13 score assessment accurately predicted patient response to Sunitinib, and higher remission rates in the low-risk group led to longer PFS (Low- vs. high-risk, 13.9 vs. 5.8 months, P = 5.0e-12). Taken together, the CuAGS-13 score assessment serves as a robust predictor for survival, recurrence, and response to ICIs, ICI plus anti-angiogenic drugs and Sunitinib in ccRCC patients, which significantly improves patient stratifications for precision medicine of ccRCC.
Tumor cell-based vaccine contributes to local tumor irradiation by eliciting a tumor model-dependent systemic immune response
Authors: Remic Tinkara , Sersa Gregor , Levpuscek Kristina , Lampreht Tratar Ursa , Ursic Valentinuzzi Katja , Cör Andrej , Kamensek Urska
Published: September 2022

Multimodal treatment approaches, such as radio-immunotherapy, necessitate regimen optimization and the investigation of the interactions of different modalities. The aim of this study was two-fold. Firstly, to select the most effective combination of irradiation and the previously developed tumor cell-based vaccine and then to provide insight into the immune response to the selected combinatorial treatment. The study was performed in immunologically different murine tumor models: B16F10 melanoma and CT26 colorectal carcinoma. The most effective combinatorial treatment was selected by comparing three different IR regimens and three different vaccination regimens. We determined the local immune response by investigating immune cell infiltration at the vaccination site and in tumors. Lastly, we determined the systemic immune response by investigating the amount of tumor-specific effector lymphocytes in draining lymph nodes. The selected most effective combinatorial treatment was 5× 5 Gy in combination with concomitant single-dose vaccination (B16F10) or with concomitant multi-dose vaccination (CT26). The combinatorial treatment successfully elicited a local immune response at the vaccination site and in tumors in both tumor models. It also resulted in the highest amount of tumor-specific effector lymphocytes in draining lymph nodes in the B16F10, but not in the CT26 tumor-bearing mice. However, the amount of tumor-specific effector lymphocytes was intrinsically higher in the CT26 than in the B16F10 tumor model. Upon the selection of the most effective combinatorial treatment, we demonstrated that the vaccine elicits an immune response and contributes to the antitumor efficacy of tumor irradiation. However, this interaction is multi-faceted and appears to be dependent on the tumor immunogenicity.