bluuebunny/crossref_metadata_2025 huggingface dataset:
Ten years of coverage of trophy hunting in UK newspapers
Authors: Yeomans Nikita , Hare Darragh , Dröge Egil , Hart Adam G.
Published: December 2022

Hunting is an increasingly contentious topic. Trophy hunting, whereby people hunt individual animals with desirable characteristics in order to keep body parts (e.g. horns, heads, hides, antlers) as mementos, is especially contested. Political pressure, often in the form of trophy import bans, is being applied in multiple nations, and campaigns to ban trophy hunting, or trophy imports, attract considerable media attention. However, trophy hunting often has conservation value, acting to protect habitat and provide income for local communities. Assuming that media coverage can influence public and political opinion, negative or simplistic media coverage of trophy hunting has the potential to cause adverse outcomes for conservation and local communities. Here, we analyse coverage of trophy hunting from July 2010 - June 2020 (five years before and five years after the death of Cecil the Lion) in the most popular UK media outlets (624 articles in total), assessing the overall sentiment of each article, and the species and countries covered. Ninety percent of all coverage occurred after the death of Cecil the lion, marking this event as a watershed moment in UK mainstream media depiction of trophy hunting. The overall sentiment of articles was largely against trophy hunting (63.1%), and this was more pronounced in tabloids (84.2%) than broadsheets (42.2%). Pro-trophy hunting articles were very uncommon overall (3.5%). Articles that described the complexity of trophy hunting decreased following Cecil and were most common in pre-Cecil broadsheets (35.7%, dropping to 30.6%) and rarest in post-Cecil tabloids (3.1%). Articles focussed mainly on charismatic but rarely hunted species including lion, elephant and rhino, with commonly hunted species (such as impala or Cape buffalo) only rarely being mentioned. When countries were mentioned, southern African nations predominated, with four nations (Zimbabwe, South Africa, Namibia and Botswana) being named in 68% of qualifying articles. We conclude that simplistic media depiction of trophy hunting has the potential to cause negative outcomes for conservation through its impact on public perception and political opinion.
Cardiovascular outcomes in patients treated with sodium-glucose transport protein 2 inhibitors, a network meta-analysis of randomized trials
Authors: Tornyos Dániel , Meuer Maximilian , Lukács Réka , El Alaoui El Abdallaoui Oumaima , Kupó Péter , Faludi Réka , Komócsi András
Published: December 2022

Background

Gliflozins altering the sodium-glucose transport protein 2 (SGLT2) in the nephron, represent alone or in combination a promising treatment option for patients with type II diabetes mellitus. In addition to glucose control, these drugs provide benefits including reduced risk of long-term cardiovascular (CV) and renal complications. Several trials evaluated gliflozins in patients with various degrees of cardiac dysfunction with heterogeneous results.

Objectives

We aimed to perform a comprehensive analysis of the effect of gliflozins on CV outcomes.

Methods

Systematic searches of electronic databases were conducted until September 2022. Multiple treatment network meta-analysis was performed in R. Random-effects model was used to combine risk estimates across trials calculating risk ratio (RR) with 95% confidence intervals as summary statistics. The primary endpoint of interest was the rate of heart failure-related hospitalization (HHF) and the composite of HHF with CV mortality (HHF + CVD). Secondary outcomes included major adverse cardiac events (MACE), CV- and overall mortality, myocardial infarction (MI), and stroke.

Results

Twenty-nine studies randomizing 88,418 patients were identified. Gliflozins reduced the risk of HHF (RR: 0.72 [0.69; 0.76]) and HHF + CVD (RR: 0.78 [0.75; 0.82]). The risk of MACE and its component also improved significantly except for stroke. The network analyses did not explore major differences among the individual substances. The only exception was sotagliflozin which appeared to be more effective regarding HHF + CVD, stroke, and MI compared to ertugliflozin, in HHF + CVD and stroke compared to dapagliflozin, and in stroke endpoint compared to empagliflozin.

Conclusion

Our meta-analysis supports a group effect of gliflozins beneficial in a wide spectrum of patients with a risk of heart failure (HF) development. In addition to the improvement of HF-related outcomes, the risk of major adverse events is also reduced with SGLT2 inhibition.

Systematic review registration

[www.ClinicalTrials.gov], identifier [CRD42022358078].
Prediction model of obstructive sleep apnea–related hypertension: Machine learning–based development and interpretation study
Authors: Shi Yewen , Ma Lina , Chen Xi , Li Wenle , Feng Yani , Zhang Yitong , Cao Zine , Yuan Yuqi , Xie Yushan , Liu Haiqin , Yin Libo , Zhao Changying , Wu Shinan , Ren Xiaoyong
Published: December 2022

Background

Obstructive sleep apnea (OSA) is a globally prevalent disease closely associated with hypertension. To date, no predictive model for OSA-related hypertension has been established. We aimed to use machine learning (ML) to construct a model to analyze risk factors and predict OSA-related hypertension.

Materials and methods

We retrospectively collected the clinical data of OSA patients diagnosed by polysomnography from October 2019 to December 2021 and randomly divided them into training and validation sets. A total of 1,493 OSA patients with 27 variables were included. Independent risk factors for the risk of OSA-related hypertension were screened by the multifactorial logistic regression models. Six ML algorithms, including the logistic regression (LR), the gradient boosting machine (GBM), the extreme gradient boosting (XGBoost), adaptive boosting (AdaBoost), bootstrapped aggregating (Bagging), and the multilayer perceptron (MLP), were used to develop the model on the training set. The validation set was used to tune the model hyperparameters to determine the final prediction model. We compared the accuracy and discrimination of the models to identify the best machine learning algorithm for predicting OSA-related hypertension. In addition, a web-based tool was developed to promote its clinical application. We used permutation importance and Shapley additive explanations (SHAP) to determine the importance of the selected features and interpret the ML models.

Results

A total of 18 variables were selected for the models. The GBM model achieved the most extraordinary discriminatory ability (area under the receiver operating characteristic curve = 0.873, accuracy = 0.885, sensitivity = 0.713), and on the basis of this model, an online tool was built to help clinicians optimize OSA-related hypertension patient diagnosis. Finally, age, family history of hypertension, minimum arterial oxygen saturation, body mass index, and percentage of time of SaO2 < 90% were revealed by the SHAP method as the top five critical variables contributing to the diagnosis of OSA-related hypertension.

Conclusion

We established a risk prediction model for OSA-related hypertension patients using the ML method and demonstrated that among the six ML models, the gradient boosting machine model performs best. This prediction model could help to identify high-risk OSA-related hypertension patients, provide early and individualized diagnoses and treatment plans, protect patients from the serious consequences of OSA-related hypertension, and minimize the burden on society.
Sustained high glucose intake accelerates type 1 diabetes in NOD mice
Authors: Li Xiangqian , Wang Lina , Meng Gang , Chen Xiaoling , Yang Shushu , Zhang Mengjun , Zheng Zhengni , Zhou Jie , Lan Zhu , Wu Yuzhang , Wang Li
Published: December 2022

Introduction

Epidemiological studies have suggested that dietary factors, especially high consumption of high glycaemic index carbohydrates and sugars, may trigger or exacerbate the progression of type 1 diabetes. We aimed to provide experimental evidence to confirm this relevance and to explore the underlying mechanisms.

Methods

NOD mice were given sustained high-glucose drinking or glucose-free water and observed for the incidence of type 1 diabetes and islet inflammation. RNAseq was performed to detect the transcriptome changes of the NOD islet beta cell line NIT-1 after high glucose treatment, and mass spectrometry was performed to detect the proteome changes of NIT-1-cells-derived sEVs.

Results

Sustained high glucose drinking significantly aggravates islet inflammation and accelerates the onset of type 1 diabetes in NOD mice. Mechanistically, high glucose treatment induces aberrant ER stress and up-regulates the expression of autoantigens in islet beta cell. Moreover, high glucose treatment alters the proteome of beta-cells-derived sEVs, and significantly enhances the ability of sEVs to promote DC maturation and stimulate immune inflammatory response.

Discussion

This study provides evidence for negative effect of high glucose intake as a dietary factor on the pathogenesis of type 1 diabetes in genetically predisposed individuals. Therefore, avoiding high sugar intake may be an effective disease prevention strategy for children or adults susceptible to type 1 diabetes.
GDF15 is an exercise-induced hepatokine regulated by glucagon and insulin in humans
Authors: Plomgaard Peter , Hansen Jakob S. , Townsend Logan K. , Gudiksen Anders , Secher Niels H. , Clemmesen Jens O. , Støving Rene K. , Goetze Jens P. , Wright David C. , Pilegaard Henriette
Published: December 2022

Objective

Growth differentiation factor (GDF)-15 is implicated in regulation of metabolism and circulating GDF15 increases in response to exercise. The source and regulation of the exercise-induced increase in GDF15 is, however not known.

Method

Plasma GDF15 was measured by ELISA under the following conditions: 1) Arterial-to-hepatic venous differences sampled before, during, and after exercise in healthy male subjects (n=10); 2) exogenous glucagon infusion compared to saline infusion in resting healthy subjects (n=10); 3) an acute exercise bout with and without a pancreatic clamp (n=6); 4) healthy subjects for 36 hours (n=17), and 5) patients with anorexia nervosa (n=25) were compared to healthy age-matched subjects (n=25). Tissue GDF15 mRNA content was determined in mice in response to exhaustive exercise (n=16).

Results

The splanchnic bed released GDF15 to the circulation during exercise and increasing the glucagon-to-insulin ratio in resting humans led to a 2.7-fold (P<0.05) increase in circulating GDF15. Conversely, inhibiting the exercise-induced increase in the glucagon-to-insulin ratio blunted the exercise-induced increase in circulating GDF15. Fasting for 36 hours did not affect circulating GDF15, whereas resting patients with anorexia nervosa displayed elevated plasma concentrations (1.4-fold, P<0.05) compared to controls. In mice, exercise increased GDF15 mRNA contents in liver, muscle, and adipose tissue.

Conclusion

In humans, GDF15 is a “hepatokine” which increases during exercise and is at least in part regulated by the glucagon-to-insulin ratio. Moreover, chronic energy deprivation is associated with elevated plasma GDF15, which supports that GDF15 is implicated in metabolic signalling in humans.
Relationship of the metabolic score for insulin resistance and the risk of stroke in patients with hypertension: A cohort study
Authors: Cai Xintian , Hu Junli , Zhu Qing , Wang Mengru , Liu Shasha , Dang Yujie , Hong Jing , Li Nanfang
Published: December 2022

Background

The current status of the dose-response relationship between the metabolic score for insulin resistance (METS-IR) and new-onset stroke in hypertensive patients and its subtypes is unclear. This study aimed to determine the association between METS-IR and incident stroke and its subtypes within a cohort of Chinese hypertensive patients.

Methods

A total of 14032 hospitalized patients with hypertension from January 1, 2010, to December 31, 2021, were included in this retrospective cohort study. Cox models and restricted cubic splines were applied to determine the association between METS-IR and the risk of stroke.

Results

During a median follow-up of 4.80 years, 1067 incident stroke cases occurred. Patients in the highest quartile group of METS-IR levels exhibited a higher risk of stroke (HR, 1.80; 95% CI, 1.50-2.17) and ischemic stroke (HR, 1.96; 95% CI, 1.60–2.42) than those in the lowest quartile group. However, no significant associations were observed between METS-IR and the risk of hemorrhagic stroke. Restricted cubic spline analysis suggested a nearly J-shaped association between METS-IR and risk of stroke and ischemic stroke (P for nonlinearity < 0.001). METS-IR did produce a significant improvement in the C statistic when added to the basic model (from 0.637 to 0.664, P < 0.001). Notably, the addition of METS-IR to the basic model resulted in a significant improvement in predicting incident total stroke and ischemic stroke.

Conclusions

This cohort study suggests a relationship between METS-IR and the risk of stroke and ischemic stroke. Further studies are required to elucidate the underlying mechanisms.
Association between metabolic scores for visceral fat and chronic kidney disease: A cross-sectional study
Authors: Yu Peng , Meng Xiaoyu , Kan Ranran , Wang Zhihan , Yu Xuefeng
Published: December 2022

Introduction

Central obesity is closely linked to the risk of chronic kidney disease (CKD). This study aimed to evaluate the association between the novel central obesity index- metabolic score for visceral fat (METS-VF) and the risk of CKD in a Chinese population, and to compare its ability to predict CKD with other central obesity indices including waist circumference (WC), waist-to-height ratio (WHtR), lipid accumulation product (LAP), visceral adiposity index (VAI), a body shape index (ABSI), body roundness index (BRI), and cardiometabolic index (CMI).

Methods

This cross-sectional study included 8866 individuals from China. Demographic information, lifestyle data, and medical history data were collected, and physical examinations, anthropometric measurements and laboratory tests were performed for each participant. CKD was defined as an estimated GFR< 60 ml/min/1.73m2. Multivariate logistic regression models were used to evaluate the association between the METS-VF and the prevalence of CKD. Receiver operating characteristic (ROC) analyses were performed to assess and compare the predictive abilities of the central obesity indices and determine the optimal cut-off points.

Results

A graded increase in the prevalence of CKD was observed with increasing METS-VF tertiles. Moreover, the METS-VF was independently associated with the risk of CKD after adjustment for current smoking, current drinking, physical activity level, diabetes, hypertension, CVD history and BMI. Compared with participants with a METS-VF in the lowest tertile, the multivariate-adjusted ORs and 95% CIs for participants with a METS-VF in the highest tertile were 3.943 (2.435-6.385) in the overall population, 3.585 (1.585-8.109) for men and 4.627 (2.485-8.616) for women. Significant interactions were found between the METS-VF and the risk of CKD by age (P value for interaction = 0.023). In ROC analysis, the METS-VF had a higher AUC value than other indices for predicting CKD in men and had comparable or higher AUC than other indices for women. For predicting CKD, the optimal cut-off value of the METS-VF was 6.891 for men and 6.744 for women. The METS-VF yielded the greatest Youden index among all indices for both sexes.

Conclusion

A higher METS-VF was independently associated with a greater risk of CKD. The METS-VF can be a useful clinical indicator for identifying CKD, as it had superior predictive power for CKD when compared with other central obesity indices.
The effect of early life events on glucose levels in first-episode psychosis
Authors: Garcia-Rizo Clemente , Cabrera Bibiana , Bioque Miquel , Mezquida Gisela , Lobo Antonio , Gonzalez-Pinto Ana , Diaz-Caneja Covadonga M. , Corripio Iluminada , Vieta Eduard , Baeza Inmaculada , Garcia-Portilla Maria Paz , Gutierrez-Fraile Miguel , Rodriguez-Jimenez Roberto , Garriga Marina , Fernandez-Egea Emilio , Bernardo Miguel ,   PEPs GROUP
Published: December 2022

First episode of psychosis (FEP) patients display a wide variety of metabolic disturbances at onset, which might underlie these patients’ increased morbidity and early mortality. Glycemic abnormalities have been previously related to pharmacological agents; however, recent research highlights the impact of early life events. Birth weight (BW), an indirect marker of the fetal environment, has been related to glucose abnormalities in the general population over time. We aim to evaluate if BW correlates with glucose values in a sample of FEP patients treated with different antipsychotics. Two hundred and thirty-six patients were included and evaluated for clinical and metabolic variables at baseline and at 2, 6, 12, and 24 months of follow-up. Pearson correlations and linear mixed model analysis were conducted to analyze the data. Antipsychotic treatment was grouped due to its metabolic risk profile. In our sample of FEP patients, BW was negatively correlated with glucose values at 24 months of follow-up [r=-0.167, p=0.037]. BW showed a trend towards significance in the association with glucose values over the 24-month period (F=3.22; p=0.073) despite other confounders such as age, time, sex, body mass index, antipsychotic type, and chlorpromazine dosage. This finding suggests that BW is involved in the evolution of glucose values over time in a cohort of patients with an FEP, independently of the type of pharmacological agent used in treatment. Our results highlight the importance of early life events in the later metabolic outcome of patients.
Functionalizing building envelopes for greening and solar energy: Between theory and the practice in Egypt
Authors: Marzouk Mai A. , Salheen Mohamed A. , Fischer Leonie K.
Published: December 2022

The building sector is one of the most resource-intensive industries. In Egypt, buildings consume 60% of electricity, produce 8% of CO2 emissions, and anthropize agricultural land, peri-urban and urban landscapes. To compensate for these consumption patterns, building envelopes can become productive in terms of greening and energy production. This encompasses the implementation of productive building systems that include (a) greening systems such as building-integrated vegetation and agriculture systems and (b) solar energy systems such as building-applied and integrated photovoltaics. For Egypt, the transformation toward more productive buildings still lacks a holistic understanding of their status and implementation requirements. This paper undergoes a comprehensive analysis of the two systems’ classifications, benefits, challenges, and implementation aspects based on a thorough assessment of 121 studies and 20 reports addressing them. This is coupled with a contextual analysis using questionnaires (n = 35) and semi-structured interviews (n = 13) with Egyptian experts and suppliers. Results showed that a large variety of systems is studied in literature and exists in the local market. Among the most purchased productive building systems in the Egyptian market, according to experts, are hydroponics (selected by 75% of respondents), planter boxes/pots (50%), roof-mounted photovoltaic panels (95%), and solar water heaters (55%). The main benefits of greening and solar energy systems are identified as enjoying the greenery view (95%) and reducing energy expenses (100%), respectively. The high initial cost was considered the main barrier for both systems. Multiple commonalities between the two systems in terms of spatial and environmental applicability aspects (e.g., accessibility and safety, net useable area, sun exposure, wind exposure) and environmental performance aspects (e.g., energy demand and emissions reduction, heat flow reduction) were identified. Lastly, we highlight the importance of analyzing integrated solutions that make use of the identified synergies between the systems and maximize the production potentials.
Effects of elevated temperature and abnormal precipitation on soil carbon and nitrogen dynamics in a Pinus densiflora forest
Authors: Woo Dong Kook , Seo Yongwon
Published: December 2022

Forests have the largest terrestrial nutrient pools. The loss of soil carbon and nitrogen in forests under ongoing climate warming is subject to severe environmental degradation. To mitigate the negative effects of global warming on soil carbon and nitrogen in forest, it is important to obtain a better understanding of how elevated temperature and altered precipitation variability impact soil nutrient dynamics. To explore such interactions, we coupled an eco-hydrological model (Multi-Layer Canopy model, MLCan) with a biogeochemical model and applied the combined model to Pinus densiflora forest in Gwangneung Experimental Forest, South Korea, from 2004 to 2020. Our results showed that there was a time lag of 4 years to trigger soil organic carbon losses under the elevated temperature of +1.11°C during 2014–2020 compared to 2010–2013. A temperature rise over a prolonged period increased microbial biomass and activity, stimulating soil organic carbon decomposition. The combination of soil nitrate accumulation and exceptional but expected delay in heavy precipitation seasons of 2 months led to nitrate leaching four times higher than the average at 1 m depth in 2010. Reduced evapotranspiration and heavy precipitation during early fall caused intense subsurface water flux, resulting in a great increase in the risk of nitrate leaching. Our results highlight that the impacts of global warming on soil carbon decompositions has a time lag of 4 years and changes in precipitation characteristics will lead to excessive nitrate loss in P. densiflora forests under climate change.
Analysis of single-nucleotide polymorphisms in genes associated with triple-negative breast cancer
Authors: G. Vigneshwaran , Hasan Qurratulain Annie , Kumar Rahul , Eranki Avinash
Published: December 2022

Triple-negative breast cancer (TNBC) is a rare variant of breast cancer (BC) known to be aggressive and refractory. TNBC lacks effective early diagnostic and therapeutic options leading to poorer outcomes. The genomic landscape and alterations leading to BC and TNBC are vast and unclear. Single nucleotide polymorphisms (SNPs) are a widespread form of genetic alterations with a multi-faceted impact on multiple diseases, including BC and TNBC. In this study, we attempted to construct a framework that could identify genes associated with TNBC and screen the SNPs reported in these genes using a set of computational predictors. This framework helped identifyBRCA1, BRCA2, EGFR, PIK3CA, PTEN,andTP53as recurrent genes associated with TNBC. We found 2%–29% of reported SNPs across genes to be typed pathogenic by all the predictors in the framework. We demonstrate that our framework prediction on BC samples identifies 99% of alterations as pathogenic by at least one predictor and 32% as pathogenic by all the predictors. Our framework could be an initial step in developing an early diagnosis of TNBC and potentially help improve the understanding of therapeutic resistance and sensitivity.
Targeting 4-1BB and PD-L1 induces potent and durable antitumor immunity in B-cell lymphoma
Authors: Wang Yichen , Zhang Xuyao , Xu Caili , Nan Yanyang , Fan Jiajun , Zeng Xian , Kwon Byoung S. , Ju Dianwen
Published: December 2022

Introduction

Although PD-1/L1 mAb has demonstrated clinical benefits in certain cancer types, low response rate and resistance remain the main challenges for the application of these immune checkpoint inhibitors (ICIs). 4-1BB is a co-stimulator molecule expressed in T cells, which could enhance T cell proliferation and activation. Herein, the synergetic antitumor effect and underlying mechanism of 4-1BB agonist combined with PD-1/PD-L1 blockade were determined in B-cell lymphoma (BCL).

Methods

Subcutaneous transplantation BCL tumor models and metastasis models were established to evaluate the therapeutic effect of PD-L1 antibody and/or 4-1BB agonist in vivo. For the mechanistic study, RNA-seq was applied to analyze the tumor microenvironment and immune-related signal pathway after combination treatment. The level of IFN-γ, perforin, and granzyme B were determined by ELISA and Real-time PCR assays, while tumor-infiltrating T cells were measured by flow cytometry and immunohistochemical analysis. CD4/CD8 specific antibodies were employed to deplete the related T cells to investigate the role CD4+ and CD8+ T cells played in combination treatment.

Results

Our results showed that combining anti-PD-L1 ICI and 4-1BB agonists elicited regression of BCL and significantly extended the survival of mice compared to either monotherapy. Co-targeting PD-L1 and 4-1BB preferentially promoted intratumoral cytotoxic lymphocyte infiltration and remodeled their function. RNA-sequence analysis uncovered a series of up-regulated genes related to the activation and proliferation of cytotoxic T lymphocytes, further characterized by increased cytokines including IFN-γ, granzyme B, and perforin. Furthermore, depleting CD8+ T cells not CD4+ T cells totally abrogated the antitumor efficacy, indicating the crucial function of the CD8+ T cell subset in the combination therapy.

Discussion

In summary, our findings demonstrated that 4-1BB agonistic antibody intensified the antitumor immunity of anti-PD-1/PD-L1 ICI via promoting CD8+ T cell infiltration and activation, providing a novel therapeutic strategy to BCL.
Disparities in inflammation between non-Hispanic black and white individuals with lung cancer in the Greater Chicago Metropolitan area
Authors: Byrne Cecily A. , Gomez Sandra L. , Kim Sage , Oddo Vanessa M. , Koh Timothy J. , Fantuzzi Giamila
Published: December 2022

Background

Lung cancer incidence and mortality rates are higher in Non-Hispanic Black (NHB) compared to Non-Hispanic White (NHW) individuals in the Chicago metropolitan area, which may be related to exposure to chronic stress which may increase inflammation.

Specific aim

We investigated disparities in inflammation as measured by neutrophil to lymphocyte ratio (NLR) in individuals with lung cancer by race and by neighborhood concentrated disadvantage index (CDI).

Methods

This retrospective, cross-sectional study included 263 NHB and NHW adults with lung cancer. We analyzed NLR as a continuous and categorical variable to determine degree and prevalence of inflammation. We used Mann Whitney U, t-tests, Chi square tests, linear and logistic regression models as appropriate.

Results

More than 60% of subjects had inflammation (NLR ≥ 3) at lung cancer diagnosis. The degree of inflammation was significantly lower in NHB (NLR 5.50 +/- 7.45) compared to NHW individuals (NLR 6.53 +/- 6.53; p=0.01) but did not differ by neighborhood CDI. The prevalence of inflammation (NLR ≥ 3) was significantly lower in NHB (55.07%) compared to NHW individuals (71.20%; p<0.01) and in those from the most disadvantaged (54.07%) compared to the least disadvantaged (71.88%; p<0.01) neighborhoods.

Conclusion

At lung cancer diagnosis, there is a lower degree and prevalence of inflammation in NHB compared to NHW individuals, and lower prevalence in those residing in the most disadvantaged neighborhoods. Further research is needed to determine mechanisms of inflammation that may be contributing to lung cancer disparities as well as whether NLR is an appropriate biomarker when examining racial differences in inflammation.
A novel fusion protein consisting of anti-ANGPTL3 antibody and interleukin-22 ameliorates diabetic nephropathy in mice
Authors: Ma Qianqian , Hu Xiaozhi , Liu Fangyu , Cao Zhonglian , Han Lei , Zhou Kaicheng , Bai Yu , Zhang Yuting , Nan Yanyang , Lv Qianying , Rao Jia , Wu Tao , Yang Xue , He Haidong , Ju Dianwen , Xu Hong
Published: December 2022

Introduction

The pathogenic mechanisms of diabetic nephropathy (DN) include podocyte injury, inflammatory responses and metabolic disorders. Although the antagonism of Angiopoietin-like protein 3 (ANGPTL3) can alleviate proteinuria symptoms by inhibiting the activation of integrin αvβ3 on the surface of podocytes, it can not impede other pathological processes, such as inflammatory responses and metabolic dysfunction of glucolipid. Interleukin-22 (IL-22) is considered to be a pivotal molecule involved in suppressing inflammatory responses, initiating regenerative repair, and regulating glucolipid metabolism.

Methods

Genes encoding the mIL22IgG2aFc and two chains of anti-ANGPTL3 antibody and bifunctional protein were synthesized. Then, the DN mice were treated with intraperitoneal injection of normal saline, anti-ANGPTL3 (20 mg/kg), mIL22Fc (12 mg/kg) or anti-ANGPTL3 /IL22 (25.3 mg/kg) and irrigation of positive drug losartan (20mg/kg/d) twice a week for 8 weeks.

Results

In this research, a novel bifunctional fusion protein (anti-ANGPTL3/IL22) formed by the fusion of IL-22 with the C-terminus of anti-ANGPTL3 antibody exhibited favorable stability and maintained the biological activity of anti-ANGPTL3 and IL-22, respectively. The fusion protein showed a more pronounced attenuation of proteinuria and improved dysfunction of glucolipid metabolism compared with mIL22Fc or anti-ANGPTL3. Our results also indicated that anti-ANGPTL3/IL22 intervention significantly alleviated renal fibrosis via inhibiting the expression of the inflammatory response-related protein nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) p65 and NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome. Moreover, transcriptome analysis revealed the downregulation of signaling pathways associated with injury and dysfunction of the renal parenchymal cell indicating the possible protective mechanisms of anti-ANGPTL3/IL22 in DN.

Conclusion

Collectively, anti-ANGPTL3/IL22 bifunctional fusion protein can be a promising novel therapeutic strategy for DN by reducing podocyte injury, ameliorating inflammatory response, and enhancing renal tissue recovery.
Analysis of m7G methylation modification patterns and pulmonary vascular immune microenvironment in pulmonary arterial hypertension
Authors: Wang Desheng , Mo Yanfei , Zhang Dongfang , Bai Yang
Published: December 2022

Background

M7G methylation modification plays an important role in cardiovascular disease development. Dysregulation of the immune microenvironment is closely related to the pathogenesis of PAH. However, it is unclear whether m7G methylation is involved in the progress of PAH by affecting the immune microenvironment.

Methods

The gene expression profile of PAH was obtained from the GEO database, and the m7G regulatory factors were analyzed for differences. Machine learning algorithms were used to screen characteristic genes, including the least absolute shrinkage and selection operator, random forest, and support vector machine recursive feature elimination analysis. Constructed a nomogram model, and receiver operating characteristic was used to evaluate the diagnosis of disease characteristic genes value. Next, we used an unsupervised clustering method to perform consistent clustering analysis on m7G differential genes. Used the ssGSEA algorithm to estimate the relationship between the m7G regulator in PAH and immune cell infiltration and analyze the correlation with disease-characteristic genes. Finally, the listed drugs were evaluated through the screened signature genes.

Results

We identified 15 kinds of m7G differential genes. CYFIP1, EIF4E, and IFIT5 were identified as signature genes by the machine learning algorithm. Meanwhile, two m7G molecular subtypes were identified by consensus clustering (cluster A/B). In addition, immune cell infiltration analysis showed that activated CD4 T cells, regulatory T cells, and type 2 T helper cells were upregulated in m7G cluster B, CD56 dim natural killer cells, MDSC, and monocyte were upregulated in the m7G cluster A. It might be helpful to select Calpain inhibitor I and Everolimus for the treatment of PAH.

Conclusion

Our study identified CYFIP1, EIF4E, and IFIT5 as novel diagnostic biomarkers in PAH. Furthermore, their association with immune cell infiltration may facilitate the development of immune therapy in PAH.
Quantitative spatial evaluation of tumor-immune interactions in the immunotherapy setting of metastatic melanoma lymph nodes
Authors: Maus Rachel L. G. , Leontovich Alexey A. , Moore Raymond M. , Fogarty Zachary , Guo Ruifeng , Davidson Tara M. , Tekin Burak , Atherton Chathu , Schimke Jill M. , Dicke Betty A. , Chen Benjamin J. , Markovic Svetomir N.
Published: December 2022

Introduction

Immune cell infiltration into the tumor microenvironment is generally associated with favorable clinical outcomes in solid tumors. However, the dynamic interplay among distinct immune cell subsets within the tumor-immune microenvironment as it relates to clinical responses to immunotherapy remains unresolved. In this study, we applied multiplex immunofluorescence (MxIF) to spatially characterize tumor-immune interactions within the metastatic melanoma lymph node.

Methods

Pretreatment, whole lymph node biopsies were evaluated from 25 patients with regionally metastatic melanoma who underwent subsequent anti-PD1 therapy. Cyclic MxIF was applied to quantitatively and spatially assess expression of 45 pathologist-validated antibodies on a single tissue section. Pixel-based single cell segmentation and a supervised classifier approach resolved 10 distinct tumor, stromal and immune cell phenotypes and functional expression of PD1.

Results

Single cell analysis across 416 pathologist-annotated tumor core regions of interest yielded 5.5 million cells for spatial evaluation. Cellular composition of tumor and immune cell subsets did not differ in the tumor core with regards to recurrence outcomes (p>0.05) however spatial patterns significantly differed in regional and paracrine neighborhood evaluations. Specifically, a regional community cluster comprised of primarily tumor and dendritic cells was enriched in patients that did not experience recurrence (p=0.009). By an independent spatial approach, cell-centric neighborhood analyses identified an enrichment for dendritic cells in cytotoxic T cell (CTL) and tumor cell-centric neighborhoods in the no recurrence patient response group (p<0.0001). Further evaluation of these neighborhoods identified an enrichment for CTL-dendritic cell interactions in patients that did not experience recurrence (p<0.0001) whereas CTL-macrophage interactions were more prevalent in CTL-centric neighborhoods of patients who experienced recurrence (p<0.0001).

Discussion

Overall, this study offers a more comprehensive evaluation of immune infiltrates and spatial-immune signatures in the metastatic tumor-immune microenvironment as it informs recurrence risk following immunotherapy.
Establishment and validation of a carbohydrate metabolism-related gene signature for prognostic model and immune response in acute myeloid leukemia
Authors: Yang You , Yang Yan , Liu Jing , Zeng Yan , Guo Qulian , Guo Jing , Guo Ling , Lu Haiquan , Liu Wenjun
Published: December 2022

Introduction

The heterogeneity of treatment response in acute myeloid leukemia (AML) patients poses great challenges for risk scoring and treatment stratification. Carbohydrate metabolism plays a crucial role in response to therapy in AML. In this multicohort study, we investigated whether carbohydrate metabolism related genes (CRGs) could improve prognostic classification and predict response of immunity and treatment in AML patients.

Methods

Using univariate regression and LASSO-Cox stepwise regression analysis, we developed a CRG prognostic signature that consists of 10 genes. Stratified by the median risk score, patients were divided into high-risk group and low-risk group. Using TCGA and GEO public data cohorts and our cohort (1031 non-M3 patients in total), we demonstrated the consistency and accuracy of the CRG score on the predictive performance of AML survival.

Results

The overall survival (OS) was significantly shorter in high-risk group. Differentially expressed genes (DEGs) were identified in the high-risk group compared to the low-risk group. GO and GSEA analysis showed that the DEGs were mainly involved in immune response signaling pathways. Analysis of tumor-infiltrating immune cells confirmed that the immune microenvironment was strongly suppressed in high-risk group. The results of potential drugs for risk groups showed that inhibitors of carbohydrate metabolism were effective.

Discussion

The CRG signature was involved in immune response in AML. A novel risk model based on CRGs proposed in our study is promising prognostic classifications in AML, which may provide novel insights for developing accurate targeted cancer therapies.
Evaluating IL-6 and IL-10 as rapid diagnostic tools for Gram-negative bacteria and as disease severity predictors in pediatric sepsis patients in the intensive care unit
Authors: Zhang Yunyu , Li Biru , Ning Botao
Published: December 2022

Background

To explore the diagnostic performance of interleukin (IL)-6 and IL-10 in discriminating Gram bacteria types and predicting disease severity in intensive care unit (ICU)-hospitalized pediatric sepsis patients.

Method

We retrospectively collected Th1/Th2 cytokine profiles of 146 microbiologically documented sepsis patients. Patients were categorized into Gram-positive (G+) or Gram-negative (G-) sepsis groups, and cytokine levels were compared. Subgroup analysis was designed to eliminate the influence of other inflammatory responses on cytokine levels.

Results

After propensity score matching, 78 patients were matched and categorized according to Gram bacteria types. Compared with G+ sepsis, IL-6 and IL-10 were significantly elevated in G- sepsis (p < 0.05). Spearman test proved the linear correlation between IL-6 and IL-10 (r = 0.654, p < 0.001), and their combination indicators (ratio and differences) were effective in identifying G- sepsis. In the subgroup analysis, such cytokine elevation was significant regardless of primary infection site. However, for patients with progressively deteriorating organ function [new or progressive multiple organ dysfunction syndrome (NPMODS)], differences in IL-6 and IL-10 levels were less significant between G+ and G- sepsis. In the receiver operating characteristic (ROC) curves of the G- sepsis group, the area under the curve (AUC) value for IL-6 and IL-10 was 0.679 (95% CI 0.561–0.798) and 0.637 (95% CI 0.512–0.762), respectively. The optimal cutoff value for diagnosing G- sepsis was 76.77 pg/ml and 18.90 pg/ml, respectively. While for the NPMODS group, the AUC for IL-6 and IL-10 was 0.834 (95% CI 0.766–0.902) and 0.781 (95% CI 0.701–0.860), respectively.

Conclusion

IL-6 and IL-10 are comparably effective in discriminating G+/G- sepsis in pediatric intensive care unit (PICU) patients. The deteriorated organ function observed in ICU patients reveals that complex inflammatory responses might have contributed to the cytokine pattern observed in severe sepsis patients, therefore confounding the discriminating efficacy of Th1/Th2 cytokines in predicting Gram bacteria types.
Correlation of the TIGIT-PVR immune checkpoint axis with clinicopathological features in triple-negative breast cancer
Authors: Boissière-Michot Florence , Chateau Marie-Christine , Thézenas Simon , Guiu Séverine , Bobrie Angélique , Jacot William
Published: December 2022

Background

T cell immunoreceptor with Ig and ITIM domains (TIGIT) interacts with poliovirus receptor (PVR) to contribute to cancer immune escape. Recently, TIGIT and PVR have been identified as promising immunotherapy targets. Their gene expression is upregulated in many solid tumors, but their protein expression level is not well documented, particularly in triple negative breast cancer (TNBC), the breast cancer subtype that most benefit from immunotherapy.

Methods

TIGIT and PVR expression levels were assessed by immunohistochemistry in 243 surgically resected localized TNBC and then their relationship with clinical-pathological features and clinical outcome was analyzed.

Results

TIGIT expression was observed in immune cells from the tumor microenvironment, whereas PVR was mainly expressed by tumor cells. High TIGIT expression was significantly associated with age (p=0.010), histological grade (p=0.014), non-lobular histology (p=0.024), adjuvant chemotherapy (p=0.006), and various immune cell populations (tumor infiltrating lymphocytes (TILs), CD3+, CD8+, PD-1+ cells; all p<0.0001), PD-L1+ tumor cells (p<0.0001), and PD-L1+ stromal cells (p=0.003). Infiltration by TIGIT+ cells tended to be higher in non-molecular apocrine tumors (p=0.088). PVR was significantly associated with histological grade (p<0.0001), the basal-like (p=0.003) and non-molecular apocrine phenotypes (p=0.039), high TILs infiltration (p=0.011), CD3+ (p=0.002), CD8+ (p=0.024) T cells, and PD-L1 expression in tumor (p=0.003) and stromal cells (p=0.001). In univariate analysis, only known prognostic factors (age, tumor size, lymph node status, adjuvant chemotherapy, TILs and CD3+ T-cell infiltrate) were significantly associated with relapse-free survival (RFS) and overall survival. High TIGIT and PVR expression levels tended to be associated with longer RFS (p=0.079 and 0.045, respectively). The analysis that included only non-molecular apocrine TNBC revealed longer RFS for tumors that strongly expressed TIGIT or PVR (p=0.025 for TIGIT and 0.032 for PVR).

Conclusions

These results indicated that in TNBC, TIGIT+ cells can easily interact with PVR to exert their inhibitory effects. Their wide expression in TNBC and their association with other immune checkpoint components suggest the therapeutic interest of the TIGIT-PVR axis.
Transcriptomic FHITlow/pHER2high signature as a predictive factor of outcome and immunotherapy response in non-small cell lung cancer
Authors: Brisebarre Audrey , Ancel Julien , Ponchel Théophile , Loeffler Emma , Germain Adeline , Dalstein Véronique , Dormoy Valérian , Durlach Anne , Delepine Gonzague , Deslée Gaëtan , Polette Myriam , Nawrocki-Raby Béatrice
Published: December 2022

Introduction

In recent decades, the development of immunotherapy and targeted therapies has considerably improved the outcome of non-small cell lung cancer (NSCLC) patients. Despite these impressive clinical benefits, new biomarkers are needed for an accurate stratification of NSCLC patients and a more personalized management. We recently showed that the tumor suppressor fragile histidine triad (FHIT), frequently lost in NSCLC, controls HER2 receptor activity in lung tumor cells and that tumor cells from NSCLC patients harboring a FHITlow/pHER2high phenotype are sensitive to anti-HER2 drugs. Here, we sought to identify the transcriptomic signature of this phenotype and evaluate its clinical significance.

Materials and methods

We performed RNA sequencing analysis on tumor cells isolated from NSCLC (n=12) according to FHIT/pHER2 status and a functional analysis of differentially regulated genes. We also investigated the FHITlow/pHER2high signature in The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LUAD) (n=489) and lung squamous cell carcinoma (LUSC) (n=493) cohorts and used the tumor immune dysfunction and exclusion (TIDE) model to test the ability of this signature to predict response to immune checkpoint inhibitors (ICI).

Results

We showed that up-regulated genes in FHITlow/pHER2high tumors were associated with cell proliferation, metabolism and metastasis, whereas down-regulated genes were related to immune response. The FHITlow/pHER2high signature was associated with the higher size of tumors, lymph node involvement, and late TNM stages in LUAD and LUSC cohorts. It was identified as an independent predictor of overall survival (OS) in LUAD cohort. FHITlow/pHER2high tumors were also predictive of poor response to ICI in both LUAD and LUSC cohorts.

Conclusion

These data suggest that ICI might not be a relevant option for NSCLC patients with FHITlow/pHER2high tumors and that anti-HER2 targeted therapy could be a good therapeutic alternative for this molecular subclass with poorer prognosis.
Combining PD-1 or PD-L1 inhibitors with chemotherapy is a good strategy for the treatment of extensive small cell lung cancer: A retrospective analysis of clinical studies
Authors: Luo Hao , Song Guangbin , Wang Dong , Li Mengxia , Dai Nan
Published: December 2022

Objectives

To provide an updated systematic review and meta-analysis of published randomized controlled trials (RCTs) of the efficacy and safety of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors combined with chemotherapy versus chemotherapy alone in the treatment of extensive-stage small-cell lung cancer (ES-SCLC).

Methods

PubMed, Web of Science, Embase, Clinicaltrials and the Cochrane Library were systematically searched to extract RCTs concerning the efficacy and safety of PD-1/PD-L1 inhibitors combined with chemotherapy versus chemotherapy alone in the treatment of ES-SCLC from the time of database inception to October 31, 2022. The literature was independently selected, information was extracted and the risk of bias of the RCTs was evaluated according to the inclusion and exclusion criteria. Stata14.0 was used for the meta-analysis.

Results

Six studies involving 2,600 patients were included in the analysis. The results of the meta-analysis showed that the combination of PD-1/PD-L1 inhibitors significantly improved the OS (HR: 0.73, 95% CI: 0.66-0.80; P<0.0001), prolonged PFS (HR: 0.66,95% CI: 0.55-0.79; P<0.0001) and did not increase overall incidence of treatment-related adverse events (TRAEs) (RR: 1.03, 95% CI: 0.97-1.09; P=0.330) in ES-SCLC patients compared with chemotherapy alone. The subgroup analysis found that patients with negative PD-L1 expression (< 1%) benefited in OS, whereas patients with positive PD-L1 expression (≥1%) had no statistically significant difference in OS. There was a statistically significant difference in PFS between PD-L1-negative (< 1%) and PD-L1-positive (≥1%) patients. The addition of a PD-1 inhibitor or PD-L1 inhibitor to the chemotherapy regimen can improve OS and prolong PFS in patients with ES-SCLC.

Conclusions

PD-1/PD-L1 inhibitors combination chemotherapy significantly improves PFS and OS in ES-SCLC patients without increasing the overall incidence of TRAEs.