Aspartate Transaminase-to-Albumin Ratio (ATAR), a Novel Prognostic Index, Predicts Outcomes in Patients with Small-Cell Lung Cancer.

BACKGROUND: Small cell lung cancer (SCLC) is characterized by high invasion rates, rapid progression, and poor prognoses. Thus, identifying SCLC patients at high risk of progression and death is critical to improve long-term survival. In this study, the aspartate transaminase-to-albumin ratio (ATAR) was examined as a prognostic factor for SCLC patients. METHODS: We screened 196 SCLC patients from December 2013 to September 2022 at the Sichuan Cancer Hospital. The data was collected from patients' medical information as well as from their blood results during diagnosis. Using the Youden index as a cutoff value, patients were divided into high-risk（> 0.54) and low-risk (≤ 0.54) ATAR groups. We analyzed the prognostic factors for overall survival (OS) using the Kaplan-Meier method, univariate and multivariate analyses, Cox regression, and the C-index. RESULTS: There were 109 (55.6%) smokers among the patients, and the median OS was 17.55 months. The Kaplan-Meier analysis indicated that patients with high-risk ATAR had significantly lower OS (p < 0.0001). A multivariate analysis demonstrated that elevated ATAR is an independent adverse predictor of OS (p < 0.001, HR = 1.907). Our study found that ATAR is an independent predictor of survival outcomes in SCLC, which was superior to ALB, PNI, and SII in predicting outcomes in low-risk and high-risk groups (all p < 0.05). Models combining ATAR with ALB, PNI, and SII showed more powerful prognostic value than their corresponding original models. Moreover, the prognostic indicator ATAR can significantly stratify stage I - II and III - IV SCLC patients (p ＜ 0.05). CONCLUSIONS: Peripheral blood ATAR prognostic index can be used as an independent predictor of SCLC patients before treatment.

Usefulness of baseline immature reticulocyte fraction to mature reticulocyte fraction ratio (IMR) as A prognostic predictor for patients with small cell lung cancer.

Background: Small cell lung cancer (SCLC) has a strong invasive ability and a high degree of malignancy, so accurate prognosis prediction is crucial for making the most favorable treatment decision.Unfortunately, there is a scarcity of prognostic indicators specific to SCLC. Reticulocyte levels in blood parameters have been linked to the prognosis of various malignancies. Given SCLC's aggressive characteristics, identifying reliable prognostic markers, such as reticulocyte counts, becomes pivotal in enhancing prognostic accuracy and guiding effective therapeutic strategies. Objective: This study aimed to evaluate the predictive power of the immature reticulocyte fraction (IRF) to mature reticulocyte fraction (MRF) ratio (IMR) for survival outcomes in patients with SCLC. Materials and methods: A retrospective analysis was conducted on 192 patients with small cell lung cancer (SCLC). The median values of various prognostic indicators, such as IMR, IRF, MRF, reticulocyte count (RET), SII (systemic immune-inflammatory index), were utilized as cutoff points, categorizing patients into high and low groups. The Kaplan-Meier method, univariate, multivariate analyses Cox regression, and C-index were used to analyze the prognostic factors for overall survival (OS). Results: In our cohort, 138 (71.9 %) were male, 119 (62 %) were smokers, and 82 (57.3 %) were older than 60 years old. The median survival time was 18.15 months.Higher mortality was observed in the high IMR and high IRF groups, while the high MRF group exhibited lower mortality. At the same time, mortality was lower in the high MRF group. Univariate analysis showed that smoking history (P = 0.006), tumor stage (P = 0.002), chemotherapy cycle (P = 0.014), IMR (P = 0.01), and many other factors significantly affected the prognosis of SCLC. Multivariate analysis demonstrated that elevated IMR was an independent adverse predictor of OS (P = 0.039, HR = 0.330). Spearman test confirmed that the prognostic indicators IRF, IMR, and SII were positively correlated with the overall survival rate of patients with SCLC. Kaplan-Meier analysis showed that the OS rate of patients with high IMR was significantly worse (P = 0.0096). In addition, we found that IMR was superior to IRF in distinguishing patients with different outcomes in the low and high groups (P < 0.05). Our novel integration index, combining IMR with the TNM stage system and SII index, exhibited superior prognostic value compared to the original index. Additionally, the combination of prognostic indicators IMR and SII significantly stratified stage I-II SCLC patients (P ＜0.05). Conclusions: The prognostic index based on peripheral blood IMR stands out as an independent predictor for SCLC patients pre-treatment. Its accessibility through routine blood analysis facilitates immediate clinical application without requiring prolonged scientific research validation. The integration of IMR with the TNM score enhances survival prediction and risk stratification. Notably, when combined with the SII score, the new IMR index demonstrates significant improvements in prognostication for stage I-II small cell lung cancer.

Research progress on the interaction between oxidative stress and platelets: Another avenue for cancer?

Oxidative stress (OS) is a chemical imbalance between an oxidant and an antioxidant, causing damage to redox signaling and control or causing molecular damage. Unbalanced oxidative metabolism can produce excessive reactive oxygen species (ROS). These excess ROS can cause drastic changes in platelet metabolism and further affect platelet function. It will also lead to an increase in platelet procoagulant phenotype and cell apoptosis, which will increase the risk of thrombosis. The creation of ROS and subsequent platelet activation, adhesion, and recruitment are then further encouraged in an auto-amplifying loop by ROS produced from platelets. Meanwhile, cancer cells produce a higher concentration of ROS due to their fast metabolism and high proliferation rate. However, excessive ROS can result in damage to and modification of cellular macromolecules. The formation of cancer and its progression is strongly associated with oxidative stress and the resulting oxidative damage. In addition, platelets are an important part of the tumor microenvironment, and there is a significant cross-communication between platelets and cancer cells. Cancer cells alter the activation status of platelets, their RNA spectrum, proteome, and other properties. The "cloaking" of cancer cells by platelets providing physical protection，avoiding destruction from shear stress and the attack of immune cells, promoting tumor cell invasion.We explored the vicious circle interaction between ROS, platelets, and cancer in this review, and we believe that ROS can play a stimulative role in tumor growth and metastasis through platelets.

Factors influencing platelet isolation: a prospective multicenter study from Western China.

Tumor-educated platelets (TEPs) have been widely reported to have promising application potential; nonetheless, platelet isolation from peripheral blood is an important but neglected step in TEPs research for platelet-based liquid biopsy. In this article, we discussed some common influence factors for platelet isolation. To investigate the factors involved in platelet isolation, a prospective multicenter study was conducted on healthy Han Chinese adults (18 to 79 years of age). A total of 208 individuals were included in the final statistical analysis out of the 226 healthy volunteers who were prospectively enrolled from four hospitals. The primary study metric was the platelet recovery rate (PRR). The similar pattern was observed in the four hospitals, The PRR at room temperature (23°C±2°C) was slightly higher than the PRR at cold temperature (4°C±2°C). Moreover, the PRR gradually decreased as the storage time increased. The PRR for samples within 2 hours of storage is significantly higher than for samples beyond 2 hours (p < .05). Additionally, PRR was also affected by the equipment used in different centers. This study confirmed several factors that influence platelet isolation. In our study, we indicated that platelet isolation should be performed within two hours of peripheral blood draw and held at room temperature until isolation, and that centrifuge models should be fixed during the extraction process, which will further improve the research progress of platelet-based liquid biopsy in cancer.

What is the context? Globally, cancer is one of the leading cause of premature death. Early screening is important for cancer diagnosis and treatment and can even significantly lower cancer mortalityGlobally, cancer is one of the leading cause of premature death. Early screening is important for cancer diagnosis and treatment and can even significantly lower cancer mortalityFor the liquid biopsy, isolation is an important step. Early studies have explored the influencing factors of exosome, circulating tumor cells (CTCs), and other components extraction in liquid biopsy.Despite platelet also being an excellent source of liquid biopsy, few studies have explored the factors that influence platelet isolation.Considering the importance of platelet isolation in tumor-based platelet liquid biopsy, our aim is to optimize platelet isolation conditions as much as possible to obtain a high platelet recovery rate.What is new? In this study, we conducted a prospective multicenter study ofhealthy adults from four centers, combining whole blood with platelet-richplasma to investigate factors influencing platelet recovery rate (PRR) during platelet isolation.In our study, we indicated that platelet isolation should be performed within two hours at room temperature, and that centrifuge models should be fixed during the extraction process, which will further improve the research progress of platelet-based liquid biopsy in cancer.What is the impact? In future platelet-related studies, we should fix the sample storage temperature, storage time and centrifuge model in the process of platelet extraction, so as to reduce the variables affecting platelet extraction as much as possible and ensure the stable recovery rate of platelet extraction.

Fibrinogen to albumin ratio, a novel serum indicator for evaluating the severity of preeclampsia: A single-center retrospective study.

Preeclampsia (PE) is a disorder that affects approximately 5% to 10% of pregnant women. Timely and accurate identification of PE and assessment of its severity are crucial. Therefore, it is necessary to develop predictive indicators which are easily measured in routine antenatal examinations to enable the early detection of PE and assess its severity. We designed a single-center retrospective study in our daily work to assess whether the serum levels of fibrinogen to albumin ratio (FAR), fibrinogen (Fib), albumin (ALB), prothrombin time, calcium (Ca), activated partial thrombin time, creatinine (Cr), D-dimer(D-D), platelet, white blood cell, neutrophil, and lymphocyte counts could help in assessing PE and evaluating its severity. Our findings showed that the serum levels of FAR, Cr, Fib, and D-D were significantly higher in the severe preeclampsia group (sPE) compared with the control and mild preeclampsia groups, whereas the levels of ALB and Ca were significantly lower in sPE patients. In addition, no differences were found between the control and PE groups in terms of prothrombin time, activated partial thrombin time, platelet, white blood cell, neutrophils, and lymphocytes counts. Furthermore, FAR is a novel and better indicator for evaluating the severity of PE, which has not been reported before. And it is an independent risk factor for the development of sPE. In conclusion, the serum levels of FAR, Cr, D-D and Fib were positively correlated with PE, whereas ALB and Ca were negatively correlated with PE severity, which might be valuable in evaluating the severity of PE. FAR proved to be a feasible diagnostic marker for sPE with sensitivity and specificity comparable to those of ALB and Fib.

IL-35 enhances angiogenic effects of small extracellular vesicles in breast cancer.

As an indispensable process for breast cancer metastasis, tumour angiogenesis requires a tight interaction between cancer cells and endothelial cells in tumour microenvironment. Here, we explored the participation of small extracellular vesicles (sEVs) derived from breast cancer cells in modulating angiogenesis and investigated the effect of IL-35 in facilitating this process. Firstly, we characterized breast cancer cells-derived sEVs untreated or treated with IL-35 and visualized the internalization of these sEVs by human umbilical vein endothelial cells (HUVECs). Breast cancer cells-derived sEVs promoted endothelial cell proliferation through facilitating cell cycle progression and enhanced capillary-like structures formation and microvessel formation. Subsequent results proved that IL-35 further reinforced the angiogenic effect induced by breast cancer cells-derived sEVs. Moreover, sEVs from breast cancer cells significantly enhanced tumour growth and microvessel density in breast tumour-bearing mice model. Microarray analysis showed that IL-35 might alter the mRNA profiles of sEVs and activate the Ras/Raf/MEK/ERK signalling pathway. These findings demonstrated that IL-35 indirectly promoted angiogenesis in breast cancer through regulating the content of breast cancer cells-derived sEVs, which could be internalized by HUVECs.

Diagnostic value of dysregulated microribonucleic acids in the placenta and circulating exosomes in gestational diabetes mellitus.

AIMS/INTRODUCTION: Differentially expressed microribonucleic acids (miRNAs) in the placenta and circulating exosomes are of diagnostic value for gestational diabetes mellitus (GDM). In a cross-sectional study, we identified miRNAs expressed both in the placenta and circulating exosomes of pregnant women with GDM, and estimated their diagnostic value. MATERIALS AND METHODS: Next-generation sequencing was used to identify miRNAs in the placenta that were differentially expressed between GDM and normal glucose tolerance pregnancies. Quantitative polymerase chain reaction was used to validate the identified targets. Western blot and transmission electron microscopy were used to validate exosomes. Univariate logistic regression analysis was used to establish diagnostic models based on miRNAs expression, and the diagnostic value was estimated using the receiver operator characteristic curve. RESULTS: We identified 157 dysregulated miRNAs in the placental tissue obtained from GDM pregnancies. Of these, miRNA-125b was downregulated (P < 0.001), whereas miRNA-144 was upregulated (P < 0.001). The patterns of these two miRNAs remained the same in circulating exosomes from GDM pregnancies (all P < 0.001). miRNA-144 levels in the circulating exosomes negatively correlated with body mass index both before pregnancy (P = 0.018) and before delivery (P = 0.039), and positively correlated with blood glucose at 1 h, estimated using the oral glucose tolerance test (P = 0.044). The area under curve for the established diagnostic model was 0.898, which was higher than blood glucose levels at 0 h. CONCLUSIONS: These findings suggest that miRNA-125b and miRNA-144 are consistently dysregulated in circulating exosomes and the placenta from GDM pregnancies, and are of excellent diagnostic value for GDM.

Human placental trophoblast cells contribute to maternal-fetal tolerance through expressing IL-35 and mediating iTR35 conversion.

During pregnancy, trophoblast cells sustain the maternal-fetal tolerance via expressing and secreting various chemokines and cytokines. Our previous study revealed the expression of interleukin-35 (IL-35) in human first-trimester trophoblasts. Here we show that IL-35 is expressed in both human first-trimester primary trophoblast cells and a trophoblast cell line. Trophoblast cells inhibit the proliferation of human naive conventional T cells (Tconv cells) and convert suppressed Tconv cells into iTR35 in an IL-35-dependent manner. Mechanistically, trophoblast cell derived IL-35 mediates its function through phosphorylation of STAT1 and STAT3. In vivo studies confirm that mice with immunologically spontaneous abortion have lower levels of IL-35 and iTR35 cells at the maternal-fetal interface, and neutralizing anti-IL-35 mAb enhances abortion rates. Meanwhile, exogenous IL-35 induces iTR35 and prevents immunological abortion. Our findings thus suggest that trophoblast cells have a critical function in preserving maternal-fetal tolerance via secreting IL-35 during pregnancy.

Human chorionic gonadotropin and IL-35 contribute to the maintenance of peripheral immune tolerance during pregnancy through mediating the generation of IL-10+ or IL-35+ Breg cells.

Regulatory B cells (Breg cells) play critical roles in modulating immune responses during autoimmune diseases and infection. Here we explored the participation of two main Breg subsets, including IL-10+ Breg (B10) and IL-35+ Breg cells, in maintaining successful pregnancy. We first observed an elevated percentage of B10 cells in peripheral blood from first-trimester pregnant women compared with non-pregnant controls. Serum from pregnancy induced the augmentation of B10  in peripheral blood mononuclear cells from non-pregnant women. In animal models, we demonstrated that there were significant augmentation of B10 cells and obvious increase of IL-10 level in splenic B cells from normal pregnant mice compared to that in abortion-prone pregnant mice and virgin mice. Further analysis showed that both hCG and IL-35 suppressed the proliferation of mouse splenic B cells. Moreover, IL-35 induced the expansion of both mouse splenic B10 and IL-35+ Breg cells while hCG only mediated the generation of B10 cells. Subsequent study in mice demonstrated that the activation of STAT1 and STAT3 in B cells caused by IL-35 and the activation of STAT3 caused by hCG were the predominant mechanism of IL-35+ Breg and B10 cells augmentation. These findings suggested that hCG and IL-35 induced the amplification of B10 and IL-35+ Breg cells which played a vital peripheral regulatory role during pregnancy.

Breast cancer cell-derived IL-35 promotes tumor progression via induction of IL-35-producing induced regulatory T cells.

Interleukin 35 (IL-35) is a potent immunosuppressive cytokine, consisting of an Epstein-Barr virus-induced gene 3 (EBI3) subunit and a p35 subunit. IL-35 is mainly produced by regulatory T and regulatory B cells, and plays a crucial role in the development and prevention of infectious and autoimmune diseases. However, the effect of IL-35 in malignant disease is not well understood. In this study, we demonstrated that breast cancer cells (BCCs) also expressed and secreted IL-35 and higher level of IL-35 in BCCs was closely associated with poor prognosis of patients and was an independent unfavorable prognostic factor for breast cancer. Subsequent study revealed that BCC-derived IL-35 inhibited conventional T (Tconv) cell proliferation and further induced suppressed Tconv cells into IL-35-producing induced regulatory T (iTr35) cells. Furthermore, BCC-derived IL-35 promoted the secretion of inhibitory cytokine IL-10 and obviously decreased the secretion of Th1-type cytokine IFN-γ and Th17-type cytokine IL-17 in Tconv cells. Meanwhile, the expression of inhibitory receptor CD73 was also elevated on the surface of Tconv cells following the BCCs' supernatant treatment. Mechanistically, BCC-derived IL-35 exhausted Tconv cells and induced iTr35 by activating transcription factor STAT1/STAT3. Hence, our results indicate functions of BCC-derived IL-35 in promoting tumor progression through proliferation inhibition of tumor-infiltrating Tconv cells and induction of iTr35 cells in tumor microenvironment. This study highlights that IL-35 produced by BCCs are a potential therapeutic target for breast cancer.

MiR-326 antagomir delays the progression of age-related cataract by upregulating FGF1-mediated expression of betaB2-crystallin.

Age-related cataract, the most common cause of blindness worldwide, has been found closely associated with ß-crystallin B2 (ßB2 or CRYBB2). MicroRNAs (miRNAs) are the primary epigenetic regulators important for various biological processes. However, the role of miRNAs in the progression of lens cataract remains to be elucidated. In this study, we found a novel signal cascade miR-326-fibroblast growth factor 1 (FGF1)-ßB2 modulating the progression of lens cataract. In brief, miR-326 exacerbated but its antagomirs attenuated H2O2-induced apoptosis of HLEC-B3 human lens epithelial cells. Dual-luciferase reporter assay and Western blot showed that miR-326 inhibited FGF1 expression by directly targeting its mRNA 3'-UTR. Consistent with this result, miR-326 antagomir enhanced FGF1 protein level. In addition to FGF1, miR-326 antagomir also enhanced ßB2 expression and this enhancement was abolished by transfection of HLEC-B3 cells with FGF1 shRNA. These data demonstrated that miR-326 antagomir increased ßB2 expression via upregulating FGF1, which was further confirmed by the studies in a rat model of selenite-induced cataract. This work suggests that miR-326 antagomir might be a promising candidate to prevent progression of age-related cataract.

Identification of long non-coding RNA and mRNA expression in ßΒ2-crystallin knockout mice.

ßΒ2-crystallin (CRYBB2) is expressed at an increased level in the postnatal lens cortex and is associated with cataracts. Improved understanding of the underlying biology of cataracts is likely to be critical for the development of early detection strategies and new therapeutics. The present study aimed to identify long non-coding RNAs (lncRNAs) and mRNAs associated with CRYBB2 knockdown (KO)-induced cataracts. RNAs from 3 non-treated mice and 3 CRYBB2 KO mice were analyzed using the Affymetrix GeneChip Mouse Gene 2.0 ST array. A total of 149 lncRNAs and 803 mRNAs were identified to have upregulated expression, including Snora73b, Klk1b22 and Rnu3a, while the expression levels of 180 lncRNAs and 732 mRNAs were downregulated in CRYBB2 KO mice, including Snord82, Snhg9 and Foxn3. This lncRNA and mRNA expression profile of mice with CRYBB2 KO provides a basis for studying the genetic mechanisms of cataract progression.

Long non-coding RNAs regulate effects of ß-crystallin B2 on mouse ovary development.

ß-crystallin B2 (CRYBB2) knockout mice exhibit morphological and functional abnormalities in the ovary. Long non­coding RNAs (lncRNAs) regulate gene transcription and translation, and epigenetic modification of genomic DNA. The present study investigated the role of lncRNAs in mediating the effects of CRYBB2 in the regulation of ovary development in mice. In the current study, ovary tissues from wild­type (WT) and CRYBB2 knockout mice were subjected to lncRNA and mRNA microarray profiling. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to group the differentially expressed lncRNAs into regulated gene pathways and functions. The correlation matrix method was used to establish a network of lncRNA and mRNA co­expression. Quantitative reverse transcription-polymerase chain reaction (RT­qPCR) was used to verify expression of a number of these differentially expressed lncRNAs and mRNAs. There were 157 differentially expressed lncRNAs and 1,085 differentially expressed mRNAs between ovary tissues from WT and CRYBB2 knockout mice. The GO and KEGG analyses indicated that these differentially expressed lncRNAs and mRNAs were important in Ca2+ signaling and ligand and receptor interactions. The correlation matrix method established an lncRNA and mRNA co­expression network, consisting of 53 lncRNAs and 45 mRNAs with 98 nodes and 75 connections. RT­qPCR confirmed downregulation of lncRNA A­30­P01019163 expression, which further downregulated its downstream gene purinergic receptor P2X, ligand­gated ion channel, 7 (P2rx7) expression in ovary tissues from CRYBB2 knockout mice. In conclusion, CRYBB2 regulates expression of different lncRNAs to influence ovary development. lncRNA A­30­P01019163 may affect ovarian cell cycle and proliferation by regulating P2rx7 expression in the ovary.