The intersection of the nervous system and breast cancer.

Breast cancer (BC) represents a paradigm of heterogeneity, manifesting as a spectrum of molecular subtypes with divergent clinical trajectories. It is fundamentally characterized by the aberrant proliferation of malignant cells within breast tissue, a process modulated by a myriad of factors that govern its progression. Recent endeavors outline the interplay between BC and the nervous system, illuminate the complex symbiosis between neural structures and neoplastic cells, and elucidate nerve dependence as a cornerstone of BC progression. This includes the neural modulations on immune response, neurovascular formation, and multisystem interactions. Such insights have unveiled the critical impact of neural elements on tumor dynamics and patient prognosis. This revelation beckons a deeper exploration into the neuro-oncological interface, potentially unlocking novel therapeutic vistas. This review endeavors to delineate the intricate mechanisms between the nervous system and BC, aiming to accentuate the implications and therapeutic strategies of this intersection for tumor evolution and the formulation of innovative therapeutic approaches.

The contribution of the nervous system in the cancer progression.

Cancer progression is driven by genetic mutations, environmental factors, and intricate interactions within the tumor microenvironment (TME). The TME comprises of diverse cell types, such as cancer cells, immune cells, stromal cells, and neuronal cells. These cells mutually influence each other through various factors, including cytokines, vascular perfusion, and matrix stiffness. In the initial or developmental stage of cancer, neurotrophic factors such as nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor are associated with poor prognosis of various cancers by communicating with cancer cells, immune cells, and peripheral nerves within the TME. Over the past decade, research has been conducted to prevent cancer growth by controlling the activation of neurotrophic factors within tumors, exhibiting a novel attemt in cancer treatment with promising results. More recently, research focusing on controlling cancer growth through regulation of the autonomic nervous system, including the sympathetic and parasympathetic nervous systems, has gained significant attention. Sympathetic signaling predominantly promotes tumor progression, while the role of parasympathetic signaling varies among different cancer types. Neurotransmitters released from these signalings can directly or indirectly affect tumor cells or immune cells within the TME. Additionally, sensory nerve significantly promotes cancer progression. In the advanced stage of cancer, cancer-associated cachexia occurs, characterized by tissue wasting and reduced quality of life. This process involves the pathways via brainstem growth and differentiation factor 15-glial cell line-derived neurotrophic factor receptor alpha-like signaling and hypothalamic proopiomelanocortin neurons. Our review highlights the critical role of neurotrophic factors as well as central nervous system on the progression of cancer, offering promising avenues for targeted therapeutic strategies. [BMB Reports 2024; 57(4): 167-175].

Tumor microenvironment crosstalk between tumors and the nervous system in pancreatic cancer: Molecular mechanisms and clinical perspectives.

Pancreatic ductal adenocarcinoma (PDAC) exhibits the highest incidence of perineural invasion among all solid tumors. The intricate interplay between tumors and the nervous system plays an important role in PDAC tumorigenesis, progression, recurrence, and metastasis. Various clinical symptoms of PDAC, including anorexia and cancer pain, have been linked to aberrant neural activity, while the presence of perineural invasion is a significant prognostic indicator. The use of conventional neuroactive drugs and neurosurgical interventions for PDAC patients is on the rise. An in-depth exploration of tumor-nervous system crosstalk has revealed novel therapeutic strategies for mitigating PDAC progression and effectively relieving symptoms. In this comprehensive review, we elucidate the regulatory functions of tumor-nervous system crosstalk, provide a succinct overview of the relationship between tumor-nervous system dialogue and clinical symptomatology, and deliberate the current research progress and forthcoming avenues of neural therapy for PDAC.

Fluoride impairs mitochondrial translation by targeting miR-221-3p/c-Fos/RMND1 axis contributing to neurodevelopment defects.

Evidence suggests that fluoride-induced neurodevelopment damage is linked to mitochondrial disorder, yet the detailed mechanism remains unclear. A cohort of Sprague-Dawley rats developmentally exposed to sodium fluoride (NaF) was established to simulate actual exposure of human beings. Using high-input proteomics and small RNA sequencing technology in rat hippocampus, we found mitochondrial translation as the most striking enriched biological process after NaF treatment, which involves the differentially expressed Required Meiotic Nuclear Division 1 homolog (RMND1) and neural-specific miR-221-3p. Further experiments in vivo and in vitro neuroendocrine pheochromocytoma (PC12) cells demonstrated that NaF impaired mitochondrial translation and function, as shown by declined mitochondrial membrane potential and inhibited expression of mitochondrial translation factors, mitochondrial translation products, and OXPHOS complexes, which was concomitant with decreased RMND1 and transcription factor c-Fos in mRNA and proteins as well as elevated miR-221-3p. Notably, RMND1 overexpression alleviated the NaF-elicited mitochondrial translation impairment by up-regulating translation factors, but not vice versa. Interestingly, ChIP-qPCR confirmed that c-Fos specifically controls the RMND1 transcription through direct binding with Rmnd1 promotor. Interference of gene expression verified c-Fos as an upstream positive regulator of RMND1, implicating in fluoride-caused mitochondrial translation impairment. Furthermore, dual-luciferase reporter assay evidenced that miR-221-3p targets c-Fos by binding its 3' untranslated region. By modulating the miR-221-3p expression, we identified miR-221-3p as a critical negative regulator of c-Fos. More importantly, we proved that miR-221-3p inhibitor improved mitochondrial translation and mitochondrial function to combat NaF neurotoxicity via activating the c-Fos/RMND1 axis, whereas miR-221-3p mimic tended towards opposite effects. Collectively, our data suggest fluoride impairs mitochondrial translation by dysregulating the miR-221-3p/c-Fos/RMND1 axis to trigger mitochondrial dysfunction, leading to neuronal death and neurodevelopment defects.

Lipofibromatosis: Central Nervous System Involvement by a Benign Neoplasm.

Background: Lipofibromatosis is a relatively new entity, considered in the differential diagnosis of soft tissue tumors in children, involving mainly the extremities. Most cases can be completely resected without recurrence. Atypical forms have been described and their highly infiltrative capability can lead to severe clinical impairment. Case report: We report an infant with rapidly growing posterior cervicothoracic tumor, extending from the bulbo-medullary junction to T6 vertebra, leading to loss of spontaneous breathing, quadriparesis and devastating long-term consequences. Spinal tomography scan at 35 days suggested myelomeningocele. Prenatal and early postnatal ultrasounds were reviewed and no central nervous system involvement or fusion defects were present. Magnetic resonance at 40 days showed infiltrative mass, later confirmed by pathology as lipofibromatosis. Two resections failed to completely remove the tumor. Discussion: Lipofibromatosis can involve critical structures in the central nervous system and is difficult to treat surgically in those circumstances.

[Chinese expert consensus on diagnosis and treatment of neurologic immune-related adverse events associated with immune checkpoint inhibitors (2022 edition)].

Neurologic immune-related adverse events (NAEs) are rare complications of immune checkpoint inhibitors (ICI). NAEs can affect the central nervous system, peripheral nervous system and neuroendocrine system, they can lead to death and serious dysfunction. NAEs requires standardized diagnosis, treatment and clinicians' high attention. The diagnosis of NAEs is very challenging due to its complexity, diversity and some non-specific clinical manifestations. It needs to be carefully distinguished from neurological dysfunction caused by other diseases such as tumor, infection, metabolism and iatrogenic (non-immune mediated) complications. Therefore, Committee of Neoplastic Supportive-Care of China Anti-Cancer Association and Cancer Clinical Chemotherapy Committee of China Anti-Cancer Association organized experts to conduct literature analysis and evidence level discussion on the clinical key issues related to NAEs, including the epidemiology, pathogenesis, risk factors, general principles of diagnosis and treatment, clinical manifestations and diagnosis and treatment strategies of specific types of NAEs, and the principles of ICI rechallenge after NAEs. Based on the latest clinical evidence and combined with China's clinical practice, the expert committee finally formulated a Chinese expert consensus on diagnosis and treatment of nAEs (2022 edition) for the prevention, diagnosis, comprehensive treatment and follow-up of NAEs.

The role of Calmodulin Binding Transcription Activator 1 (CAMTA1) gene and its putative genetic partners in the human nervous system.

The Calmodulin Binding Transcription Activator 1 (CAMTA1) gene plays a central role in the human nervous system. Here evidence-based perspectives on its clinical value for the screening of CAMTA1 malfunction is provided and argued that in future, patients suffering from brain tumours and/or neurological disorders could benefit from this diagnostic. In neuroblastomas as well as in low-grade gliomas, the influence of reduced expression of CAMTA1 results in opposite prognosis, probably because of different carcinogenic pathways in which CAMTA1 plays different roles, but the exact genetics bases remains unsolved. Rearrangements, mutations and variants of CAMTA1 were associated with human neurodegenerative disorders, while some CAMTA1 single nucleotide polymorphisms were associated with poorer memory in clinical cases and also amyotrophic lateral sclerosis. So far, the follow-up of patients with neurological diseases with alterations in CAMTA1 indicates that defects (expression, mutations, and rearrangements) in CAMTA1 alone are not sufficient to drive carcinogenesis. It is necessary to continue studying CAMTA1 rearrangements and expression in more cases than done by now. To understand the influence of CAMTA1 variants and their role in nervous system tumours and in several psychiatric disorders is currently a challenge.

The Nervous System Contributes to the Tumorigenesis and Progression of Human Digestive Tract Cancer.

Tumors of the gastrointestinal tract are one of the highest incidences of morbidity and mortality in humans. Recently, a growing number of researchers have indicated that nerve fibers and nerve signals participate in tumorigenesis. The current overarching view based on the responses to therapy revealed that tumors are partly promoted by the tumor microenvironment (TME), endogenous oncogenic factors, and complex systemic processes. Homeostasis of the neuroendocrine-immune axis (NEI axis) maintains a healthy in vivo environment in humans, and dysfunction of the axis contributes to various cancers, including the digestive tract. Interestingly, nerves might promote tumor development via multiple mechanisms, including perineural invasion (PNI), central level regulation, NEI axis effect, and neurotransmitter induction. This review focuses on the association between digestive tumors and nerve regulation, including PNI, the NEI axis, stress, and neurotransmitters, as well as on the potential clinical application of neurotherapy, aiming to provide a new perspective on the management of digestive cancers.

The involvement of the adrenergic nervous system in activating human brown adipose tissue and browning.

Obesity is a chronic condition of multifactorial etiology characterized by excessive body fat due to a calorie intake higher than energy expenditure. Given the intrinsic limitations of surgical interventions and the difficulties associated with lifestyle changes, pharmacological manipulation is currently one of the main therapies for metabolic diseases. Approaches aiming to promote energy expenditure through induction of thermogenesis have been explored and, in this context, brown adipose tissue (BAT) activation and browning have been shown to be promising strategies. Although such processes are physiologically stimulated by the sympathetic nervous system, not all situations that are known to increase adrenergic signaling promote a concomitant increase in BAT activation or browning in humans. Thus, a better understanding of factors involved in the thermogenesis attributed to these tissues is needed to enable the development of future therapies against obesity. Herein we carry out a critical review of original articles in humans under conditions previously known to trigger adrenergic responses-namely, cold, catecholamine-secreting tumor (pheochromocytoma and paraganglioma), burn injury, and adrenergic agonists-and discuss which of them are associated with increased BAT activation and browning. BAT is clearly stimulated in individuals exposed to cold or treated with high doses of the ß3-adrenergic agonist mirabegron, whereas browning is certainly induced in patients after burn injury or with pheochromocytoma, as well as in individuals treated with ß3-adrenergic agonist mirabegron for at least 10 weeks. Given the potential effect of increasing energy expenditure, adrenergic stimuli are promising strategies in the treatment of metabolic diseases.

The evaluation and management of monoclonal gammopathy of renal significance and monoclonal gammopathy of neurological significance.

Despite the benign nature of monoclonal gammopathy of undetermined significance (MGUS), mounting data are associating MGUS with the development of organ dysfunction, specifically monoclonal gammopathy of renal significance (MGRS) and monoclonal gammopathy of neurological significance (MGNS), which could be associated with substantial morbidity. Emerging evidence suggests that patients with MGRS and MGNS could benefit from treatments used for myeloma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia, depending on the underlying pathology. However, the treatment of MGRS and MGNS is not standardized, and potentially effective therapies might not be reimbursed because these conditions do not formally meet the criteria for malignant processes. The present review aims at establishing standards for the evaluation and management of MGRS and MGNS, which can facilitate the diagnosis of and provide therapeutic options for treating practitioners and patients affected by these conditions. The careful design and execution of clinical trials for patients with MGRS and MGNS are positively encouraged.

Immunophenotypical characterization of paraneoplastic neurological syndrome patients: a multicentric study.

Paraneoplastic neurological syndromes (PNS) are a group of rare and severe immune-mediated disorders that affect the nervous system in patients with cancer. The best way to diagnose a paraneoplastic neurological disorder is to identify anti-onconeural protein antibodies that are specifically associated with various cancers. The aim of this multicentric study was to clinically and immunologically characterize patients with PNS and study their association with cancer. Patients suspected to have PNS were enrolled from various clinical centres and were characterized immunologically. This study population consisted of 112 patients. Onset of PNS was mainly subacute (76 %). PNS patients had various neurological disorders and symptoms. PNS developed before the diagnosis of cancer in 28 definite PNS patients and in six suspected PNS patients. The most frequent autoantibodies detected in PNS patients were anti-Hu and anti-Yo. One definite PNS patient with cerebellar syndrome had anti-Tr antibody and seven patients had atypical antibodies. The literature associates these antibodies with various neurological disorders and cancers. Our observations confirm the important role of autoantibodies in PNS and their importance for the early diagnosis of cancer in PNS patients.

Endothelial Dysfunction and Extra-Articular Neurological Manifestations in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease that affects about 1% of the global population, with a female-male ratio of 3:1. RA preferably affects the joints, with consequent joint swelling and deformities followed by ankylosis. However, evidence has accumulated showing that patients suffering from RA can also develop extra-articular manifestations, including cardiovascular disease states, neuropathies, and multiorgan dysfunction. In particular, peripheral nerve disorders showed a consistent impact in the course of the disease (prevalence about 20%) mostly associated to vasculitis of the nerve vessels leading to vascular ischemia, axonal degeneration, and neuronal demyelination. The pathophysiological basis of this RA-associated microvascular disease, which leads to impairment of assonal functionality, is still to be better clarified. However, endothelial dysfunction and alterations of the so-called brain-nerve barrier (BNB) seem to play a fundamental role. This review aims to assess the potential mechanisms underlying the impairment of endothelial cell functionality in the development of RA and to identify the role of dysfunctional endothelium as a causative mechanism of extra-articular manifestation of RA. On the other hand, the potential impact of lifestyle and nutritional interventions targeting the maintenance of endothelial cell integrity in patients with RA will be discussed as a potential option when approaching therapeutic solutions in the course of the disease.

Neuropeptide Y nerve paracrine regulation of prostate cancer oncogenesis and therapy resistance.

BACKGROUND: Nerves are key factors in prostate cancer (PCa) progression. Here, we propose that neuropeptide Y (NPY) nerves are key regulators of cancer-nerve interaction. METHODS: We used in vitro models for NPY inhibition studies and subsequent metabolomics, apoptotic and migration assays, and nuclear transcription factor-κB (NF-κB) translocation studies. Human naïve and radiated PCa tissues were used for NPY nerve density biomarker studies. Tissues derived from a Botox denervation clinical trial were used to corroborate metabolomic changes in humans. RESULTS: Cancer cells increase NPY positive nerves in vitro and in preneoplastic human tissues. NPY-specific inhibition resulted in increased cancer apoptosis, decreased motility, and energetic metabolic pathway changes. A comparison of metabolomic response in NPY-inhibited cells with the transcriptome response in human PCa patients treated with Botox showed shared 13 pathways, including the tricarboxylic acid cycle. We identified that NF-κB is a potential NPY downstream mediator. Using in vitro models and tissues derived from a previous human chemical denervation study, we show that Botox specifically, but not exclusively, inhibits NPY in cancer. Quantification of NPY nerves is independently predictive of PCa-specific death. Finally, NPY nerves might be involved in radiation therapy (RT) resistance, as radiation-induced apoptosis is reduced when PCa cells are cocultured with dorsal root ganglia/nerves and NPY positive nerves are increased in prostates of patients that failed RT. CONCLUSION: These data suggest that targeting the NPY neural microenvironment may represent a therapeutic approach for the treatment of PCa and resistance through the regulation of multiple oncogenic mechanisms.

The REACH registration process: A case study of metallic aluminium, aluminium oxide and aluminium hydroxide.

The European Union's REACH Regulation requires determination of potential health and environmental effects of chemicals in commerce. The present case study examines the application of REACH guidance for health hazard assessments of three high production volume (HPV) aluminium (Al) substances: metallic aluminium, aluminium oxide, and aluminium hydroxide. Among the potential adverse health consequences of aluminium exposure, neurotoxicity is one of the most sensitive targets of Al toxicity and the most critical endpoint. This case study illustrates integration of data from multiple lines of evidence into REACH weight of evidence evaluations. This case study then explains how those results support regulatory decisions on classification and labelling. Challenges in the REACH appraisal of Al compounds include speciation, solubility and bioavailability, application of assessment factors, read-across rationale and differences with existing regulatory standards. Lessons learned from the present case study relate to identification and evaluation of toxicologic and epidemiologic data; assessing data relevance and reliability; development of derived no-effect levels (DNELs); addressing data gaps and preparation of chemical safety reports.

RADIATION DAMAGE OF THE NERVOUS SYSTEM AND ENDOCANABINOIDS. / RADIATsIINE URAZhENNIa NERVOVOÏ SYSTEMY I ENDOKANABINOÏDY.

The review analyzes the change of the existing paradigm of high radioresistance of the nervous system according tothe results of the study of neuropsychiatric disorders in in the aftermath of the Chornobyl accident in both earlyand remote post-accident period. The participation of the endocannabinoid system in ensuring homeostasis andpathology formation, potential possibilities of using cannabis drugs, agonists and antagonists of endocannabinoidreceptors for the treatment of early and long-term effects of radiation are considered.

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases.

With aging, the nervous system gradually undergoes degeneration. Increased oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and cell death are considered to be common pathophysiological mechanisms of various neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), organophosphate-induced delayed neuropathy (OPIDN), and amyotrophic lateral sclerosis (ALS). Autophagy is a cellular basic metabolic process that degrades the aggregated or misfolded proteins and abnormal organelles in cells. The abnormal regulation of neuronal autophagy is accompanied by the accumulation and deposition of irregular proteins, leading to changes in neuron homeostasis and neurodegeneration. Autophagy exhibits both a protective mechanism and a damage pathway related to programmed cell death. Because of its "double-edged sword", autophagy plays an important role in neurological damage and NDDs including AD, PD, HD, OPIDN, and ALS. Melatonin is a neuroendocrine hormone mainly synthesized in the pineal gland and exhibits a wide range of biological functions, such as sleep control, regulating circadian rhythm, immune enhancement, metabolism regulation, antioxidant, anti-aging, and anti-tumor effects. It can prevent cell death, reduce inflammation, block calcium channels, etc. In this review, we briefly discuss the neuroprotective role of melatonin against various NDDs via regulating autophagy, which could be a new field for future translational research and clinical studies to discover preventive or therapeutic agents for many NDDs.

Promising Opportunities for Treating Neurodegenerative Diseases with Mesenchymal Stem Cell-Derived Exosomes.

Neurodegenerative disease refers to any pathological condition in which there is a progressive decline in neuronal function resulting from brain atrophy. Despite the immense efforts invested over recent decades in developing treatments for neurodegenerative diseases, effective therapy for these conditions is still an unmet need. One of the promising options for promoting brain recovery and regeneration is mesenchymal stem cell (MSC) transplantation. The therapeutic effect of MSCs is thought to be mediated by their secretome, and specifically, by their exosomes. Research shows that MSC-derived exosomes retain some of the characteristics of their parent MSCs, such as immune system modulation, regulation of neurite outgrowth, promotion of angiogenesis, and the ability to repair damaged tissue. Here, we summarize the functional outcomes observed in animal models of neurodegenerative diseases following MSC-derived exosome treatment. We will examine the proposed mechanisms of action through which MSC-derived exosomes mediate their therapeutic effects and review advanced studies that attempt to enhance the improvement achieved using MSC-derived exosome treatment, with a view towards future clinical use.

Inherited genetic syndromes and meningiomas.

Meningiomas arising with inherited genetic syndromes occur nearly exclusively in the context of neurofibromatosis type 2 (NF2). NF2 is an autosomal dominant familial neoplasia syndrome that results from a mutation in the NF2 tumor suppressor gene located on the long arm of chromosome 22. The NF2 gene encodes for the protein merlin (moesin-ezrin-radixin-like protein), which has tumor suppressive effects that are reduced/inactivated in NF2-associated tumors. NF2-associated neoplasms affect the nervous system (schwannomas, meningiomas, ependymomas, astrocytomas, and neurofibromas) and skin. Other NF2 findings include ophthalmological lesions and peripheral neuropathy. Meningiomas are the second most frequent NF2-associated tumors (occurring in approximately half of all NF2 patients). They are often multiple and have unpredictable growth patterns. NF2-associated meningiomas can cause significant morbidity and mortality due to their location and a mass effect. Because of the multiplicity, frequent development of new tumors, and their protean nature, defined treatment strategies with serial surveillance is critical for optimal management of NF2-associated meningiomas. While surgical resection is the primary treatment for NF2-associated meningiomas, radiation plays an important adjunctive role in the management of recurrent and inoperable meningiomas.