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.

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.

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.

Mechanotransduction Circuits in Human Pathobiology.

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

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.

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 [...].

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.

How can cancer research be illuminated by brain research (and vice versa)?

Cancer and brain research have historically followed concrete pathways and converged mostly to studying brain cancer. Nowadays, the fields of neuro-oncology and neuroendocrine regulation of tumorigenesis are both emerging fields of intense research and promising applications. An increasing body of evidence suggests that somatic mutations in cancer-related genes are prevalent in several noncancerous brain disorders. These findings highlighting that certain aspects of cancer development/progression and pathologies of the nervous system share molecular alterations, could assist in elucidating the unique hallmarks of cancer and in cancer drugs repurposing for brain disorders. In so doing, identifying the commonalities in these conditions could be crucial not only for better understanding the basis of these pathologies but also for considering the previously underappreciated and/or neglected possibility of using drugs known to be effective in one type of pathology for the other type.

Implication of mTOR Signaling in NSCLC: Mechanisms and Therapeutic Perspectives.

Mechanistic target of the rapamycin (mTOR) signaling pathway represents a central cellular kinase that controls cell survival and metabolism. Increased mTOR activation, along with upregulation of respective upstream and downstream signaling components, have been established as oncogenic features in cancer cells in various tumor types. Nevertheless, mTOR pathway therapeutic targeting has been proven to be quite challenging in various clinical settings. Non-small cell lung cancer (NSCLC) is a frequent type of solid tumor in both genders, where aberrant regulation of the mTOR pathway contributes to the development of oncogenesis, apoptosis resistance, angiogenesis, cancer progression, and metastasis. In this context, the outcome of mTOR pathway targeting in clinical trials still demonstrates unsatisfactory results. Herewith, we discuss recent findings regarding the mechanisms and therapeutic targeting of mTOR signaling networks in NSCLC, as well as future perspectives for the efficient application of treatments against mTOR and related protein molecules.

Do 'cancer mutations' stand only for cancer? Translational and clinical implications.

DNA mutations represent a hallmark of cancer. However, next-generation sequencing (NGS) approaches have revealed that similar somatic mutations are present in healthy tissues as well as in those of several diseases, aging, abnormal vascular formation, and in placental development. These findings call for a reappraisal of whether such mutations are pathognomonic for cancer and provide further mechanistic, diagnostic, and therapeutic implications.

Lung Cancer through Transcription Factors.

The body of knowledge on the molecular mechanisms that drive lung cancer, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), is continuously growing [...].

The emerging promise of tumour mechanobiology in cancer treatment.

Tumour cell biomechanics has lately came to the fore as a disparate feature that fosters cancer development and progression. Tumour mechanosensing entails a mechanical interplay amongst tumour cells, extracellular matrix (ECM) and cells of the tumour microenvironment (TME). Sensory receptors (mechanoceptors) detect changes of extracellular mechanical inputs such as various types of mechanical forces/stress and trigger oncogenic signalling pathways advocating for cancer initiation, growth, survival, angiogenesis, invasion, metastasis, and immune evasion. Moreover, alterations in ECM stiffness and potentiation of mechanostimulated transcriptional regulatory molecules (transcription factors/cofactors) have been shown to strongly correlate with resistance to anticancer drugs. On this basis, new mechanosensitive proteins emerge as potential therapeutic targets and/or biomarkers in cancer. Accordingly, tumour mechanobiology arises as a promising field that can potentially provide novel combinatorial regimens to reverse drug resistance, as well as offer unprecedented targeting approaches that may help to more effectively treat a large proportion of solid tumours and their complications. Here, we highlight recent findings regarding various aspects of tumour mechanobiology in the clinical setting and discuss evidence-based perspectives of developing diagnostic/prognostic tools and therapeutic approaches that exploit tumour-TME physical associations.

Deciphering glioma epitranscriptome: focus on RNA modifications.

Gliomas are highly malignant tumors accounting for the majority of brain neoplasms. They are characterized by nuclear atypia, high mitotic rate and cellular polymorphism that often contributes to aggressiveness and resistance to standard therapy. They often associate with challenging treatment approaches and poor outcomes. New treatment strategies or regimens to improve the efficacy of glioma treatment require a deeper understanding of glioma occurrence and development as well as elucidation of their molecular biological characteristics. Recent studies have revealed RNA modifications as a key regulatory mechanism involved in tumorigenesis, tumor progression, immune regulation, and response to therapy. The present review discusses research advances on several RNA modifications involved in glioma progression and tumor microenvironment (TME) immunoregulation as well as in the development of adaptive drug resistance, summarizing current progress on major RNA modification targeting strategies.