Jaderson Costa da Costa

Programmed death-ligand 1 (PD-L1) has emerged as an important player in intrinsic tumor cell biology besides its canonical immune checkpoint function. Cumulative experimental data points to a role for PD-L1 in promoting and maintaining an invasive cell phenotype within different cancer cells through its interaction with mechanistic target of rapamycin (mTOR) signaling. In this review, we summarize the main experimental data pointing to the PD-L1/mTOR interaction in tumor cell invasion capacity both in vitro and in vivo. In this crosstalk, PD-L1 expression is induced by IFN-γ/STAT1 and IL-6/STAT3 pathways, as well as mTOR activity by its upstream effectors like EGFR and other tyrosine kinase receptor ligands. Interestingly, PD-L1 itself seems to play a role in mTOR activation. In many of these models, the PD-L1 importance in cell migration capacity is evidenced by two major observations: (1) its knockout impairs cell invasion capacity and, (2) its upregulation is associated with increased cell migration and both the induction and maintenance of epithelial-mesenchymal transition (EMT) phenotype markers, such as increased N-cadherin and ZEB1 and decreased E-cadherin. We also summarize the main clinical trials combining mTOR pathway inhibitors with anti-PD-L1 antibodies in different cancer types.

The mTOR signaling pathway acts as a central molecular hub, orchestrating key cellular processes ranging from autophagy to synaptic plasticity, thereby maintaining cellular and systemic homeostasis. Within the contemporary medical paradigm, mTORopathies have emerged as a complex spectrum of malformations of cortical development (MCDs), including focal cortical dysplasia type II, hemimegalencephaly, and tuberous sclerosis complex, unified by persistent dysregulation of the mTOR pathway. In this study, we examine how precision medicine (PM) is reshaping the clinical management of these conditions by transitioning from qualitative assessments to integrated multi-omic data workflows. The molecular etiology, characterized by a mosaic of somatic and germline mutations in pathway activators (e.g., AKT3, MTOR, RHEB) and repressors (e.g., TSC1, TSC2, DEPDC5), requires advanced genomic diagnostic strategies alongside high-resolution quantitative neuroimaging (e.g., 3T Magnetic Resonance Imaging (MRI) and diffusion tensor imaging) to enable digital phenotyping and connectomic mapping. In the therapeutic domain, management strategies involve the convergence of targeted pharmacology, including mTOR inhibitors such as everolimus, and metabolic interventions such as the ketogenic diet, which modulates neuronal excitability through defined molecular mechanisms. In addition, emerging screening platforms based on human induced pluripotent stem cells (iPSCs) and organoids enable compound validation in patient-specific models. Collectively, these advances support the development of next-generation clinical frameworks, exemplified by the concept of the “antiepileptogram”, a personalized prescriptive system with the potential to transform prognosis and improve quality of life in patients with drug-resistant epilepsy.

Glioblastoma (GBM) is the most prevalent and aggressive primary brain tumor. Tumor-associated epilepsy is a clinical challenge in GBM patients, with seizures being a common symptom and reflecting complex interactions within the tumor microenvironment. This review highlights key molecular mechanisms behind GBM-associated epilepsy, including genetic alterations, increased glutamate release, ion channel dysfunction, and inflammation. These factors disrupt the surrounding neurons, promoting seizures. Shared pathways between epilepsy and GBM, such as those involved in synaptic signaling and immune responses, present potential therapeutic targets. Antiseizure drugs remain the primary treatment, with newer options like perampanel showing promise in reducing seizures and possibly influencing tumor growth. Understanding the interplay between epilepsy and GBM at the molecular level is crucial for advancing personalized treatment strategies and improving outcomes for patients.

MTORopathies represent a group of neurodevelopmental disorders linked to dysregulated mTOR signaling, resulting in conditions such as tuberous sclerosis complex, focal cortical dysplasia, hemimegalencephaly, and Smith–Kingsmore Syndrome. These disorders often manifest with epilepsy, cognitive impairments, and, in some cases, structural brain anomalies. The mTOR pathway, a central regulator of cell growth and metabolism, plays a crucial role in brain development, where its hyperactivation leads to abnormal neuroplasticity, tumor formation, and heightened neuronal excitability. Current treatments primarily rely on mTOR inhibitors, such as rapamycin, which reduce seizure frequency and tumor size but fail to address underlying genetic causes. Advances in gene editing, particularly via CRISPR/Cas9, offer promising avenues for precision therapies targeting the genetic mutations driving mTORopathies. New delivery systems, including viral and non-viral vectors, aim to enhance the specificity and efficacy of these therapies, potentially transforming the management of these disorders. While gene editing holds curative potential, challenges remain concerning delivery, long-term safety, and ethical considerations. Continued research into mTOR mechanisms and innovative gene therapies may pave the way for transformative, personalized treatments for patients affected by these complex neurodevelopmental conditions.

Graphene nanoplatelets (UGZ–1004) are emerging as a promising biomaterial in regenerative medicine. This study comprehensively evaluates UGZ–1004, focusing on its physical properties, cytotoxicity, intracellular interactions, and, notably, its effects on mesenchymal stem cells (MSCs). UGZ–1004 was characterized by lateral dimensions and layer counts consistent with ISO standards and demonstrated a high carbon purity of 0.08%. Cytotoxicity assessments revealed that UGZ–1004 is non-toxic to various cell lines, including 3T3 fibroblasts, VERO kidney epithelial cells, BV–2 microglia, and MSCs, in accordance with ISO 10993–5:2020/2023 guidelines. The study focused on MSCs and revealed that UGZ–1004 supports their gene expression alterations related to self-renewal and proliferation. MSCs exposed to UGZ–1004 maintained their characteristic surface markers. Importantly, UGZ–1004 promoted significant upregulation of genes crucial for cell cycle regulation and DNA repair, such as CDK1, CDK2, and MDM2. This gene expression profile suggests that UGZ–1004 can enhance MSC self-renewal capabilities, ensuring robust cellular function and longevity. Moreover, UGZ–1004 exposure led to the downregulation of genes associated with tumor development, including CCND1 and TFDP1, mitigating potential tumorigenic risks. These findings underscore the potential of UGZ–1004 to not only bolster MSC proliferation but also enhance their self-renewal processes, which are critical for effective regenerative therapies. The study highlights the need for continued research into the long-term impacts of graphene nanoplatelets and their application in MSC-based regenerative medicine.

Rasmussen’s encephalitis (RE) stands as a rare neurological disorder marked by progressive cerebral hemiatrophy and epilepsy resistant to medical treatment. Despite extensive study, the primary cause of RE remains elusive, while its histopathological features encompass cortical inflammation, neuronal degeneration, and gliosis. The underlying molecular mechanisms driving disease progression remain largely unexplored. In this case study, we present a patient with RE who underwent hemispherotomy and has remained seizure-free for over six months, experiencing gradual motor improvement. Furthermore, we conducted molecular analysis on the excised brain tissue, unveiling a decrease in the expression of cell-cycle-associated genes coupled with elevated levels of BDNF and TNF-α proteins. These findings suggest the potential involvement of cell cycle regulators in the progression of RE.

Graphene nanoplatelets (UGZ-1004) are advancing as a promising biomaterial for regenerative medicine. This study provides a detailed assessment of UGZ-1004, emphasizing its physical properties, cytotoxicity, intracellular interactions, and particularly its effects on mesenchymal stem cells (MSCs). UGZ-1004 was characterized to have lateral sizes and layer counts in line with ISO standards and exhibited high carbon purity (0.08%). Cytotoxicity evaluations demonstrated that UGZ-1004 is non-toxic to various cell lines, including fibroblast 3T3, epithelial kidney VERO, microglia BV-2, and MSCs, in accordance with ISO-10993-5/2020/2023 guidelines. The study focused on MSCs, revealing that UGZ-1004 supports their self-renewal and proliferation. MSCs exposed to UGZ-1004 maintained their characteristic surface markers and proliferation rates. Importantly, UGZ-1004 promoted significant upregulation of genes crucial for cell cycle regulation and DNA repair, such as CDK1, CDK2, and MDM2. This gene expression profile suggests that UGZ-1004 enhances MSC self-renewal capabilities, ensuring robust cellular function and longevity. Moreover, UGZ-1004 exposure led to the downregulation of genes associated with tumor development, including CCND1 and TFDP1, mitigating potential tumorigenic risks. These findings underscore the potential of UGZ-1004 to not only bolster MSC proliferation but also enhance their self-renewal processes, which are critical for effective regenerative therapies. The study highlights the need for continued research into the long-term impacts of graphene nanoplatelets and their application in MSC-based regenerative medicine.