bluuebunny/crossref_metadata_2025 huggingface dataset:
Combination of immune checkpoint blockade and targeted gene regulation of angiogenesis for facilitating antitumor immunotherapy
Authors: Zhan Jing , Zhang Manli , Zhou Lili , He Chuan
Published: March 2023

The rapid development of tumor immunotherapy has improved the management of patients with cancer. However, several key problems of tumor immunotherapy, including the insufficient activation of effector T cells, poor tumor invasion, and poor immune killing ability, lead to a low response rate. In the present study, a synergistic strategy was developed by combining in situ tumor vaccines, gene-mediated downregulation of tumor angiogenesis, and anti-PD-L1 therapy. In situ tumor vaccines and antitumor angiogenesis were achieved by codelivering unmethylated cytosine-phosphate-guanine (CpG) and vascular endothelial growth factor (VEGF)-silencing gene (shVEGF) via a hyaluronic acid (HA)-modified HA/PEI/shVEGF/CpG system. Necrotic tumor cells and CpG adjuvants formed in situ tumor vaccines and activated the host immune response. Moreover, VEGF silencing reduced tumor angiogenesis and prompted the homogeneous distribution of tumor blood vessels to facilitate immune cell infiltration. Meanwhile, anti-angiogenesis also improved the immunosuppressive tumor microenvironment. To further improve the specific tumor-killing effect, an anti-PD-L1 antibody was introduced for immune checkpoint blockade, thereby boosting antitumor immune responses. The combination therapy strategy presented in the present study could act in the multiple stages of the tumor immunotherapy cycle, which is expected to offer a new avenue for clinical tumor immunotherapy.
Bioconversion of inorganic selenium to less toxic selenium forms by microbes: A review
Authors: Nie Xinling , Yang Xurui , He Junyi , Liu Pei , Shi Hao , Wang Tao , Zhang Daihui
Published: March 2023

In recent years, microbial conversion of inorganic selenium into an efficient and low-toxic form of selenium has attracted much attention. With the improvement of scientific awareness and the continuous progress of nanotechnology, selenium nanoparticles can not only play the unique functions of organic selenium and inorganic selenium but also have higher safety, absorption and biological activity than other selenium forms. Therefore, the focus of attention has gradually shifted beyond the level of selenium enrichment in yeast to the combination of biosynthetic selenium nanoparticles (BioSeNPs). This paper primarily reviews inorganic selenium and its conversion to less toxic organic selenium and BioSeNPs by microbes. The synthesis method and potential mechanism of organic selenium and BioSeNPs are also introduced, which provide a basis for the production of specific forms of selenium. The methods to characterize selenium in different forms are discussed to understand the morphology, size and other characteristics of selenium. In general, to obtain safer and higher selenium content products, it is necessary to develop yeast resources with higher selenium conversion and accumulation.
Disruption of the foxe1 gene in zebrafish reveals conserved functions in development of the craniofacial skeleton and the thyroid
Authors: Raterman Sophie T. , Von Den Hoff Johannes W. , Dijkstra Sietske , De Vriend Cheyenne , Te Morsche Tim , Broekman Sanne , Zethof Jan , De Vrieze Erik , Wagener Frank A. D. T. G. , Metz Juriaan R.
Published: March 2023

Introduction: Mutations in the FOXE1 gene are implicated in cleft palate and thyroid dysgenesis in humans.

Methods: To investigate whether zebrafish could provide meaningful insights into the etiology of developmental defects in humans related to FOXE1, we generated a zebrafish mutant that has a disruption in the nuclear localization signal in the foxe1 gene, thereby restraining nuclear access of the transcription factor. We characterized skeletal development and thyroidogenesis in these mutants, focusing on embryonic and larval stages.

Results: Mutant larvae showed aberrant skeletal phenotypes in the ceratohyal cartilage and had reduced whole body levels of Ca, Mg and P, indicating a critical role for foxe1 in early skeletal development. Markers of bone and cartilage (precursor) cells were differentially expressed in mutants in post-migratory cranial neural crest cells in the pharyngeal arch at 1 dpf, at induction of chondrogenesis at 3 dpf and at the start of endochondral bone formation at 6 dpf. Foxe1 protein was detected in differentiated thyroid follicles, suggesting a role for the transcription factor in thyroidogenesis, but thyroid follicle morphology or differentiation were unaffected in mutants.

Discussion: Taken together, our findings highlight the conserved role of Foxe1 in skeletal development and thyroidogenesis, and show differential signaling of osteogenic and chondrogenic genes related to foxe1 mutation.
Hormonal drugs: Influence on growth, biofilm formation, and adherence of selected gut microbiota
Authors: Hammouda Zainab K. , Wasfi Reham , Abdeltawab Nourtan F.
Published: March 2023

Many studies have reported the influence of hormonal drugs on gut microbiota composition. However, the underlying mechanism of this interaction is still under study. Therefore, this study aimed to evaluate the possible in vitro changes in selected members of gut bacteria exposed to oral hormonal drugs used for years. Selected members of gut bacteria were Bifidobacterium longum, Limosilactobacillus reuteri, Bacteroides fragilis, and Escherichia coli representing the four main phyla in the gut. Selected hormonal drugs used for a long time were estradiol, progesterone, and thyroxine. The effect of intestinal concentrations of these drugs on the selected bacterial growth, biofilm formation, and adherence to Caco-2/HT-29 cell line was assessed. Short-chain fatty acids (SCFAs) have been included in host functions including the gut, immune and nervous functions; thus, the drug’s effects on their production were assayed using High- Performance Liquid Chromatography. Sex steroids significantly increased the growth of all tested bacteria except B. longum, similarly, thyroxine increased the growth of tested Gram-negative bacteria however reducing that of tested Gram-positive bacteria. The effect of drugs on biofilm formation and bacterial adherence to cell lines cocultures was variable. Progesterone decreased the biofilm formation of tested Gram-positive bacteria, it nevertheless increased L. reuteri adherence to Caco-2/HT-29 cell line cell lines coculture. By contrast, progesterone increased biofilm formation by Gram-negative bacteria and increased adherence of B. fragilis to the cell lines coculture. Moreover, thyroxine and estradiol exhibited antibiofilm activity against L. reuteri, while thyroxine increased the ability of E. coli to form a biofilm. Moreover, hormones affected bacterial adherence to cell lines independently of their effect on hydrophobicity suggesting other specific binding factors might contribute to this effect. Tested drugs affected SCFAs production variably, mostly independent of their effect on bacterial growth. In conclusion, our results showed that the microbiota signature associated with some hormonal drug consumption could be the result of the direct effect of these drugs on bacterial growth, and adherence to enterocytes besides the effect of these drugs on the host tissue targets. Additionally, these drugs affect the production of SCFAs which could contribute to some of the side effects of these drugs.
The impact of meteorological changes on the quality of life regarding thermal comfort in the Amazon region
Authors: Santos Adrian Felipe dos , Moura Flávio Rafael Trindade , Seruffo Marcos César da Rocha , Santos Waldeir Pereira dos , Costa Gabriel Brito , Costa Fernando Augusto Ribeiro
Published: March 2023

The meteorological imbalances in Brazil have a strong impact on the lives of the population across the country, especially in the Amazon region. These impacts extend to meteorological phenomena, such as extreme rainfall, droughts, and an increase in temperature in several regions, as well as impacts on health, the economy, and, as the object of this study, the quality of life. This study presents the impact of meteorological changes on the quality of life in the Amazon region, based on (i) the thermal discomfort index (TDI), (ii) the temperature and humidity index (THI), and (iii) the effective temperature index as a function of the wind (TEFW). For this, meteorological data from the years 2003–2021 were used, in which the variables include total precipitation, global radiation, air-dry bulb temperature, the maximum temperature in the previous hour, the minimum temperature in the previous hour, relative humidity, and wind speed. This analysis indicates that for this tropical region, the sensation of mild discomfort was predominant in about 70% of the measurements, indicating a certain level of impact on the population's quality of life, in addition to the fluctuation of levels of discomfort during periods of winter in that there are high rates of precipitation. The data control was performed with the removal of null data and calculation of monthly and annual averages, by using the compression (average) empty data frames in order to receive the values without losing the indexing of dates. At first, it was considered to use the kriging process to fill in the missing data; however, due to the existence of microclimates in the regions, the data could characterize remote regions in a generalized way, which would make it difficult to understand these data in comparison with the data from the National Institute of Meteorology (INMET, in Portuguese).
Obesity and cardiovascular disease: An executive document on pathophysiological and clinical links promoted by the Italian Society of Cardiovascular Prevention (SIPREC)
Authors: Volpe Massimo , Gallo Giovanna
Published: March 2023

The prevalence of obesity worldwide has increased in recent decades not only among adults, but also in children and adolescents. This phenomenon contributes to an increased risk of cardiovascular diseases (CVD), also after the adjustment for conventional risk factors such as hypertension, diabetes and dyslipidemia. Indeed, obesity contributes to the development of insulin resistance, endothelial dysfunction, sympathetic nervous system activation, increased vascular resistance and inflammatory and prothrombotic state which promote the incidence of major cardiovascular events. On the basis of this evidence, in 2021 obesity has been acknowledged as a definite pathological identity and identified as a recurrent, chronic non-communicable disease. Therapeutic strategies for the pharmacological treatment of obesity include the combination of naltrexone and bupropione and the lipase inhibitor orlistat and they have been recently implemented with the glucagon like peptide-1 receptor agonists semaglutide and liraglutide, which have produced positive and sustained effects on body weight reduction. If drug interventions are not effective, bariatric surgery may be considered, representing an efficacious treatment option for extreme obesity or obesity with comorbidities. The present executive paper is aimed to increase knowledge on the relationships between obesity and CVD, to raise the perception of this condition which is currently insufficient and to support the clinical practice management.
Ethical and legal considerations influencing human involvement in the implementation of artificial intelligence in a clinical pathway: A multi-stakeholder perspective
Authors: Redrup Hill Elizabeth , Mitchell Colin , Brigden Tanya , Hall Alison
Published: March 2023

Introduction

Ethical and legal factors will have an important bearing on when and whether automation is appropriate in healthcare. There is a developing literature on the ethics of artificial intelligence (AI) in health, including specific legal or regulatory questions such as whether there is a right to an explanation of AI decision-making. However, there has been limited consideration of the specific ethical and legal factors that influence when, and in what form, human involvement may be required in the implementation of AI in a clinical pathway, and the views of the wide range of stakeholders involved. To address this question, we chose the exemplar of the pathway for the early detection of Barrett's Oesophagus (BE) and oesophageal adenocarcinoma, where Gehrung and colleagues have developed a “semi-automated”, deep-learning system to analyse samples from the CytospongeTM TFF3 test (a minimally invasive alternative to endoscopy), where AI promises to mitigate increasing demands for pathologists' time and input.

Methods

We gathered a multidisciplinary group of stakeholders, including developers, patients, healthcare professionals and regulators, to obtain their perspectives on the ethical and legal issues that may arise using this exemplar.

Results

The findings are grouped under six general themes: risk and potential harms; impacts on human experts; equity and bias; transparency and oversight; patient information and choice; accountability, moral responsibility and liability for error. Within these themes, a range of subtle and context-specific elements emerged, highlighting the importance of pre-implementation, interdisciplinary discussions and appreciation of pathway specific considerations.

Discussion

To evaluate these findings, we draw on the well-established principles of biomedical ethics identified by Beauchamp and Childress as a lens through which to view these results and their implications for personalised medicine. Our findings are not only relevant to this context but have implications for AI in digital pathology and healthcare more broadly.
The teaching of physics at upper secondary school level: A comparative study between Indonesia and Ireland
Authors: Sudirman Sudirman , Kennedy Declan , Soeharto Soeharto
Published: March 2023

This study aims to investigate the teaching approaches taken by physics teachers in Indonesia and Ireland when teaching a module on Medical Physics in the classroom. Additionally, students’ attitudes to the module on Medical Physics were also explored. In particular, the views of these teachers toward inquiry based science education (IBSE) and direct instruction (DI) when implementing this module with students in the 14–16 age group were examined. Data were collected to investigate how teachers in the two countries used combinations of the IBSE and DI teaching approaches when teaching the module to their students. Arising out of the implementation of the module, it was hoped that the module would serve as a “hook” to interest students in physics by teaching topics in physics via real-life applications of physics. Thus, the attitudes of the students toward science on completion of the module were assessed. A total of 15 schools in Indonesia (402 students) and 15 schools in Ireland (263 students) participated in the project. Data were collected from the teachers and students using questionnaires. Among the findings were that while teachers in Ireland were unanimous in their agreement with the inclusion of IBSE activities in the lesson plans supplied, only 67% of the teachers in Indonesia agreed with the inclusion of these activities in the module. There was a strong relationship between the type of school and the students’ attitude toward the module. Students in the more academic type schools in both Ireland and Indonesia were less positive about the module. Among the problems highlighted by teachers in Indonesia was the lack of laboratory facilities. Also, students in both countries commented on the problems with terminology and literacy in general when studying physics. While the module brought out a positive response from students convincing them to continue with their study of physics at the upper secondary school level.
Systematic review of acupuncture to improve ovarian function in women with poor ovarian response
Authors: Wang Rong-Rong , Su Meng-Hua , Liu Li-Ying , Lai Yuan-Yuan , Guo Xiao-Li , Gan Di , Zheng Xiao-Yan , Yang Han , Yu Si-Yi , Liang Fan-Rong , Wei Wei , Zhong Ying , Yang Jie
Published: March 2023

Objective

To determine the effect of acupuncture in treating poor ovarian response (POR).

Methods

We searched MEDLINE (via PubMed), EMBASE, Allied and Complementary Medicine Database, CNKI, CBM, VIP database, Wanfang Database, and relevant registration databases from inception to January 30, 2023. In this review, both Chinese and English peer-reviewed literature were included. Only randomized controlled trials (RCTs) using acupuncture as an intervention for POR patients undergoing in vitro fertilization were considered.

Results

Seven clinical randomized controlled trials (RCTs) were eventually included for comparison (516 women). The quality of included studies was generally low or very low. For the meta-analysis, seven studies showed that compared with controlled ovarian hyperstimulation (COH) therapy, acupuncture combined with COH therapy could significantly increase the implantation rate (RR=2.13, 95%CI [1.08, 4.21], p=0.03), the number of oocytes retrieved (MD=1.02, 95%CI [0.72, 1.32], p<0.00001), the thickness of endometrium (MD=0.54, 95%CI [0.13, 0.96], p=0.01), and the antral follicle count (MD=1.52, 95%CI [1.08, 1.95], p<0.00001), reduce follicle-stimulating hormone (FSH) levels (MD=-1.52, 95%CI [-2.41, -0.62], p=0.0009) and improve estradiol (E2) levels (MD=1667.80, 95%CI [1578.29, 1757.31], p<0.00001). Besides, there were significant differences in the duration of Gn (MD=0.47, 95%CI [-0.00, 0.94], p=0.05) between the two groups. However, no statistical variation was observed in improving clinical pregnancy rate (CPR), fertilization rate, high-quality embryo rate, luteinizing hormone (LH) value, anti-mullerian hormone (AMH) value, or reducing the dose of gonadotropin (Gn) values between the acupuncture plus COH therapy group and the COH therapy group.

Conclusion

Acupuncture combined with COH therapy is doubtful in improving the pregnancy outcome of POR patients. Secondly, acupuncture can also improve the sex hormone level of POR women, and improve ovarian function. Furthermore, more RCTs of acupuncture in POR are needed to be incorporated into future meta-analyses.

Systematic review registration

PROSPERO, identifier CRD42020169560.
Disparities in health condition diagnoses among aging transgender and cisgender medicare beneficiaries, 2008-2017
Authors: Hughto Jaclyn M. W. , Varma Hiren , Babbs Gray , Yee Kim , Alpert Ash , Hughes Landon , Ellison Jacqueline , Downing Jae , Shireman Theresa I.
Published: March 2023

Introduction

The objective of this research is to provide national estimates of the prevalence of health condition diagnoses among age-entitled transgender and cisgender Medicare beneficiaries. Quantification of the health burden across sex assigned at birth and gender can inform prevention, research, and allocation of funding for modifiable risk factors.

Methods

Using 2009–2017 Medicare fee-for-service data, we implemented an algorithm that leverages diagnosis, procedure, and pharmacy claims to identify age-entitled transgender Medicare beneficiaries and stratify the sample by inferred gender: trans feminine and nonbinary (TFN), trans masculine and nonbinary (TMN), and unclassified. We selected a 5% random sample of cisgender individuals for comparison. We descriptively analyzed (means and frequencies) demographic characteristics (age, race/ethnicity, US census region, months of enrollment) and used chi-square and t-tests to determine between- (transgender vs. cisgender) and within-group gender differences (e.g., TMN, TFN, unclassified) difference in demographics (p<0.05). We then used logistic regression to estimate and examine within- and between-group gender differences in the predicted probability of 25 health conditions, controlling for age, race/ethnicity, enrollment length, and census region.

Results

The analytic sample included 9,975 transgender (TFN n=4,198; TMN n=2,762; unclassified n=3,015) and 2,961,636 cisgender (male n=1,294,690, female n=1,666,946) beneficiaries. The majority of the transgender and cisgender samples were between the ages of 65 and 69 and White, non-Hispanic. The largest proportion of transgender and cisgender beneficiaries were from the South. On average, transgender individuals had more months of enrollment than cisgender individuals. In adjusted models, aging TFN or TMN Medicare beneficiaries had the highest probability of each of the 25 health diagnoses studied relative to cisgender males or females. TFN beneficiaries had the highest burden of health diagnoses relative to all other groups.

Discussion

These findings document disparities in key health condition diagnoses among transgender Medicare beneficiaries relative to cisgender individuals. Future application of these methods will enable the study of rare and anatomy-specific conditions among hard-to-reach aging transgender populations and inform interventions and policies to address documented disparities.
Regulation of the immune system by the insulin receptor in health and disease
Authors: Makhijani Priya , Basso Paulo José , Chan Yi Tao , Chen Nan , Baechle Jordan , Khan Saad , Furman David , Tsai Sue , Winer Daniel A.
Published: March 2023

The signaling pathways downstream of the insulin receptor (InsR) are some of the most evolutionarily conserved pathways that regulate organism longevity and metabolism. InsR signaling is well characterized in metabolic tissues, such as liver, muscle, and fat, actively orchestrating cellular processes, including growth, survival, and nutrient metabolism. However, cells of the immune system also express the InsR and downstream signaling machinery, and there is increasing appreciation for the involvement of InsR signaling in shaping the immune response. Here, we summarize current understanding of InsR signaling pathways in different immune cell subsets and their impact on cellular metabolism, differentiation, and effector versus regulatory function. We also discuss mechanistic links between altered InsR signaling and immune dysfunction in various disease settings and conditions, with a focus on age related conditions, such as type 2 diabetes, cancer and infection vulnerability.
Research on energy storage allocation strategy considering smoothing the fluctuation of renewable energy
Authors: Lv You , Qin Ruijun , Sun Hao , Guo Ziming , Fang Fang , Niu Yuguang
Published: March 2023

Energy storage technology can effectively solve the problems caused by large-scale grid connection of renewable energy with volatility and uncertainty. Due to the high cost of the energy storage system, the research on capacity allocation of energy storage system has important theoretical and application value. In this paper, an optimization method for determining the capacity of energy storage system for smoothing the power output of renewable energy is proposed. First, based on the actual data of Ulanqab, the output characteristics of wind power and photovoltaic power generation are studied, and the K-means algorithm is used to select typical days. Then, the energy storage configuration model is built according to the objective function and constraints. Finally, genetic algorithm is used to solve the optimization model, obtain the corresponding parameters, and complete the configuration of energy storage capacity. Based on the results of renewable energy spectrum analysis, the minimum capacity of the energy storage system that meets the constraint of target power output volatility after compensation by the energy storage system can be optimized. The simulation results show that at 1 and 10 min, the flattened volatility is about 2% and 5%, while the actual penetration volatility is about 20% and 30%. The volatility of the optimized model is greatly reduced, which proves the effectiveness of the proposed strategy.
Contribution of a groundwater-influenced hinterland drainage system to the restoration of salmonid spawning grounds at the upper river Danube
Authors: Pander Joachim , Casas-Mulet Roser , Geist Juergen
Published: March 2023

Groundwater-influenced ditches, so called hinterland drainage systems (HDS), accompany many heavily modified water bodies (HMWBs). Herein, we evaluate the usefulness of including HDS as functional habitats in river restoration approaches by assessing their role as salmonid recruitment areas in HMWBs. We tested the functionality of spawning grounds in a groundwater-influenced HDS compared to the quality of those not influenced by groundwater (OHB 1 and OHB 2), based on bioindication using brown trout eggs. Eggs were placed in each compartment of a two-layered container of 20 cm diameter and 30 cm total depth (known as the HydroEcoSedimentary Tool or HEST) pre-filled with sediment, mimicking hyporheic conditions. A total of 81 HESTs were evenly distributed across the three sites to assess egg and larvae mortality whilst exposed at two substrate depths (5–10 cm and 17–22 cm). In addition, key physico-chemical variables such as dissolved oxygen, temperature, pH, turbidity, electric conductance and substratum composition were analyzed. Mean egg mortality in the HDS was 33% lower than in both non-groundwater-influenced spawning grounds, whereas mean larval mortality was highest in the HDS (95%) compared to 74% at OHB 1 and 66% at OHB 2. The exposure depth of eggs had a significant influence on mortality, with more dead eggs and larvae in the deeper substrate layers, most likely attributed to an increase of fine sediment and a decrease of oxygen availability over time. Particularly the HDS revealed high mortality rates of larvae since it had a 17% lower mean oxygen level compared to the other spawning grounds. These findings suggest that if additional measures such as substratum restoration were undertaken to increase oxygen availability within HDS, these groundwater-dominated ditches could be incorporated as part of an efficient river restoration strategy.
Diabetic retinopathy as a potential risk factor for ptosis: A 13-year nationwide population-based cohort study in Taiwan
Authors: Lin Chun-Ju , Hsu Alan Y. , Tien Peng-Tai , Chang Cheng-Hsien , Lai Chun-Ting , Hsia Ning-Yi , Yang Yu-Cih , Bair Henry , Chen Huan-Sheng , Chen Wen-Lu , Tsai Yi-Yu
Published: March 2023

Purpose

To determine the risk of ptosis among diabetic retinopathy (DR) patients.

Methods

This is a population-based, retrospective, matched-cohort study where DR patients were recruited from the Taiwan National Health Insurance Research Database (NHIRD) to investigate the risk of developing ptosis. Preexisting co-factors of interest included smoking status and medical comorbidities of hyperlipidemia and hypertension. Statistical analysis was performed using T-test, Cox-proportional hazard ratios adjusted for comorbidities (aHR), Wilcoxon rank sum test, Kaplan–Meier estimators, and log rank tests.

Results

Follow-up data of 9,494 patients with DR and 37,976 matched control cohort (non-DR) from 2000 to 2012 were analyzed. DR patients were found to have significantly increased risk of developing ptosis (adjusted hazard ratio (HR) [95% CI]: 2.76 [1.74–4.38], p < 0.001) when compared to the control cohort. From analysis in different strata, adult age and non-smokers were shown to have higher risk for ptosis development among DR patients. Furthermore, DR patients was also found to have increased risk of developing ptosis when compared to matched controls, regardless of whether they had medical comorbidities of lipid metabolism disorders or hypertension.

Conclusions

In this large-scale study using real-world data, our results showed that DR patients were found to have increased risk of developing ptosis. Female gender, adult age, and non-smokers were also shown to increase the risk of ptosis among DR patients. This has implications towards the care of diabetic patients, complications such as ptosis should be properly screened for when encountering such patients. Before ptosis surgery, the possibility of underlying diabetes or DR should be also scrutinized and treated properly to avoid undesirable postoperative dissension.
C1QC is a prognostic biomarker with immune-related value in kidney renal clear cell carcinoma
Authors: Yao Wentao , Liu Hanyuan , Xu Feng , Cai Zhenyu , Hang Lijing , Lu Mingya , Zhao Yuan , Yang Chendi , Zong Yang
Published: March 2023

Background: Kidney renal clear cell carcinoma (KIRC) is a representative histologic subtype of renal cell carcinoma (RCC). RCC exhibits a strong immunogenicity with a prominent dysfunctional immune infiltration. Complement C1q C chain (C1QC) is a polypeptide in serum complement system and is involved in tumorigenesis and the modulation of tumor microenvironment (TME). However, researches have not explored the effect of C1QC expression on prognosis and tumor immunity of KIRC.

Methods: The difference in a wide variety of tumor tissues and normal tissues in terms of the C1QC expression was detected using TIMER and TCGA portal databases, and further validation of protein expression of C1QC was conducted via Human Protein Atlas. Then, the associations of C1QC expression with clinicopathological data and other genes were studied with the use of UALCAN database. Subsequently, the association of C1QC expression with prognosis was predicted by searching the Kaplan-Meier plotter database. A protein-protein interaction (PPI) network with the Metascape database was built using STRING software, such that the mechanism underlying the C1QC function can be studied in depth. The TISCH database assisted in the evaluation of C1QC expression in different cell types in KIRC at the single-cell level. Moreover, the association of C1QC and the infiltration level of tumor immune cell was assessed using TIMER platform. The TISIDB website was selected to deeply investigate the Spearman correlation between C1QC and immune-modulator expression. Lastly, how C1QC affected the cell proliferation, migration, and invasion in vitro was assessed using knockdown strategies.

Results: KIRC tissues had notably upregulated C1QC level in comparison with adjacent normal tissues, with showed a positive relevance to clinicopathological features including tumor stage, grade, and nodal metastasis, and a negative relevance to clinical prognosis in KIRC. C1QC knockdown inhibited KIRC cell proliferation, migration, and invasion, as indicated by the results of the in vitro experiment. Furthermore, functional and pathway enrichment analysis demonstrated that C1QC was involved in immune system-related biological processes. According to single-cell RNA analysis, C1QC exhibited a specific upregulation in macrophages cluster. Additionally, there was an obvious association of C1QC and a wide variety of tumor-infiltrating immune cells in KIRC. Also, high C1QC expression presented inconsistent prognosis in different enriched immune cells subgroups in KIRC. Immune factors might contribute to C1QC function in KIRC.

Conclusion: C1QC is qualified to predict KIRC prognosis and immune infiltration biologically. Targeting C1QC may bring new hope for the treatment of KIRC.
Women's beliefs about methods and contraceptive discontinuation: Results from a prospective study from Nairobi and Homa Bay counties in Kenya
Authors: Wado Yohannes Dibaba , Mutua Martin K. , Odwe George , Obare Francis , Machiyama Kazuyo , Casterline John B. , Cleland John
Published: March 2023

Background

Rates of contraceptive discontinuation are high in many low and middle countries contributing to unmet need for contraception and other adverse reproductive health outcomes. Few studies have investigated how women's beliefs about methods and strength of fertility preferences affect discontinuation rates. This study examines this question using primary data collected in Nairobi and Homa Bay counties in Kenya.

Methods

We used data from two rounds of a longitudinal study of married women ages 15–39 years (2,812 and 2,424 women from Nairobi and Homa Bay respectively at round 1). Information on fertility preferences, past and current contraceptive behavior, and method-related beliefs about six modern contraceptive methods were collected, along with a monthly calendar of contraceptive use between the two interviews. The analysis focused on discontinuation of the two most commonly used methods in both sites, injectables and implants. We carry out competing risk survival analysis to identify which method related beliefs predict discontinuation among women using at the first round.

Results

The percentages of episodes discontinued in the 12 months between the two rounds was 36%, with a higher rate of discontinuation in Homa Bay (43%) than in the Nairobi slums (32%) and higher for injectables than implants. Method related concerns and side effects were the major self-reported reasons for discontinuation in both sites. The competing risk survival analysis showed that the probability of method related discontinuation of implants and injectables was significantly lower among respondents who believed that the methods do not cause serious health problems (SHR = 0.78, 95% CI: 0.62–0.98), do not interfere with regular menses (SHR = 0.76, 95% CI: 0.61–0.95) and do not cause unpleasant side effects (SHR = 0.72, 95% CI 0.56–0.89). By contrast, there were no net effects of three method related beliefs that are commonly cited as obstacles to contraceptive use in African societies: safety for long-term use, ability to have children after stopping the method, and the approval of the husband.

Conclusion

This study is unique in its examination of the effect of method-specific beliefs on subsequent discontinuation for a method-related reason, using a longitudinal design. The single most important result is that concerns about serious health problems, which are largely unjustified and only moderately associated with beliefs about side effects, are a significant influence on discontinuation. The negative results for other beliefs show that the determinants of discontinuation differ from the determinants of method adoption and method choice.
A deep look into the storm: Israeli multi-center experience of coronavirus disease 2019 (COVID-19) in patients with autoimmune inflammatory rheumatic diseases before and after vaccinations
Authors: Kharouf Fadi , Eviatar Tali , Braun Maya , Pokroy-Shapira Elisheva , Brodavka Michal , Zloof Yair , Agmon-Levin Nancy , Toledano Kochava , Oren Shirly , Lidar Merav , Zisman Devy , Tavor Yonit , Amit-Vazina Mirit , Sabbah Firas , Breuer Gabriel S. , Dagan Amir , Beshara-Garzuzi Rima , Markovits Doron , Elias Muna , Feld Joy , Tayer-Shifman Oshrat , Gazitt Tal , Reitblatt Tatiana , Rubin Limor , Haddad Amir , Giryes Sami , Paran Daphna , Peleg Hagit , Molad Yair , Elkayam Ori , Mevorach Dror , Balbir-Gurman Alexandra , Braun-Moscovici Yolanda
Published: March 2023

Objective

We aimed to characterize the course of COVID-19 in autoimmune inflammatory rheumatic disease (AIIRD) patients in Israel, taking into consideration several remarkable aspects, including the outcomes of the different outbreaks, the effect of vaccination campaigns, and AIIRD activity post-recovery.

Methods

We established a national registry of AIIRD patients diagnosed with COVID-19, including demographic data, AIIRD diagnosis, duration and systemic involvement, comorbidities, date of COVID-19 diagnosis, clinical course, and dates of vaccinations. COVID-19 was diagnosed by a positive SARS-CoV-2 polymerase chain reaction.

Results

Israel experienced 4 outbreaks of COVID-19 until 30.11.2021. The first three outbreaks (1.3.2020 – 30.4.2021) comprised 298 AIIRD patients. 64.9% had a mild disease and 24.2% had a severe course; 161 (53.3%) patients were hospitalized, 27 (8.9%) died. The 4th outbreak (delta variant), starting 6 months after the beginning of the vaccination campaign comprised 110 patients. Despite similar demographic and clinical characteristics, a smaller proportion of AIIRD patients had negative outcomes as compared to the first 3 outbreaks, with regards to severity (16 patients,14.5%), hospitalization (29 patients, 26.4%) and death (7 patients, 6.4%). COVID-19 did not seem to influence the AIIRD activity 1-3 months post-recovery.

Conclusions

COVID-19 is more severe and has an increased mortality in active AIIRD patients with systemic involvement, older age and comorbidities. Vaccination with 3 doses of the mRNA vaccine against SARS-CoV-2 protected from severe COVID-19, hospitalization and death during the 4th outbreak. The pattern of spread of COVID-19 in AIIRD patients was similar to the general population.
Safety and efficacy of radiotherapy/chemoradiotherapy combined with immune checkpoint inhibitors for non-small cell lung cancer: A systematic review and meta-analysis
Authors: Wu Jing , Ni Tingting , Deng Rong , Li Yan , Zhong Qin , Tang Fei , Zhang Qi , Fang Chunju , Xue Yingbo , Zha Yan , Zhang Yu
Published: March 2023

Background

It is now widely accepted that radiotherapy (RT) can provoke a systemic immune response, which gives a strong rationale for the combination of RT and immune checkpoint inhibitors (ICIs). However, RT is a double-edged sword that not only enhances systemic antitumor immune response, but also promotes immunosuppression to some extent. Nevertheless, many aspects regarding the efficacy and safety of this combination therapy remain unknown. Therefore, a systematic review and meta-analysis was performed in order to assess the safety and efficacy of RT/chemoradiotherapy (CRT) and ICI combination therapy for non-small cell lung cancer (NSCLC) patients.

Methods

PubMed and several other databases were searched (according to specific criteria) to find relevant studies published prior to the 28th of February 2022.

Results

3,652 articles were identified for screening and 25 trials containing 1,645 NSCLC patients were identified. For stage II-III NSCLC, the one- and two-year overall survival (OS) was 83.25% (95% confidence interval (CI): 79.42%-86.75%) and 66.16% (95% CI: 62.3%-69.92%), respectively. For stage IV NSCLC, the one- and two-year OS was 50% and 25%. In our study, the pooled rate of grade 3-5 adverse events (AEs) and grade 5 AEs was 30.18% (95% CI: 10.04%-50.33%, I2: 96.7%) and 2.03% (95% CI: 0.03%-4.04%, I2: 36.8%), respectively. Fatigue (50.97%), dyspnea (46.06%), dysphagia (10%-82.5%), leucopenia (47.6%), anaemia (5%-47.6%), cough (40.09%), esophagitis (38.51%), fever (32.5%-38.1%), neutropenia (12.5%-38.1%), alopecia (35%), nausea (30.51%) and pneumonitis (28.53%) were the most common adverse events for the combined treatment. The incidence of cardiotoxicity (0%-5.00%) was low, but it was associated with a high mortality rate (0%-2.56%). Furthermore, the incidence of pneumonitis was 28.53% (95% CI: 19.22%-38.88%, I2: 92.00%), grade ≥ 3 pneumonitis was 5.82% (95% CI: 3.75%-8.32%, I2: 57.90%) and grade 5 was 0%-4.76%.

Conclusion

This study suggests that the addition of ICIs to RT/CRT for NSCLC patients may be both safe and feasible. We also summarize details of different RT combinations with ICIs to treat NSCLC. These findings may help guide the design of future trials, the testing of concurrent or sequential combinations for ICIs and RT/CRT could be particularly useful to guide the treatment of NSCLC patients.
The role of Th-17 cells and IL-17 in the metastatic spread of breast cancer: As a means of prognosis and therapeutic target
Authors: Shibabaw Tewodros , Teferi Banchamlak , Ayelign Birhanu
Published: March 2023

Metastatic breast cancer is one of the most common and well-known causes of death for women worldwide. The inflammatory tumor cell and other cancer hallmarks dictate the metastatic form and dissemination of breast cancer. Taking these into account, from various components of the tumor microenvironment, a pro-inflammatory infiltrative cell known as Th-17 plays an immense role in breast cancer proliferation, invasiveness, and metastasis. It has been demonstrated that IL-17, a pleiotropic pro-inflammatory cytokine generated by Th-17, is upregulated in a metastatic form of breast cancer. Recent research updates stated that chronic inflammation and mediators like cytokines and chemokines are causative hallmarks in many human cancers, including breast cancer. Therefore, IL-17 and its multiple downward signaling molecules are the centers of research attention to develop potent treatment options for cancer. They provide information on the role of IL-17-activated MAPK, which results in tumor cell proliferation and metastasis via NF-kB-mediated expression of MMP signaling. Overall, this review article emphasizes IL-17A and its intermediate signaling molecules, such as ERK1/2, NF-kB, MMPs, and VEGF, as potential molecular targets for the prevention and treatment of breast cancer.
Sirtuin-dependent metabolic and epigenetic regulation of macrophages during tuberculosis
Authors: Zhang Kangling , Sowers Mark L. , Cherryhomes Ellie I. , Singh Vipul K. , Mishra Abhishek , Restrepo Blanca I. , Khan Arshad , Jagannath Chinnaswamy
Published: March 2023

Macrophages are the preeminent phagocytic cells which control multiple infections. Tuberculosis a leading cause of death in mankind and the causative organism Mycobacterium tuberculosis (MTB) infects and persists in macrophages. Macrophages use reactive oxygen and nitrogen species (ROS/RNS) and autophagy to kill and degrade microbes including MTB. Glucose metabolism regulates the macrophage-mediated antimicrobial mechanisms. Whereas glucose is essential for the growth of cells in immune cells, glucose metabolism and its downsteam metabolic pathways generate key mediators which are essential co-substrates for post-translational modifications of histone proteins, which in turn, epigenetically regulate gene expression. Herein, we describe the role of sirtuins which are NAD+-dependent histone histone/protein deacetylases during the epigenetic regulation of autophagy, the production of ROS/RNS, acetyl-CoA, NAD+, and S-adenosine methionine (SAM), and illustrate the cross-talk between immunometabolism and epigenetics on macrophage activation. We highlight sirtuins as emerging therapeutic targets for modifying immunometabolism to alter macrophage phenotype and antimicrobial function.
KW2449 ameliorates collagen-induced arthritis by inhibiting RIPK1-dependent necroptosis
Authors: Wang Qiong , Ye Qinbin , Xi Xiaoyu , Cao Xiaoxue , Wang Xing , Zhang Mengxiao , Xu Yuan , Deng Tingting , Deng Xiaobing , Zhang Guoqiang , Xiao Cheng
Published: March 2023

Objective

Necroptosis has recently been found to be associated with the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). This study was undertaken to explore the role of RIPK1-dependent necroptosis in the pathogenesis of RA and the potential new treatment options.

Methods

The plasma levels of receptor-interacting protein kinase 1 (RIPK1) and mixed lineage kinase domain-like pseudokinase (MLKL) in 23 controls and 42 RA patients were detected by ELISA. Collagen-induced arthritis (CIA) rats were treated with KW2449 by gavage for 28 days. Arthritis index score, H&E staining, and Micro-CT analysis were used to evaluate joint inflammation. The levels of RIPK1-dependent necroptosis related proteins and inflammatory cytokines were detected by qRT-PCR, ELISA and Western blot, and the cell death morphology was detected by flow cytometry analysis and high-content imaging analysis.

Results

The plasma levels of RIPK1 and MLKL in RA patients were higher than those in healthy people, and were positively correlated with the severity of RA. KW2449 could reduce joint swelling, joint bone destruction, tissue damage, and the plasma levels of inflammatory cytokines in CIA rats. Lipopolysaccharide combined with zVAD (LZ) could induce necroptosis in RAW 264.7 cells, which could be reduced by KW2449. RIPK1-dependent necroptosis related proteins and inflammatory factors increased after LZ induction and decreased after KW2449 treatment or knockdown of RIPK1.

Conclusion

These findings suggest that the overexpression of RIPK1 is positively correlated with the severity of RA. KW2449, as a small molecule inhibitor targeting RIPK1, has the potential to be a therapeutic strategy for RA treatment by inhibiting RIPK1-dependent necroptosis.
Impact of homologous and heterologous boosters in neutralizing antibodies titers against SARS-CoV-2 Omicron in solid-organ transplant recipients
Authors: Gaete-Argel Aracelly , Saavedra-Alarcón Vicente , Sauré Denis , Alonso-Palomares Luis , Acevedo Mónica L. , Alarcón Marion , Bueno Susan M. , Kalergis Alexis M. , Soto-Rifo Ricardo , Valiente-Echeverría Fernando , Cortes Claudia P.
Published: March 2023

Introduction

Booster doses of SARS-CoV-2 vaccines improve seroconversion rates in solid organ transplant recipients (SOTRs) but the impact of homologous and heterologous booster doses in neutralizing antibody (NAb) titers and their ability to interfere with the variant of concern Omicron are not well studied.

Methods

We designed a prospective, open-label, observational clinical cohort study. 45 participants received two doses of BNT162b2 or CoronaVac (21-day or 28-day intervals, respectively) followed by a first and second booster with BNT162b2 (5-month apart each) and we analyzed the neutralizing antibody titers against SARSCoV-2 D614G (B.1 lineage) and Omicron (BA.1 lineage).

Results

Our results show that SOTRs receiving an initial two-dose scheme of CoronaVac or BNT162b2 generate lower NAbs titers against the ancestral variant of SARS-CoV-2 when compared with healthy controls. Although these NAb titers were further decreased against the SARS-CoV-2 Omicron, a single BNT162b2 booster in both groups was sufficient to increase NAb titers against the variant of concern. More importantly, this effect was only observed in those participants responding to the first two shots but not in those not responding to the initial vaccination scheme.

Discussion

The data provided here demonstrate the importance of monitoring antibody responses in immunocompromised subjects when planning booster vaccination programs in this risk group.
Brain endothelial cells exposure to malaria parasites links type I interferon signalling to antigen presentation, immunoproteasome activation, endothelium disruption, and cellular metabolism
Authors: Shafi Abdul Muktadir , Végvári Ákos , Howland Shanshan Wu , Zubarev Roman A. , Rénia Laurent , Penha-Gonçalves Carlos
Published: March 2023

Introduction

Cerebral malaria (CM) lethality is attributable to induction of brain edema induction but the cellular mechanisms involving brain microvascular endothelium in CM pathogenesis are unexplored.

Results

Activation of the STING-INFb-CXCL10 axis in brain endothelial cells (BECs) is a prominent component of the innate immune response in CM development in mouse models. Using a T cell-reporter system, we show that Type 1 IFN signaling in BECs exposed to Plasmodium berghei-infected erythrocytes (PbA-IE), functionally enhances MHC Class-I antigen presentation through gamma-interferon independent immunoproteasome activation and impacted the proteome functionally related to vesicle trafficking, protein processing/folding and antigen presentation. In vitro assays showed that Type 1 IFN signaling and immunoproteasome activation are also involved in the dysfunction of the endothelial barrier through disturbing gene expression in the Wnt/ß-catenin signaling pathway. We demonstrate that IE exposure induces a substantial increase in BECs glucose uptake while glycolysis blockade abrogates INFb secretion impairing immunoproteasome activation, antigen presentation and Wnt/ß-catenin signaling.

Discussion

Metabolome analysis show that energy demand and production are markedly increased in BECs exposed to IE as revealed by enriched content in glucose and amino acid catabolites. In accordance, glycolysis blockade in vivo delayed the clinical onset of CM in mice. Together the results show that increase in glucose uptake upon IE exposure licenses Type 1 IFN signaling and subsequent immunoproteasome activation contributing to enhanced antigen presentation and impairment of endothelial barrier function. This work raises the hypothesis that Type 1 IFN signaling-immunoproteasome induction in BECs contributes to CM pathology and fatality (1) by increasing antigen presentation to cytotoxic CD8+ T cells and (2) by promoting endothelial barrier dysfunction, that likely favor brain vasogenic edema.