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.

A nomenclature consensus for nervous system organoids and assembloids.

Self-organizing three-dimensional cellular models derived from human pluripotent stem cells or primary tissue have great potential to provide insights into how the human nervous system develops, what makes it unique and how disorders of the nervous system arise, progress and could be treated. Here, to facilitate progress and improve communication with the scientific community and the public, we clarify and provide a basic framework for the nomenclature of human multicellular models of nervous system development and disease, including organoids, assembloids and transplants.

[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.

Neuroinflammation: A Potential Risk for Dementia.

Dementia is a neurodegenerative condition that is considered a major factor contributing to cognitive decline that reduces independent function. Pathophysiological pathways are not well defined for neurodegenerative diseases such as dementia; however, published evidence has shown the role of numerous inflammatory processes in the brain contributing toward their pathology. Microglia of the central nervous system (CNS) are the principal components of the brain's immune defence system and can detect harmful or external pathogens. When stimulated, the cells trigger neuroinflammatory responses by releasing proinflammatory chemokines, cytokines, reactive oxygen species, and nitrogen species in order to preserve the cell's microenvironment. These proinflammatory markers include cytokines such as IL-1, IL-6, and TNFα chemokines such as CCR3 and CCL2 and CCR5. Microglial cells may produce a prolonged inflammatory response that, in some circumstances, is indicated in the promotion of neurodegenerative diseases. The present review is focused on the involvement of microglial cell activation throughout neurodegenerative conditions and the link between neuroinflammatory processes and dementia.

Antibiotics and the Nervous System-Which Face of Antibiotic Therapy Is Real, Dr. Jekyll (Neurotoxicity) or Mr. Hyde (Neuroprotection)?

Antibiotics as antibacterial drugs have saved many lives, but have also become a victim of their own success. Their widespread abuse reduces their anti-infective effectiveness and causes the development of bacterial resistance. Moreover, irrational antibiotic therapy contributes to gastrointestinal dysbiosis, that increases the risk of the development of many diseases, including neurological and psychiatric. One of the potential options for restoring homeostasis is the use of oral antibiotics that are poorly absorbed from the gastrointestinal tract (e.g., rifaximin alfa). Thus, antibiotic therapy may exert neurological or psychiatric adverse drug reactions which are often considered to be overlooked and undervalued issues. Drug-induced neurotoxicity is mostly observed after beta-lactams and quinolones. Penicillin may produce a wide range of neurological dysfunctions, including encephalopathy, behavioral changes, myoclonus or seizures. Their pathomechanism results from the disturbances of gamma-aminobutyric acid-GABA transmission (due to the molecular similarities between the structure of the ß-lactam ring and GABA molecule) and impairment of the functioning of benzodiazepine receptors (BZD). However, on the other hand, antibiotics have also been studied for their neuroprotective properties in the treatment of neurodegenerative and neuroinflammatory processes (e.g., Alzheimer's or Parkinson's diseases). Antibiotics may, therefore, become promising elements of multi-targeted therapy for these entities.

Optimal time lags from causal prediction model help stratify and forecast nervous system pathology.

Traditional clinical approaches diagnose disorders of the nervous system using standardized observational criteria. Although aiming for homogeneity of symptoms, this method often results in highly heterogeneous disorders. A standing question thus is how to automatically stratify a given random cohort of the population, such that treatment can be better tailored to each cluster's symptoms, and severity of any given group forecasted to provide neuroprotective therapies. In this work we introduce new methods to automatically stratify a random cohort of the population composed of healthy controls of different ages and patients with different disorders of the nervous systems. Using a simple walking task and measuring micro-fluctuations in their biorhythmic motions, we combine non-linear causal network connectivity analyses in the temporal and frequency domains with stochastic mapping. The methods define a new type of internal motor timings. These are amenable to create personalized clinical interventions tailored to self-emerging clusters signaling fundamentally different types of gait pathologies. We frame our results using the principle of reafference and operationalize them using causal prediction, thus renovating the theory of internal models for the study of neuromotor control.

ATG7 safeguards human neural integrity.

ATG7 drives macroautophagy, hereafter "autophagy", by generating ATG12-ATG5 conjugates and lipidating Atg8 homologs including LC3. A pioneering body of work has defined the requirement of ATG7 for survival in mice and shown that neural-specific atg7 deletion causes neurodegeneration, but it has not been ascertained whether human life is compatible with ATG7 dysfunction. Recently, we defined the importance of ATG7 in human physiology by identifying twelve patients from five families harboring pathogenic, biallelic ATG7 variants causing a neurodevelopmental disorder. Patient fibroblasts show undetectable or severely diminished ATG7 protein levels, and biochemical assessment via autophagic flux and long-lived protein degradation assays demonstrated that attenuated autophagy underpins the pathology. Confirming the pathogenicity of patient variants, mouse cells expressing mutated ATG7 are unable to rescue LC3/Atg8 lipidation to wild-type levels. Our work defines mutated ATG7 as an important cause of human neurological disease and expands our understanding of autophagy in longevity and human health. We demonstrated that in certain circumstances, human survival with relatively mild phenotypes is possible even with undetectable levels of a nonredundant core autophagy protein.

Therapeutic Effect and Mechanisms of Essential Oils in Mood Disorders: Interaction between the Nervous and Respiratory Systems.

Essential oils (EOs) are extracted from plants and contain active components with therapeutic effects. Evidence shows that various types of EOs have a wide range of health benefits. In our previous studies, the potential of lavender EO for prevention and even treatment of depression and anxiety symptoms was demonstrated. The favourable outcomes may be due to multiple mechanisms, including the regulation of monoamine level, the induction of neurotrophic factor expression, the regulation of the endocrine system and the promotion of neurogenesis. The molecules of EOs may reach the brain and exert an effect through two distinctive pathways, namely, the olfactory system and the respiratory system. After inhalation, the molecules of the EOs would either act directly on the olfactory mucosa or pass into the respiratory tract. These two delivery pathways suggest different underlying mechanisms of action. Different sets of responses would be triggered, such as increased neurogenesis, regulation of hormonal levels, activation of different brain regions, and alteration in blood biochemistry, which would ultimately affect both mood and emotion. In this review, we will discuss the clinical effects of EOs on mood regulation and emotional disturbances as well as the cellular and molecular mechanisms of action. Emphasis will be put on the interaction between the respiratory and central nervous system and the involved potential mechanisms. Further evidence is needed to support the use of EOs in the clinical treatment of mood disturbances. Exploration of the underlying mechanisms may provide insight into the future therapeutic use of EO components treatment of psychiatric and physical symptoms.

Arginyltransferase (Ate1) regulates the RGS7 protein level and the sensitivity of light-evoked ON-bipolar responses.

Regulator of G-protein signaling 7 (RGS7) is predominately present in the nervous system and is essential for neuronal signaling involving G-proteins. Prior studies in cultured cells showed that RGS7 is regulated via proteasomal degradation, however no protein is known to facilitate proteasomal degradation of RGS7 and it has not been shown whether this regulation affects G-protein signaling in neurons. Here we used a knockout mouse model with conditional deletion of arginyltransferase (Ate1) in the nervous system and found that in retinal ON bipolar cells, where RGS7 modulates a G-protein to signal light increments, deletion of Ate1 raised the level of RGS7. Electroretinographs revealed that lack of Ate1 leads to increased light-evoked response sensitivities of ON-bipolar cells, as well as their downstream neurons. In cultured mouse embryonic fibroblasts (MEF), RGS7 was rapidly degraded via proteasome pathway and this degradation was abolished in Ate1 knockout MEF. Our results indicate that Ate1 regulates RGS7 protein level by facilitating proteasomal degradation of RGS7 and thus affects G-protein signaling in neurons.

Sorting Out Sorting Nexins Functions in the Nervous System in Health and Disease.

Endocytosis is a fundamental process that controls protein/lipid composition of the plasma membrane, thereby shaping cellular metabolism, sensing, adhesion, signaling, and nutrient uptake. Endocytosis is essential for the cell to adapt to its surrounding environment, and a tight regulation of the endocytic mechanisms is required to maintain cell function and survival. This is particularly significant in the central nervous system (CNS), where composition of neuronal cell surface is crucial for synaptic functioning. In fact, distinct pathologies of the CNS are tightly linked to abnormal endolysosomal function, and several genome wide association analysis (GWAS) and biochemical studies have identified intracellular trafficking regulators as genetic risk factors for such pathologies. The sorting nexins (SNXs) are a family of proteins involved in protein trafficking regulation and signaling. SNXs dysregulation occurs in patients with Alzheimer's disease (AD), Down's syndrome (DS), schizophrenia, ataxia and epilepsy, among others, establishing clear roles for this protein family in pathology. Interestingly, restoration of SNXs levels has been shown to trigger synaptic plasticity recovery in a DS mouse model. This review encompasses an historical and evolutionary overview of SNXs protein family, focusing on its organization, phyla conservation, and evolution throughout the development of the nervous system during speciation. We will also survey SNXs molecular interactions and highlight how defects on SNXs underlie distinct pathologies of the CNS. Ultimately, we discuss possible strategies of intervention, surveying how our knowledge about the fundamental processes regulated by SNXs can be applied to the identification of novel therapeutic avenues for SNXs-related disorders.

Cannabidiol-dihydroartemisinin conjugates for ameliorating neuroinflammation with reduced cytotoxicity.

Cannabidiol (CBD) and dihydroartemisinin (DHA) can alleviate neuroinflammatory responses. However, they show cytotoxicity, which severely limits their therapeutic windows. Therefore, there is a great need to develop neuroprotective agents with improved safety. Drug-drug conjugate is an emerging approach for enhancing therapeutic index. Herein, the development, synthesis, and the pharmacological characterization of CBD-DHA conjugates were performed. Meanwhile, the combination of CBD and DHA as separate entities was also quantitatively analyzed for direct comparison with CBD-DHA conjugates. In this study, BV-2 microglial cell line was used to mimic primary microglia and the effects of CBD, DHA, the combination of CBD and DHA, as well as CBD-DHA conjugates on LPS-activated signaling molecules and pro-inflammatory factors were assessed. The interaction of CBD and DHA in inhibiting LPS-induced nitric oxide (NO) production was found to be additive. In contrast, DHA was found to synergize with CBD in inhibiting BV-2 cellular viability which implies that the combination of CBD and DHA amplifies their cytotoxicity. CBD-DHA conjugate C3D eliminated the cytotoxicity associated with single CBD/DHA use without significantly compromising the anti-neuroinflammation activity. C3D was more potent than C2D and C4D in inhibiting LPS-induced NO and mRNAs of iNOS and IL-1ß, which implies that the linker length is critical for CBD-DHA conjugates' anti-inflammatory activities. Further signaling characterizations showed that C3D inhibited LPS-induced NF-κB but not MAPKs activation in BV-2 cells, therefore blocking LPS-induced neuroinflammation. This work provides a good example that conjugated drug-drug approach may improve the therapeutic index by increasing the maximum tolerated concentration/dose compared to traditional combination strategy.

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.