Proteomic characterization of extracellular vesicles in programmed cell death.

Programmed cell death (PCD) is a fundamental biological process that plays a critical role in cell development, differentiation, and homeostasis. The secretion and uptake of extracellular vesicles (EVs) is one of the important regulatory mechanisms for PCD. EVs are natural membrane structures secreted by cells that contain a variety of proteins, lipids, nucleic acids, and other bioactive molecules. Due to their important roles in intercellular communication and disease progression, there is great interest in studying EVs and their cargo. Different protein components are sorted and packaged in EVs, allowing EVs to perform their functions. The study of EV proteomics helps us understand the role of PCD in the development of diseases. Meanwhile, proteomics is a powerful tool for studying the composition and function of EVs, which assists in the identification, quantification, and profiling of protein components of EVs, and provides insight into the molecular mechanisms involved in PCD and related diseases. In this review, we summarize the characteristics of EV proteomics in different types of PCD, compare different proteomic profiling strategies for EVs, and discuss the impact of EV proteomics on cell function and regulation during PCD, to understand its role in the pathogenesis of related diseases.

Evaluating the Diagnostic Performance of Large Language Models on Complex Multimodal Medical Cases.

Large language models showed interpretative reasoning in solving diagnostically challenging medical cases.

Circulating exosomal microRNAs as potential prognostic biomarkers in gastrointestinal cancers: a systematic review and meta-analysis.

BACKGROUND: Recent reports suggested that circulating exosomal microRNAs (exomiRs) may serve as non-invasive prediction biomarkers in gastrointestinal (GI) cancers, yet their clinicopathological and prognostic values need to be more clarified. Hence, the present meta-analysis was aimed to quantitatively assess the evidence regarding the association between circulating exomiRs and prognosis in GI cancer patients. METHODS: A comprehensive search was carried out in prominent literature databases, including PubMed, ISI Web of Science, Scopus, and Embase. Odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs) were gathered to evaluate the strength of the association. The quality assessment was investigated through the Newcastle-Ottawa Scale (NOS) and publication bias via Eggers' test and funnel plots. RESULTS: A total of 47 studies, comprising of 4881 patients, were considered eligible for this meta-analysis. Both up-regulated and down-regulated circulating exomiRs are significantly associated with differentiation (HR = 1.353, P = 0.015; HR = 1.504, P = 0.016), TNM stage (HR = 2.058, P < 0.001; HR = 2.745, P < 0.001), lymph node metastasis (HR = 1.527, P = 0.004; HR = 2.009, P = 0.002), distant metastasis (HR = 2.006, P < 0.001; HR = 2.799, P = 0.002), worse overall survival (OS) (HR = 2.053, P < 0.001; HR = 1.789, P = 0.001) and poorer disease/relapse/progression-free survival (DFS/RFS/PFS) (HR = 2.086, P < 0.001; HR = 1.607, P = 0.001) in GI cancer patients, respectively. In addition, subgroup analyses based on seven subcategories indicated the robustness of the association. The majority of findings were lack of publication bias except for the association between up-regulated exomiRs and OS or DFS/RFS/PFS and for the down-regulated exomiRs and TNM stage. CONCLUSION: This study supports that up- and down-regulated circulating exomiRs are associated with poorer survival outcomes and could be served as potential prognostic biomarkers in GI cancers. Given the limitations of the current findings, such as significant heterogeneity, more investigations are needed to fully clarify the exomiRs prognostic role.

Bioinformatics Identification of Regulatory Genes and Mechanism Related to Hypoxia-Induced PD-L1 Inhibitor Resistance in Hepatocellular Carcinoma.

The combination of a PD-L1 inhibitor and an anti-angiogenic agent has become the new reference standard in the first-line treatment of non-excisable hepatocellular carcinoma (HCC) due to the survival advantage, but its objective response rate remains low at 36%. Evidence shows that PD-L1 inhibitor resistance is attributed to hypoxic tumor microenvironment. In this study, we performed bioinformatics analysis to identify genes and the underlying mechanisms that improve the efficacy of PD-L1 inhibition. Two public datasets of gene expression profiles, (1) HCC tumor versus adjacent normal tissue (N = 214) and (2) normoxia versus anoxia of HepG2 cells (N = 6), were collected from Gene Expression Omnibus (GEO) database. We identified HCC-signature and hypoxia-related genes, using differential expression analysis, and their 52 overlapping genes. Of these 52 genes, 14 PD-L1 regulator genes were further identified through the multiple regression analysis of TCGA-LIHC dataset (N = 371), and 10 hub genes were indicated in the protein-protein interaction (PPI) network. It was found that POLE2, GABARAPL1, PIK3R1, NDC80, and TPX2 play critical roles in the response and overall survival in cancer patients under PD-L1 inhibitor treatment. Our study provides new insights and potential biomarkers to enhance the immunotherapeutic role of PD-L1 inhibitors in HCC, which can help in exploring new therapeutic strategies.

Exploring the Role of Circulating Cell-Free RNA in the Development of Colorectal Cancer.

Circulating tumor RNA (ctRNA) has recently emerged as a novel and attractive liquid biomarker. CtRNA is capable of providing important information about the expression of a variety of target genes noninvasively, without the need for biopsies, through the use of circulating RNA sequencing. The overexpression of cancer-specific transcripts increases the tumor-derived RNA signal, which overcomes limitations due to low quantities of circulating tumor DNA (ctDNA). The purpose of this work is to present an up-to-date review of current knowledge regarding ctRNAs and their status as biomarkers to address the diagnosis, prognosis, prediction, and drug resistance of colorectal cancer. The final section of the article discusses the practical aspects involved in analyzing plasma ctRNA, including storage and isolation, detection technologies, and their limitations in clinical applications.

Development and validation of a preoperative CT-based radiomic nomogram to predict pathology invasiveness in patients with a solitary pulmonary nodule: a machine learning approach, multicenter, diagnostic study.

OBJECTIVES: To develop and validate a preoperative CT-based nomogram combined with radiomic and clinical-radiological signatures to distinguish preinvasive lesions from pulmonary invasive lesions. METHODS: This was a retrospective, diagnostic study conducted from August 1, 2018, to May 1, 2020, at three centers. Patients with a solitary pulmonary nodule were enrolled in the GDPH center and were divided into two groups (7:3) randomly: development (n = 149) and internal validation (n = 54). The SYSMH center and the ZSLC Center formed an external validation cohort of 170 patients. The least absolute shrinkage and selection operator (LASSO) algorithm and logistic regression analysis were used to feature signatures and transform them into models. RESULTS: The study comprised 373 individuals from three independent centers (female: 225/373, 60.3%; median [IQR] age, 57.0 [48.0-65.0] years). The AUCs for the combined radiomic signature selected from the nodular area and the perinodular area were 0.93, 0.91, and 0.90 in the three cohorts. The nomogram combining the clinical and combined radiomic signatures could accurately predict interstitial invasion in patients with a solitary pulmonary nodule (AUC, 0.94, 0.90, 0.92) in the three cohorts, respectively. The radiomic nomogram outperformed any clinical or radiomic signature in terms of clinical predictive abilities, according to a decision curve analysis and the Akaike information criteria. CONCLUSIONS: This study demonstrated that a nomogram constructed by identified clinical-radiological signatures and combined radiomic signatures has the potential to precisely predict pathology invasiveness. KEY POINTS: • The radiomic signature from the perinodular area has the potential to predict pathology invasiveness of the solitary pulmonary nodule. • The new radiomic nomogram was useful in clinical decision-making associated with personalized surgical intervention and therapeutic regimen selection in patients with early-stage non-small-cell lung cancer.

Proteomic profiling in extracellular vesicles for cancer detection and monitoring.

Extracellular vesicles (EVs) are nanometer-size lipid vesicles released by cells, which play essential biological functions in intercellular communication. Increasing evidence indicates that EVs participate in cancer development, including invasion, migration, metastasis, and cancer immune modulation. One of the key mechanisms is that EVs affect different cells in the tumor microenvironment through surface-anchor proteins and protein cargos. Moreover, proteins specifically expressed in tumor-derived EVs can be applied in cancer diagnosis and monitoring. Besides, the EV proteome also helps to understand drug resistance in cancers and to guide clinical medication. With the development of mass spectrometry and array-based multi-protein detection, the research of EV proteomics has entered a new era. The high-throughput parallel proteomic profiling based on these new platforms allows us to study the impact of EV proteome on cancer progression more comprehensively and to describe the proteomic landscape in cancers with more details. In this article, we review the role and function of different types of EVs in cancer progression. More importantly, we summarize the proteomic profiling of EVs based on different methods and the application of EV proteome in cancer detection and monitoring.

Optimised tissue clearing minimises distortion and destruction during tissue delipidation.

AIMS: A variety of tissue clearing techniques have been developed to render intact tissue transparent. For thicker samples, additional partial tissue delipidation is required before immersion into the final refractive index (RI)-matching solution, which alone is often inadequate to achieve full tissue transparency. However, it is difficult to determine a sufficient degree of tissue delipidation, excess of which can result in tissue distortion and protein loss. Here, we aim to develop a clearing strategy that allows better monitoring and more precise determination of delipidation progress. METHODS: We combined the detergent sodium dodecyl sulphate (SDS) with OPTIClear, a RI-matching solution, to form a strategy termed Accurate delipidation with Optimal Clearing (Accu-OptiClearing). Accu-OptiClearing allows for a better preview of the final tissue transparency achieved when immersed in OPTIClear alone just before imaging. We assessed for the changes in clearing rate, protein loss, degree of tissue distortion, and preservation of antigens. RESULTS: Partial delipidation using Accu-OptiClearing accelerated tissue clearing and better preserved tissue structure and antigens than delipidation with SDS alone. Despite achieving similar transparency in the final OPTIClear solution, more lipids were retained in samples cleared with Accu-OptiClearing compared to SDS. CONCLUSIONS: Combining the RI-matching solution OPTIClear with detergents, Accu-OptiClearing, can avoid excessive delipidation, leading to accelerated tissue clearing, less tissue damage and better preserved antigens.

A GLP-1 analog lowers ER stress and enhances protein folding to ameliorate homocysteine-induced endothelial dysfunction.

Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases and increases mortality in type 2 diabetic patients. HHcy induces endoplasmic reticulum (ER) stress and oxidative stress to impair endothelial function. The glucagon-like peptide 1 (GLP-1) analog exendin-4 attenuates endothelial ER stress, but the detailed vasoprotective mechanism remains elusive. The present study investigated the beneficial effects of exendin-4 against HHcy-induced endothelial dysfunction. Exendin-4 pretreatment reversed homocysteine-induced impairment of endothelium-dependent relaxations in C57BL/6 mouse aortae ex vivo. Four weeks subcutaneous injection of exendin-4 restored the impaired endothelial function in both aortae and mesenteric arteries isolated from mice with diet-induced HHcy. Exendin-4 treatment lowered superoxide anion accumulation in the mouse aortae both ex vivo and in vivo. Exendin-4 decreased the expression of ER stress markers (e.g., ATF4, spliced XBP1, and phosphorylated eIF2α) in human umbilical vein endothelial cells (HUVECs), and this change was reversed by cotreatment with compound C (CC) (AMPK inhibitor). Exendin-4 induced phosphorylation of AMPK and endothelial nitric oxide synthase in HUVECs and arteries. Exendin-4 increased the expression of endoplasmic reticulum oxidoreductase (ERO1α), an important ER chaperone in endothelial cells, and this effect was mediated by AMPK activation. Experiments using siRNA-mediated knockdown or adenoviral overexpression revealed that ERO1α mediated the inhibitory effects of exendin-4 on ER stress and superoxide anion production, thus ameliorating HHcy-induced endothelial dysfunction. The present results demonstrate that exendin-4 reduces HHcy-induced ER stress and improves endothelial function through AMPK-dependent ERO1α upregulation in endothelial cells and arteries. AMPK activation promotes the protein folding machinery in endothelial cells to suppress ER stress.

Herb-drug interactions between androgenic Chinese herbal medicines and androgen receptor antagonist on tumor growth: Studies on two xenograft prostate cancer animal models.

Our previous study revealed that Epimedii Folium (EF) and Codonopsis Radix (CNR) significantly promoted tumor growth on a subcutaneous mouse model of prostate cancer (PCa) via enhancing the mRNA and protein expressions of androgen receptor (AR), while Astragali Radix (AGR) inhibited tumor growth via suppressing the protein expression of AR. In the present study, we aimed to investigate the potential interactions between EF, CNR or AGR and AR antagonist (abiraterone acetate [ABI]) on the tumor growth using subcutaneous and orthotopic PCa mouse models. EF, CNR, AGR and ABI were intragastrically given to mice once every 2 days for 4 weeks. The pharmacokinetics of ABI were evaluated in the plasma of rats when combined with EF, CNR, or AGR. Our results demonstrated that EF or CNR could weaken the anti-tumor effects of ABI via increasing the AR expression involving activation of the PI3K/AKT and Rb/E2F pathways and decreasing the bioavailability of ABI, while AGR could enhance the anti-tumor effects of ABI through suppressing the AR expression via inhibiting the activations of PI3K/AKT and Rb/E2F pathways and increasing the bioavailability of ABI. These findings imply that cautions should be exercised when prescribing EF and CNR for PCa patients.

The role of miR-34 in cancer drug resistance.

Resistance to conventional chemotherapy remains a major cause of cancer relapse and cancer-related deaths. Therefore, there is an urgent need to overcome resistance barriers. To improve cancer treatment approaches, it is critical to elucidate the basic mechanisms underlying drug resistance. Increasingly, the mechanisms involving micro-RNAs (miRNAs) are studied because miRNAs are also considered practical therapeutic options due to high degrees of specificity, efficacy, and accuracy, as well as their ability to target multiple genes at the same time. Years of research have firmly established miR-34 as a key tumor suppressor miRNA whose target genes are involved in drug resistance mechanisms. Indeed, numerous articles show that low levels of circulating miR-34 or tumor-specific miR-34 expression are associated with poor response to chemotherapy. In addition, elevation of inherently low miR-34 levels in resistant cancer cells effectively restores sensitivity to chemotherapeutic agents. Here, we review this literature, also highlighting some contradictory observations. In addition, we discuss the potential utility of miR-34 expression as a predictive biomarker for chemotherapeutic drug response. Although caution needs to be exercised, miR-34 is emerging as a biomarker that could improve cancer precision medicine.

CRISPR-Cas, a robust gene-editing technology in the era of modern cancer immunotherapy.

Cancer immunotherapy has been emerged as a promising strategy for treatment of a broad spectrum of malignancies ranging from hematological to solid tumors. One of the principal approaches of cancer immunotherapy is transfer of natural or engineered tumor-specific T-cells into patients, a so called "adoptive cell transfer", or ACT, process. Construction of allogeneic T-cells is dependent on the employment of a gene-editing tool to modify donor-extracted T-cells and prepare them to specifically act against tumor cells with enhanced function and durability and least side-effects. In this context, CRISPR technology can be used to produce universal T-cells, equipped with recombinant T cell receptor (TCR) or chimeric antigen receptor (CAR), through multiplex genome engineering using Cas nucleases. The robust potential of CRISPR-Cas in preparing the building blocks of ACT immunotherapy has broaden the application of such therapies and some of them have gotten FDA approvals. Here, we have collected the last investigations in the field of immuno-oncology conducted in partnership with CRISPR technology. In addition, studies that have addressed the challenges in the path of CRISPR-mediated cancer immunotherapy, as well as pre-treatment applications of CRISPR-Cas have been mentioned in detail.

Correction to: CRISPR-Cas, a robust gene-editing technology in the era of modern cancer immunotherapy.

[This corrects the article DOI: 10.1186/s12935-020-01546-8.].

Exosomes in Inflammation and Inflammatory Disease.

Exosomes are a subset of extracellular vesicles released by all cell types and involved in local and systemic intercellular communication. In the past decade, research into exosomes has swelled as their important role in the mediation of health and disease has been increasingly established and acknowledged. Exosomes carry a diverse range of cargo including proteins, nucleic acids, and lipids derived from their parental cell that, when delivered to the recipient cell, can confer pathogenic or therapeutic effects through modulation of immunity and inflammation. In this review, the role of exosomes on mediation of immune and inflammatory responses, and their participation in diseases with a significant inflammatory component is discussed. The considerable potential for exosomes in therapy and diagnosis of inflammatory diseases is also highlighted.

Non-Coding RNAs in Cartilage Development: An Updated Review.

In the development of the skeleton, the long bones are arising from the process of endochondral ossification (EO) in which cartilage is replaced by bone. This complex process is regulated by various factors including genetic, epigenetic, and environmental elements. It is recognized that DNA methylation, higher-order chromatin structure, and post-translational modifications of histones regulate the EO. With emerging understanding, non-coding RNAs (ncRNAs) have been identified as another mode of EO regulation, which is consist of microRNAs (miRNAs or miRs) and long non-coding RNAs (lncRNAs). There is expanding experimental evidence to unlock the role of ncRNAs in the differentiation of cartilage cells, as well as the pathogenesis of several skeletal disorders including osteoarthritis. Cutting-edge technologies such as epigenome-wide association studies have been employed to reveal disease-specific patterns regarding ncRNAs. This opens a new avenue of our understanding of skeletal cell biology, and may also identify potential epigenetic-based biomarkers. In this review, we provide an updated overview of recent advances in the role of ncRNAs especially focus on miRNA and lncRNA in the development of bone from cartilage, as well as their roles in skeletal pathophysiology.

Moxibustion for alleviating side effects of chemotherapy or radiotherapy in people with cancer.

BACKGROUND: Moxibustion, a common treatment in traditional Chinese medicine, involves burning herbal preparations containing Artemisia vulgaris on or above the skin at acupuncture points. Its intended effect is to enhance body function, and it could reduce the side effects of chemotherapy or radiotherapy and improve quality of life (QoL) in people with cancer. OBJECTIVES: To assess the effects of moxibustion for alleviating side effects associated with chemotherapy, radiotherapy or both in people with cancer. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE via Ovid, Embase via Ovid and AMED (Allied and Complementary Medicine Database) from their inception to February 2018. We also searched databases in China including the Chinese BioMedical Literature Database (CBM), Chinese Medical Current Contents (CMCC), TCMonline, Chinese Dissertation Database (CDDB), China Medical Academic Conference (CMAC) and Index to Chinese Periodical Literature from inception to August 2017. Registries for clinical trials and other resources were also searched. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing moxibustion treatment, including moxa cone and moxa stick, versus sham, no treatment or conventional treatment. DATA COLLECTION AND ANALYSIS: Two review authors (HWZ and FC) independently extracted data on study design, participants, treatment and control intervention, and outcome measures, and they also assessed risk of bias in the included studies. We performed meta-analyses, expressing dichotomous outcomes as risk ratios (RR) and continuous outcomes as mean differences (MD), with 95% confidence intervals (CI). MAIN RESULTS: We included 29 RCTs involving 2569 participants. Five RCTs compared moxibustion versus no treatment, 15 compared moxibustion plus conventional treatment versus conventional treatment, one compared moxibustion versus sham moxibustion, and eight compared moxibustion versus conventional medicine. The overall risk of bias was high in 18 studies and unclear in 11 studies. Studies measured outcomes in various ways, and we could rarely pool data.Moxibustion versus no treatment: low-certainty evidence from single small studies suggested that moxibustion was associated with higher white blood cell counts (MD 1.77 × 109/L; 95% CI 0.76 to 2.78; 80 participants, low-certainty evidence) and higher serum haemoglobin concentrations (MD 1.33 g/L; 95% CI 0.59 to 2.07; 66 participants, low-certainty evidence) in people with cancer, during or after chemotherapy/radiotherapy, compared with no treatment. There was no evidence of an effect on leukopenia (RR 0.50, 95% CI 0.10 to 2.56; 72 participants, low-certainty evidence) between study groups. The effects on immune function (CD3, CD4, and CD8 counts) were inconsistent.Moxibustion versus sham moxibustion: low-certainty evidence from one study (50 participants) suggested that moxibustion improved QoL (measured as the score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30)) compared with sham treatment (MD 14.88 points; 95% CI 4.83 to 24.93). Low-certainty evidence from this study also showed reductions in symptom scores for nausea and vomiting (MD -38.57 points, 95% CI -48.67 to -28.47) and diarrhoea (MD -13.81, 95% CI -27.52 to -0.10), and higher mean white blood cell count (MD 1.72 × 109/L, 95% CI 0.97 to 2.47), serum haemoglobin (MD 2.06 g/L, 95% CI 1.26 to 2.86) and platelets (MD 210.79 × 109/L, 95% CI 167.02 to 254.56) when compared with sham moxibustion.Moxibustion versus conventional medicines: low-certainty evidence from one study (90 participants) suggested that moxibustion improved WBC count eight days after treatment ended compared with conventional medicines (MD 0.40 × 109/L; 95% CI 0.15 to 0.65). Low-certainty evidence from two studies (235 participants) suggested moxibustion improved serum haemoglobin concentrations compared with conventional medicines (MD 10.28 g/L; 95% CI 4.51 to 16.05).Moxibustion plus conventional treatment versus conventional treatment alone: low-certainty evidence showed that moxibustion plus conventional treatment was associated with lower incidence and severity of leukopenia (WHO grade 3 to 4) (RR 0.14, 95% CI 0.01 to 2.64; 1 study, 56 participants), higher QoL scores on the EORTC QLQ-C30 (MD 8.85 points, 95% CI 4.25 to 13.46; 3 studies, 134 participants, I² = 26%), lower symptom scores for nausea and vomiting (RR 0.43, 95% CI 0.25 to 0.74; 7 studies, 801participants; I² = 19%), higher white blood cell counts (data not pooled due to heterogeneity), higher serum haemoglobin (MD 3.97 g/L, 95% CI 1.40 to 6.53; 2 studies, 142 participants, I² = 0%). There was no difference in platelet counts between the two groups (MD 13.48 × 109/L; 95% CI -16.00 to 42.95; 2 studies, 142 participants; I² = 34%).Most included studies did not report related adverse events, such as burning or allergic reactions. AUTHORS' CONCLUSIONS: Limited, low-certainty evidence suggests that moxibustion treatment may help to reduce the haematological and gastrointestinal toxicities of chemotherapy or radiotherapy, improving QoL in people with cancer; however, the evidence is not conclusive, and we cannot rule out benefits or risks with this treatment. High-quality studies that report adverse effects are needed.

Expression of Iron-Related Proteins Differentiate Non-Cancerous and Cancerous Breast Tumors.

We have previously reported hepcidin and ferritin increases in the plasma of breast cancer patients, but not in patients with benign breast disease. We hypothesized that these differences in systemic iron homeostasis may reflect alterations in different iron-related proteins also play a key biochemical and regulatory role in breast cancer. Thus, here we explored the expression of a bundle of molecules involved in both iron homeostasis and tumorigenesis in tissue samples. Enzyme-linked immunosorbent assay (ELISA) or reverse-phase protein array (RPPA), were used to measure the expression of 20 proteins linked to iron processes in 24 non-cancerous, and 56 cancerous, breast tumors. We found that cancerous tissues had higher level of hepcidin than benign lesions (p = 0.012). The univariate analysis of RPPA data highlighted the following seven proteins differentially expressed between non-cancerous and cancerous breast tissue: signal transducer and transcriptional activator 5 (STAT5), signal transducer and activator of transcription 3 (STAT3), bone morphogenetic protein 6 (BMP6), cluster of differentiation 74 (CD74), transferrin receptor (TFRC), inhibin alpha (INHA), and STAT5_pY694. These findings were confirmed for STAT5, STAT3, BMP6, CD74 and INHA when adjusting for age. The multivariate statistical analysis indicated an iron-related 10-protein panel effective in separating non-cancerous from cancerous lesions including STAT5, STAT5_pY694, myeloid differentiation factor 88 (MYD88), CD74, iron exporter ferroportin (FPN), high mobility group box 1 (HMGB1), STAT3_pS727, TFRC, ferritin heavy chain (FTH), and ferritin light chain (FTL). Our results showed an association between some iron-related proteins and the type of tumor tissue, which may provide insight in strategies for using iron chelators to treat breast cancer.

The yin-yang of DNA damage response: roles in tumorigenesis and cellular senescence.

Senescent cells are relatively stable, lacking proliferation capacity yet retaining metabolic activity. In contrast, cancer cells are rather invasive and devastating, with uncontrolled proliferative capacity and resistance to cell death signals. Although tumorigenesis and cellular senescence are seemingly opposite pathological events, they are actually driven by a unified mechanism: DNA damage. Integrity of the DNA damage response (DDR) network can impose a tumorigenesis barrier by navigating abnormal cells to cellular senescence. Compromise of DDR, possibly due to the inactivation of DDR components, may prevent cellular senescence but at the expense of tumor formation. Here we provide an overview of the fundamental role of DDR in tumorigenesis and cellular senescence, under the light of the Yin-Yang concept of Chinese philosophy. Emphasis is placed on discussing DDR outcome in the light of in vivo models. This information is critical as it can help make better decisions for clinical treatments of cancer patients.

The discovery and development of mRNA vaccines for the prevention of SARS-CoV-2 infection.

INTRODUCTION: COVID-19 pandemic is one of the most serious public health events of this century. There have been more than 670 million confirmed cases and more than 6 million deaths worldwide. From the emergence of the Alpha variant to the later rampant Omicron variant, the high transmissibility and pathogenicity of SARS-CoV-2 accelerate the research and development of effective vaccines. Against this background, mRNA vaccines stepped onto the historical stage and became an important tool for COVID-19 prevention. AREAS COVERED: This article introduces the characteristics of different mRNA vaccines in the prevention of COVID-19, including antigen selection, therapeutic mRNA design and modification, and different delivery systems of mRNA molecules. It also summarizes and discusses the mechanisms, safety, effectiveness, side effects, and limitations of current COVID-19 mRNA vaccines. EXPERT OPINION: Therapeutic mRNA molecules have plenty of advantages, including flexible design, rapid production, sufficient immune activation, safety without the risk of genome insertion in the host cells, and no viral vectors or particles involved, making them an important tool to fight diseases in the future. However, the application of COVID-19 mRNA vaccines also faces many challenges, such as storage and transportation, mass production, and nonspecific immunity.

Synergistic Anti-Tumor Effect of Toosendanin and Paclitaxel on Triple-Negative Breast Cancer via Regulating ADORA2A-EMT Related Signaling.

Triple negative breast cancer (TNBC) is an aggressive cancer with very poor prognosis. Combination therapy has proven to be a promising strategy for enhancing TNBC treatment efficacy. Toosendanin (TSN), a plant-derived triterpenoid, has shown pleiotropic effects against a variety of tumors. Herein, it is evaluated whether TSN can enhance the efficacy of paclitaxel (PTX), a common chemotherapeutic agent, against TNBC. It is found that TSN and PTX synergistically suppress the proliferation of TNBC cell lines such as MDA-MB-231 and BT-549, and the combined treatment also inhibits the colony formation and induces cell apoptosis. Furthermore, this combination shows more marked migratory inhibition when compared to PTX alone. Mechanistic study shows that the ADORA2A pathway in TNBC is down-regulated by the combination treatment via mediating epithelial-to-mesenchymal transition (EMT) process. In addition, the combined treatment of TSN and PTX significantly attenuates the tumor growth when compared to PTX monotherapy in a mouse model bearing 4T1 tumor. The results suggest that combination of TSN and PTX is superior to PTX alone, suggesting that it may be a promising alternative adjuvant chemotherapy strategy for patients with TNBC, especially those with metastatic TNBC.