Endothelin-1 (ET-1) is involved in the regulation of a myriad of processes highly relevant for physical and mental well-being; female and male health; in the modulation of senses, pain, stress reactions and drug sensitivity as well as healing processes, amongst others. Shifted ET-1 homeostasis may influence and predict the development and progression of suboptimal health conditions, metabolic impairments with cascading complications, ageing and related pathologies, cardiovascular diseases, neurodegenerative pathologies, aggressive malignancies, modulating, therefore, individual outcomes of both non-communicable and infectious diseases such as COVID-19. This article provides an in-depth analysis of the involvement of ET-1 and related regulatory pathways in physiological and pathophysiological processes and estimates its capacity as a predictor of ageing and related pathologies,a sensor of lifestyle quality and progression of suboptimal health conditions to diseases for their targeted preventionand as a potent target for cost-effective treatments tailored to the person.

/pdf/endothelin-1-axes-in-the-framework-of-predictive-preventive-3h13jjxwqo.pdf

Endothelin-1 axes in the framework of predictive, preventive and personalised (3P) medicine.

Simple Summary In this review, we describe the basic functions of endothelin and related molecules, including their receptors and enzymes. Furthermore, we discuss the important role of endothelin in several cardiovascular diseases, the relevant clinical evidence for targeting the endothelin pathway, and the scope of endothelin-targeting treatments in the future. We highlight the present uses of endothelin receptor antagonists and the advancements in the development of future treatment options, thereby providing an overview of endothelin research over the years and its future scope. Abstract Endothelin was first discovered more than 30 years ago as a potent vasoconstrictor. In subsequent years, three isoforms, two canonical receptors, and two converting enzymes were identified, and their basic functions were elucidated by numerous preclinical and clinical studies. Over the years, the endothelin system has been found to be critical in the pathogenesis of several cardiovascular diseases, including hypertension, pulmonary arterial hypertension, heart failure, and coronary artery disease. In this review, we summarize the current knowledge on endothelin and its role in cardiovascular diseases. Furthermore, we discuss how endothelin-targeting therapies, such as endothelin receptor antagonists, have been employed to treat cardiovascular diseases with varying degrees of success. Lastly, we provide a glimpse of what could be in store for endothelin-targeting treatment options for cardiovascular diseases in the future.

/pdf/endothelin-and-the-cardiovascular-system-the-long-journey-2hmnvhwf.pdf

Endothelin and the Cardiovascular System: The Long Journey and Where We Are Going

Intercellular communication plays an important role in cancer initiation and progression through direct contact and indirect interactions, such as via secretory molecules. Cancer-associated fibroblasts (CAFs) are one of the principal components of such communication with cancer cells, modulating cancer metastasis and tumour mechanics and influencing angiogenesis, the immune system, and therapeutic resistance. Over the past few years, there has been a significant increase in research on extracellular vesicles (EVs) as regulatory agents in intercellular communication. EVs enable the transfer of functional molecules, including proteins, mRNAs and microRNAs (miRNAs), to recipient cells. Cancer cells utilize EVs to dictate the specific characteristics of CAFs within the tumour microenvironment, thereby promoting cancer progression. In response to such "education" by cancer cells, CAFs contribute to cancer progression via EVs. In this review, we summarize experimental data indicating the pivotal roles of EVs in intercellular communication between cancer cells and CAFs. 

/pdf/intercellular-crosstalk-between-cancer-cells-and-cancer-2sa3rixq.pdf

Intercellular crosstalk between cancer cells and cancer-associated fibroblasts via extracellular vesicles

Simple Summary The world of small molecules in solid tumors as cancer stem cells (CSCs), circulating tumor cells (CTCs) and cancer-associated fibroblasts (CAFs) continues to be under-debated, but not of minor interest in recent decades. One of the main problems in regard to cancer is the development of tumor recurrence, even in the early stages, in addition to drug resistance and, consequently, ineffective or an incomplete response against the tumor. The findings behind this resistance are probably justified by the presence of small molecules such as CSCs, CTCs and CAFs connected with the tumor microenvironment, which may influence the aggressiveness and the metastatic process. The mechanisms, connections, and molecular pathways behind them are still unknown. Our review would like to represent an important step forward to highlight the roles of these molecules and the possible connections among them. Abstract The importance of defining new molecules to fight cancer is of significant interest to the scientific community. In particular, it has been shown that cancer stem cells (CSCs) are a small subpopulation of cells within tumors with capabilities of self-renewal, differentiation, and tumorigenicity; on the other side, circulating tumor cells (CTCs) seem to split away from the primary tumor and appear in the circulatory system as singular units or clusters. It is becoming more and more important to discover new biomarkers related to these populations of cells in combination to define the network among them and the tumor microenvironment. In particular, cancer-associated fibroblasts (CAFs) are a key component of the tumor microenvironment with different functions, including matrix deposition and remodeling, extensive reciprocal signaling interactions with cancer cells and crosstalk with immunity. The settings of new markers and the definition of the molecular connections may present new avenues, not only for fighting cancer but also for the definition of more tailored therapies.

/pdf/cancer-stem-cells-cscs-circulating-tumor-cells-ctcs-and-2jrup0we.pdf

Cancer Stem Cells (CSCs), Circulating Tumor Cells (CTCs) and Their Interplay with Cancer Associated Fibroblasts (CAFs): A New World of Targets and Treatments

Small extracellular vesicles (sEVs) such as exosomes are nanoscale membranous particles (<200 nm) that have emerged as crucial targets for liquid biopsy and as promising drug delivery vehicles. They play a significant role in tumor progression as intercellular messengers. They can serve as biomarkers for tumor diagnosis and as drug carriers for cancer treatment. This article reviews recent studies on sEVs in oncology and explores their potential as biomarkers and drug delivery vehicles. Following tumorigenesis, sEVs in the tumor microenvironment (TME) and circulatory system undergo modifications to regulate various events in the TME, including angiogenesis, epithelial-mesenchymal transition (EMT), and tumor immunity, with either pro- or anti-tumor effects. sEVs have been investigated for use as diagnostic and prognostic biomarkers for a variety of tumors, including lung cancer, melanoma, breast cancer, prostate cancer, and hepatocellular carcinoma. sEVs can be used for cancer therapy by packaging drugs or proteins into them through pre- and post-isolation modification techniques. The clinical trials of sEVs as biomarkers and drug carriers are also summarized. Finally, the challenges in the use of sEVs are described and the possible approaches to tackling them are suggested. Overall, sEVs will advance the precision cancer medicine and has shown great potential in clinical applications. 

Small extracellular vesicles: Non-negligible vesicles in tumor progression, diagnosis, and therapy.

Non-small cell lung cancer (NSCLC): A review of risk factors, diagnosis, and treatment.

Background The five-year survival rate of lung adenocarcinoma patients (LUAD) is very low,and the methods of predicting survival are a great obstacle for LUAD therapies. Endothelin receptor type B (EDNRB) gene is associated with tumorigenesis. In this study, we aimed to evaluate the predictive value of EDNRB on LUAD. Methods Survival analyses was performed to assess the correlation between EDNRB expression and survival of LUAD patients from the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) datasets. Gene set enrichment analysis (GSEA) was conducted to illustrate possible biological functions of EDNRB. Laboratory methods were used to verify the function of EDNRB in LUAD. Results The TCGA results showed that a low expression of EDNRB was found in LUAD patients which led to poor outcome and worse survival, compared with the high expression in GSEA results which suggested that expression of EDNRB might be associated with regulation of the ERK pathway. Laboratory results suggested that EDNRB could inhibit the proliferation and migration of LUAD H1299 cells. Conclusions EDNRB is a potential prognostic marker for LUAD patients and might exert its functions by regulating the ERK pathway in LUAD.

Role of endothelin receptor type B (EDNRB) in lung adenocarcinoma

Sulfonylurea receptor 1-expressing cancer cells induce cancer-associated fibroblasts to promote non-small cell lung cancer progression.

Hematologic malignancies (HMs) mainly include acute and chronic leukemia, lymphoma, myeloma and other heterogeneous tumors that seriously threaten human life and health. The common effective treatments are radiotherapy, chemotherapy and hematopoietic stem cell transplantation (HSCT), which have limited options and are prone to tumor recurrence and (or) drug resistance. Metformin is the first-line drug for the treatment of type 2 diabetes (T2DM). Recently, studies identified the potential anti-cancer ability of metformin in both T2DM patients and patients that are non-diabetic. The latest epidemiological and preclinical studies suggested a potential benefit of metformin in the prevention and treatment of patients with HM. The mechanism may involve the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway by metformin as well as other AMPK-independent pathways to exert anti-cancer properties. In addition, combining current conventional anti-cancer drugs with metformin may improve the efficacy and reduce adverse drug reactions. Therefore, metformin can also be used as an adjuvant therapeutic agent for HM. This paper highlights the anti-hyperglycemic effects and potential anti-cancer effects of metformin, and also compiles the in vitro and clinical trials of metformin as an anti-cancer and chemosensitizing agent for the treatment of HM. The need for future research on the use of metformin in the treatment of HM is indicated.

/pdf/action-mechanism-of-metformin-and-its-application-in-30w4wom2.pdf

Action Mechanism of Metformin and Its Application in Hematological Malignancy Treatments: A Review

ABSTRACT Objectives This review aims to see the progress of several clinically-used monoclonal antibodies in treating ALL patients and how they improved patients' outcomes. Methods We searched Web of Science, Elsevier and PubMed for relevant published studies, and summarized eligible evidence on the management of newly-diagnosed and relapsed or refractory ALL with monoclonal antibodies. Ongoing trials were identified from ClinicalTrials.gov. Results Rituximab, an anti-CD20 monoclonal antibody, prolonged patients' complete remission duration and overall survival when combined with hyper-CVAD regimen. Another anti-CD20 monoclonal antibody, Ofatumumab, was reported to have similar benefits. Blinatumomab allows endogenous CD3-positive cytotoxic T cells to target and eliminate CD19-positive blasts. FDA has approved its efficacy in patients with R/R B-ALL and eliminating minimal residual disease (MRD). It serves as a bridge to eradicate MRD before transplantation, and may also be a new choice for patients unable to undergo transplantation. An anti-CD22 monoclonal antibody named Inotuzumab Ozogamicin showed great improvement in patients' outcome, but its toxicity to liver is also worthy of our attention. Conclusion Monoclonal antibodies are proven to be a promising immunotherapeutic strategy to improve ALL patients' outcome in the long term. There's still a need for individualized treatment with effective and well-tolerated medicines. Trial registration: ClinicalTrials.gov identifier: NCT01363128. Trial registration: ClinicalTrials.gov identifier: NCT01466179. Trial registration: ClinicalTrials.gov identifier: NCT02013167. Trial registration: ClinicalTrials.gov identifier: NCT02000427. Trial registration: ClinicalTrials.gov identifier: NCT01564784. Trial registration: ClinicalTrials.gov identifier: NCT03677596. Trial registration: ClinicalTrials.gov identifier: NCT01363297. Trial registration: ClinicalTrials.gov identifier: NCT02981628. Trial registration: ClinicalTrials.gov identifier: NCT03094611. Trial registration: ClinicalTrials.gov identifier: NCT01371630. Trial registration: ClinicalTrials.gov identifier: NCT04224571. Trial registration: ClinicalTrials.gov identifier: NCT02458014. Trial registration: ClinicalTrials.gov identifier: NCT04546399. Trial registration: ClinicalTrials.gov identifier: NCT02879695. Trial registration: ClinicalTrials.gov identifier: NCT03913559. Trial registration: ClinicalTrials.gov identifier: NCT03441061. Trial registration: ClinicalTrials.gov identifier: NCT03739814. Trial registration: ClinicalTrials.gov identifier: NCT02877303. Trial registration: ClinicalTrials.gov identifier: NCT03698552. Trial registration: ClinicalTrials.gov identifier: NCT04601584. Trial registration: ClinicalTrials.gov identifier: NCT04684147. Trial registration: ClinicalTrials.gov identifier: NCT04681105.

https://www.tandfonline.com/doi/pdf/10.1080/16078454.2022.2074704?needAccess=true

Monoclonal antibodies: new chance in the management of B-cell acute lymphoblastic leukemia

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