Hungry for fat: Metabolic crosstalk with lipid-rich CAFs fuels pancreatic cancer.

Some cancers prefer to metabolize lipids for their growth and metastasis. In a recent Cancer Cell study, Niu et al. revealed that SET domain containing 2, histone lysine methyltransferase (SETD2)-deficient pancreatic cancer cells induce the differentiation of lipid-laden cancer-associated fibroblasts (CAFs), which, in turn, transport lipids to promote tumor growth.

Up to the Herculean Task of Tackling Cancer Therapy Resistance.

Cancer therapy resistance still poses the biggest hurdle to cancer treatment [...].

RAF and MEK Inhibitors in Non-Small Cell Lung Cancer.

Lung cancer, despite recent advancements in survival rates, represents a significant global health burden. Non-small cell lung cancer (NSCLC), the most prevalent type, is driven largely by activating mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) and receptor tyrosine kinases (RTKs), and less in v-RAF murine sarcoma viral oncogene homolog B (BRAF) and mitogen-activated protein-kinase kinase (MEK), all key components of the RTK-RAS-mitogen-activated protein kinase (MAPK) pathway. Learning from melanoma, the identification of BRAFV600E substitution in NSCLC provided the rationale for the investigation of RAF and MEK inhibition as a therapeutic strategy. The regulatory approval of two RAF-MEK inhibitor combinations, dabrafenib-trametinib, in 2017, and encorafenib-binimetinib, in 2023, signifies a breakthrough for the management of BRAFV600E-mutant NSCLC patients. However, the almost universal emergence of acquired resistance limits their clinical benefit. New RAF and MEK inhibitors, with distinct biochemical characteristics, are in preclinical and clinical development. In this review, we aim to provide valuable insights into the current state of RAF and MEK inhibition in the management of NSCLC, fostering a deeper understanding of the potential impact on patient outcomes.

Anthocyanins in Non-Small Cell Lung Cancer (NSCLC) Treatment and Prevention.

An ever-growing volume of data supports the important role of dietary interventions in cancer prevention and the beneficial effects of plant secondary metabolites in solid tumor therapeutics [...].

SOX17: escape route from immune destruction in early CRC.

In a recent report in Nature, Goto et al. reveal a novel immune-evasion mechanism adopted by early colorectal cancer (CRC) cells that is based on the transcription factor sex determining region Y (SRY)-box transcription factor 17 (SOX17). Leveraging colorectal adenoma and cancer models to perform comprehensive transcriptomic/chromatin analyses, this work shows that SOX17 generates immune-silent leucine-rich repeat-containing G protein-coupled receptor 5- (LGR5-) tumor cells, which suppress interferon gamma (IFNγ) signaling and promote immune escape.

Mechanotransduction Circuits in Human Pathobiology.

It is widely acknowledged that mechanical forces exerted throughout the human body are critical for cellular and tissue homeostasis [...].

Malolactone strikes: K-Ras-G12D's Achilles' heel.

In a recent study in Nature Chemical Biology, Zheng et al. exploiting strain release by malolactone-based electrophiles and designed a first-in-class covalent inhibitor that targets the elusive aspartate of the Kirsten rat sarcoma viral oncogene homolog (K-Ras)-G12D variant, which is highly prevalent in pancreatic cancer. The compound drastically inhibited oncogenic signaling and tumor growth in preclinical K-Ras-G12D-mutant pancreatic cancer models, expanding treatment potential beyond K-Ras-G12C-targeted therapies.

YAP/TAZ-TEAD signalling axis: A new therapeutic target in malignant pleural mesothelioma.

The Hippo signalling pathway, a highly conserved signalling cassette, regulates organ size by controlling cell growth, apoptosis and stem cell self-renewal. The tumourigenic potential of this pathway is largely attributed to the activity of YAP/TAZ, which activate the TEAD1-4 transcription factors, leading to the expression of genes involved in cell proliferation and suppression of cell death. Aberrant regulation of the YAP/TAZ-TEAD signalling axis is commonly observed in malignant pleural mesothelioma (MPM), an insidious neoplasm of the pleural tissue that lines the chest cavity and covers the lungs with poor prognosis. Given the limited effectiveness of current treatments, targeting the YAP/TAZ-TEAD signalling cascade has emerged as a promising therapeutic strategy in MPM. Several inhibitors of the YAP/TAZ-TEAD signalling axis are presently undergoing clinical development, with the goal of advancing them to clinical use in the near future.

mTOR Signaling: Recent Progress.

In the intricate landscape of human biology, the mechanistic target of rapamycin (mTOR) emerges as a key regulator, orchestrating a vast array of processes in health and disease [...].

P53 and Rb Aberrations in Small Cell Lung Cancer (SCLC): From Molecular Mechanisms to Therapeutic Modulation.

The genes coding for the tumor suppressors p53 and retinoblastoma (Rb) are inactivated in the vast majority of small cell lung cancer (SCLC) tumors. Data support the notion that these two deleterious genetic events represent the initial steps in the development of SCLC, making them essential for a lung epithelial cell to progress toward the acquisition of a malignant phenotype. With the loss of TP53 and RB1, their broad tumor suppressive functions are eliminated and a normal cell is able to proliferate indefinitely, escape entering into cellular senescence, and evade death, no matter the damage it has experienced. Within this setting, lung epithelial cells accumulate further oncogenic mutations and are well on their way to becoming SCLC cells. Understanding the molecular mechanisms of these genetic lesions and their effects within lung epithelial cells is of paramount importance, in order to tackle this aggressive and deadly lung cancer. The present review summarizes the current knowledge on p53 and Rb aberrations, their biological significance, and their prospective therapeutic potential, highlighting completed and ongoing clinical trials with agents that target downstream pathways.

Many faces, many places: delving deeper into CAF heterogeneity in NSCLC.

In a recent study published in Cancer Cell, Cords et al. employed multiplexed imaging mass cytometry to analyze cancer-associated fibroblast (CAF) heterogeneity in 1070 NSCLC patients. This work defined good and poor prognostic CAF phenotypes, the latter associated with metastasis and chemoresistance, as well as revealed that CAF spatial location correlates with immune cell infiltration and clinical outcome.

Targeting the TGF-ß Signaling Axis in Metastatic Colorectal Cancer: Where Do We Stand?

Colorectal cancer (CRC) represents the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide [...].

Angiotensin-Converting Enzyme 2 (ACE2) Signaling in Pulmonary Arterial Hypertension: Underpinning Mechanisms and Potential Targeting Strategies.

Pulmonary arterial hypertension (PAH) is a debilitating progressive disease characterized by excessive pulmonary vasoconstriction and abnormal vascular remodeling processes that lead to right-ventricular heart failure and, ultimately, death. Although our understanding of its pathophysiology has advanced and several treatment modalities are currently available for the management of PAH patients, none are curative and the prognosis remains poor. Therefore, further research is required to decipher the molecular mechanisms associated with PAH. Angiotensin-converting enzyme 2 (ACE2) plays an important role through its vasoprotective functions in cardiopulmonary homeostasis, and accumulating preclinical and clinical evidence shows that the upregulation of the ACE2/Angiotensin-(1-7)/MAS1 proto-oncogene, G protein-coupled receptor (Mas 1 receptor) signaling axis is implicated in the pathophysiology of PAH. Herein, we highlight the molecular mechanisms of ACE2 signaling in PAH and discuss its potential as a therapeutic target.

DNA origami: a tool to evaluate and harness transcription factors.

Alongside other players, such as CpG methylation and the "histone code," transcription factors (TFs) represent a key feature of gene regulation. TFs are implicated in critical cellular processes, ranging from cell death, growth, and differentiation, up to intranuclear signaling of steroid and other hormones, physical entities, and hypoxia regulation. Notwithstanding an extensive body of research in this field, several questions and therapeutic options remain unanswered and unexplored, respectively. Of note, many of these TFs represent therapeutic targets, which are either difficult to be pharmacologically tackled or are still not drugged via traditional approaches, such as small-molecule inhibition. Upon providing a brief overview of TFs, we focus herein on how synthetic biology/medicine could assist in their study as well as their therapeutic targeting. Specifically, we contend that DNA origami, i.e., a novel synthetic DNA nanotechnological approach, represents an excellent synthetic biology/medicine tool to accomplish the above goals, since it can harness several vital characteristics of DNA: DNA polymerization, DNA complementarity, DNA "programmability," and DNA "editability." In doing so, DNA origami can be applied to study TF dynamics during DNA transcription, to elucidate xeno-nucleic acids with distinct scaffolds and unconventional base pairs, and to use TFs as competitors of oncogene-engaged promoters. Overall, because of their potential for high-throughput design and their favorable pharmacodynamic and pharmacokinetic properties, DNA origami can be a novel armory for TF-related drug design. Last, we discuss future trends in the field, such as RNA origami and innovative DNA origami-based therapeutic delivery approaches.

Glucocorticoid Receptor Signaling in NSCLC: Mechanistic Aspects and Therapeutic Perspectives.

Recent advances in non-small cell lung cancer (NSCLC) biology and the discovery of novel therapeutic targets have led to the development of new pharmacological agents that may improve the clinical outcome of patients with NSCLC. The glucocorticoid receptor (GR) is an evolutionarily conserved protein belonging to the nuclear receptor superfamily of transcription factors and mediates the diverse actions of glucocorticoids in cells. Data suggest that the GR may play a relevant role in the molecular mechanisms of NSCLC tumorigenesis and malignant progression. Additionally, evidence indicates that glucocorticoids may affect the efficacy of standard treatment, including chemotherapy, immune checkpoint inhibitors, and targeted therapy. Furthermore, several findings show that GR expression may probably be associated with NSCLC patient survival. Finally, glucocorticoids may be used as therapeutic agents for the clinical management of NSCLC patients. Here, we briefly review the latest advances on the biological role of GR signaling in NSCLC and discuss the potential use of the GR as a prognostic and predictive biomarker. Importantly, we explore the therapeutic potential of glucocorticoids and the effect of adding such drugs to standard therapies for NSCLC.

Attitudes and Practices Related to COVID-19 Vaccination with the Second Booster Dose among Members of Athens Medical Association: Results from a Cross-Sectional Study.

BACKGROUND: There are limited data on the attitudes and acceptance of the second booster (fourth dose) of the COVID-19 vaccination among physicians. METHODS: A cross-sectional, questionnaire-based, online study was conducted among members of the Athens Medical Association (A.M.A.) who were invited to participate anonymously over the period from January to March 2023. RESULTS: From the 1224 members who participated in the survey, 53.9% did not receive the fourth dose of the COVID-19 vaccine. The main reasons for no vaccination were the lack of obligation to receive the fourth dose, the history of three doses of the COVID-19 vaccine and the lack of sufficient information about the effectiveness of the fourth dose. Over half of the three-dose-vaccinated participants were willing to receive the fourth dose in the near future. Interestingly, the vaccination coverage among participants who had been informed about the fourth dose through scientific sources was low. CONCLUSIONS: The low vaccination coverage with the fourth dose reported in this study can lead to broad and serious consequences, such as increase in COVID-19 infections, reduction of available healthcare staff and increased caseloads of COVID-19 in hospitals. Furthermore, hesitant physicians will adversely influence the vaccination uptake among the general population due to their key role in informing and recommending the vaccine. The healthcare system administration should acknowledge and address physician's concerns through effective communication and better support.