A Mechanism Underpinning the Bioenergetic Metabolism-Regulating Function of Gold Nanocatalysts.

Bioenergetic deficits are known to be significant contributors to neurodegenerative diseases. Nevertheless, identifying safe and effective means to address intracellular bioenergetic deficits remains a significant challenge. This work provides mechanistic insights into the energy metabolism-regulating function of colloidal Au nanocrystals, referred to as CNM-Au8, that are synthesized electrochemically in the absence of surface-capping organic ligands. When neurons are subjected to excitotoxic stressors or toxic peptides, treatment of neurons with CNM-Au8 results in dose-dependent neuronal survival and neurite network preservation across multiple neuronal subtypes. CNM-Au8 efficiently catalyzes the conversion of an energetic cofactor, nicotinamide adenine dinucleotide hydride (NADH), into its oxidized counterpart (NAD+ ), which promotes bioenergy production by regulating the intracellular level of adenosine triphosphate. Detailed kinetic measurements reveal that CNM-Au8-catalyzed NADH oxidation obeys Michaelis-Menten kinetics and exhibits pH-dependent kinetic profiles. Photoexcited charge carriers and photothermal effect, which result from optical excitations and decay of the plasmonic electron oscillations or the interband electronic transitions in CNM-Au8, are further harnessed as unique leverages to modulate reaction kinetics. As exemplified by this work, Au nanocrystals with deliberately tailored structures and surfactant-free clean surfaces hold great promise for developing next-generation therapeutic agents for neurodegenerative diseases.

Pancreatoduodenectomy with Venous Resection or Palliative Therapy? A Meta-Analysis.

This review evaluated the risks and survival benefits of pancreatoduodenectomy associated with venous resection compared with palliative surgery. A systematic review with meta-analysis was performed. Higher overall survival was observed in the pancreatic resection group (HR = 4.000; 95% CI 2.800 to 5.200). However, the palliative group had fewer complications (RD = -0.170; 95% CI -0.260 to -0.070). There was no significant difference in the mortality rates (RD = 0.000; 95% CI -0.030 to 0.030). In centres with experience in pancreatic surgery, resection may be considered for locally advanced cancer and major venous invasion. Pancreaticoduodenectomy with vascular resection may improve survival for periampullary tumours compared with palliation therapy. However, pancreaticoduodenectomy with major venous resection has potentially higher morbidity than palliation therapy. Key Words: Pancreatoduodenectomy, Pancreatic neoplasms, Vascular surgical procedures.

HER-096 is a CDNF-derived brain-penetrating peptidomimetic that protects dopaminergic neurons in a mouse synucleinopathy model of Parkinson's disease.

Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotropic factor that modulates unfolded protein response (UPR) pathway signaling and alleviates endoplasmic reticulum (ER) stress providing cytoprotective effects in different models of neurodegenerative disorders. Here, we developed a brain-penetrating peptidomimetic compound based on human CDNF. This compound called HER-096 shows similar potency and mechanism of action as CDNF, and promotes dopamine neuron survival, reduces α-synuclein aggregation and modulates UPR signaling in in vitro models. HER-096 is metabolically stable and able to penetrate to cerebrospinal (CSF) and brain interstitial fluids (ISF) after subcutaneous administration, with an extended CSF and brain ISF half-life compared to plasma. Subcutaneously administered HER-096 modulated UPR pathway activity, protected dopamine neurons, and reduced α-synuclein aggregates and neuroinflammation in substantia nigra of aged mice with synucleinopathy. Peptidomimetic HER-096 is a candidate for development of a disease-modifying therapy for Parkinson's disease with a patient-friendly route of administration.

GM1 ganglioside exerts protective effects against glutamate-excitotoxicity via its oligosaccharide in wild-type and amyotrophic lateral sclerosis motor neurons.

Alterations in glycosphingolipid metabolism have been linked to the pathophysiological mechanisms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons. Accordingly, administration of GM1, a sialic acid-containing glycosphingolipid, is protective against neuronal damage and supports neuronal homeostasis, with these effects mediated by its bioactive component, the oligosaccharide head (GM1-OS). Here, we add new evidence to the therapeutic efficacy of GM1 in ALS: Its administration to WT and SOD1G93A motor neurons affected by glutamate-induced excitotoxicity significantly increased neuronal survival and preserved neurite networks, counteracting intracellular protein accumulation and mitochondria impairment. Importantly, the GM1-OS faithfully replicates GM1 activity, emphasizing that even in ALS the protective function of GM1 strictly depends on its pentasaccharide.

GM1 oligosaccharide efficacy against α-synuclein aggregation and toxicity in vitro.

Fibrillary aggregated α-synuclein represents the neurologic hallmark of Parkinson's disease and is considered to play a causative role in the disease. Although the causes leading to α-synuclein aggregation are not clear, the GM1 ganglioside interaction is recognized to prevent this process. How GM1 exerts these functions is not completely clear, although a primary role of its soluble oligosaccharide (GM1-OS) is emerging. Indeed, we recently identified GM1-OS as the bioactive moiety responsible for GM1 neurotrophic and neuroprotective properties, specifically reverting the parkinsonian phenotype both in in vitro and in vivo models. Here, we report on GM1-OS efficacy against the α-synuclein aggregation and toxicity in vitro. By amyloid seeding aggregation assay and NMR spectroscopy, we demonstrated that GM1-OS was able to prevent both the spontaneous and the prion-like α-synuclein aggregation. Additionally, circular dichroism spectroscopy of recombinant monomeric α-synuclein showed that GM1-OS did not induce any change in α-synuclein secondary structure. Importantly, GM1-OS significantly increased neuronal survival and preserved neurite networks of dopaminergic neurons affected by α-synuclein oligomers, together with a reduction of microglia activation. These data further demonstrate that the ganglioside GM1 acts through its oligosaccharide also in preventing the α-synuclein pathogenic aggregation in Parkinson's disease, opening a perspective window for GM1-OS as drug candidate.

GM1 Oligosaccharide Efficacy in Parkinson's Disease: Protection against MPTP.

Past evidence has shown that the exogenous administration of GM1 ganglioside slowed neuronal death in preclinical models of Parkinson's disease, a neurodegenerative disorder characterized by the progressive loss of dopamine-producing neurons: however, the physical and chemical properties of GM1 (i.e., amphiphilicity) limited its clinical application, as the crossing of the blood-brain barrier is denied. Recently, we demonstrated that the GM1 oligosaccharide head group (GM1-OS) is the GM1 bioactive portion that, interacting with the TrkA-NGF complex at the membrane surface, promotes the activation of a multivariate network of intracellular events regulating neuronal differentiation, protection, and reparation. Here, we evaluated the GM1-OS neuroprotective potential against the Parkinson's disease-linked neurotoxin MPTP, which destroys dopaminergic neurons by affecting mitochondrial bioenergetics and causing ROS overproduction. In dopaminergic and glutamatergic primary cultures, GM1-OS administration significantly increased neuronal survival, preserved neurite network, and reduced mitochondrial ROS production enhancing the mTOR/Akt/GSK3ß pathway. These data highlight the neuroprotective efficacy of GM1-OS in parkinsonian models through the implementation of mitochondrial function and reduction in oxidative stress.

Rectal leiomyosarcoma as the initial phenotypic manifestation of Li-Fraumeni-like syndrome: a case report and review of the literature.

BACKGROUND: Leiomyosarcoma is a rare malignant tumor of smooth muscle origin and represents 10-20% of all soft tissue sarcomas. Primary colon and rectal sarcomas constitute < 0.1% of all large bowel malignancies. In Li-Fraumeni syndrome, sarcomas are the second most frequent cancer (25%). Li-Fraumeni syndrome is a genetic disease with a familial predisposition to multiple malignant neoplasms. This syndrome has an autosomal dominant pattern of inheritance and high penetrance characterized by germline TP53 mutations. Patients with a history of cancer who do not meet all the "classic" criteria for Li-Fraumeni syndrome are considered to have Li-Fraumeni-like syndrome. To the best of our knowledge, this article is the first report of a patient with rectal leiomyosarcoma as the initial phenotypic manifestation of Li-Fraumeni-like syndrome. The authors also present a literature review. CASE PRESENTATION: A 67-year-old Brazilian woman underwent anterior rectosigmoidectomy and panhysterectomy secondary to rectal leiomyosarcoma. She subsequently developed carcinomatosis and died 2 years after the operation. Her family medical history consisted of a daughter who died at 32 years of age from breast cancer, a granddaughter diagnosed with adrenocortical carcinoma at 6 years of age and two siblings who died from prostate cancer. A genetic study was carried out to identify a pathogenic variant of Li-Fraumeni syndrome. In the DNA extracted from the peripheral blood leukocyte, restriction fragment length polymorphism was analyzed to search for mutations in the TP53 gene. The DNA sequencing identified the germline pathogenic variant p. R337H heterozygous in exon 10 of TP53. The patient was classified as having Li-Fraumeni-like syndrome. CONCLUSION: In patients with rectal leiomyosarcoma, it is advisable to investigate the family history of cancer and perform genetic studies to screen for Li-Fraumeni syndrome.

Alpha-Synuclein: The Spark That Flames Dopaminergic Neurons, In Vitro and In Vivo Evidence.

Mitochondria, α-syn fibrils and the endo-lysosomal system are key players in the pathophysiology of Parkinson's disease. The toxicity of α-syn is amplified by cell-to-cell transmission and aggregation of endogenous species in newly invaded neurons. Toxicity of α-syn PFF was investigated using primary cultures of dopaminergic neurons or on aged mice after infusion in the SNpc and combined with mild inhibition of GBA. In primary dopaminergic neurons, application of α-syn PFF induced a progressive cytotoxicity associated with mitochondrial dysfunction, oxidative stress, and accumulation of lysosomes suggesting that exogenous α-syn reached the lysosome (from the endosome). Counteracting the α-syn endocytosis with a clathrin inhibitor, dopaminergic neuron degeneration was prevented. In vivo, α-syn PFF induced progressive neurodegeneration of dopaminergic neurons associated with motor deficits. Histology revealed progressive aggregation of α-syn and microglial activation and accounted for the seeding role of α-syn, injection of which acted as a spark suggesting a triggering of cell-to-cell toxicity. We showed for the first time that a localized SNpc α-syn administration combined with a slight lysosomal deficiency and aging triggered a progressive lesion. The cellular and animal models described could help in the understanding of the human disease and might contribute to the development of new therapies.

NX210c Peptide Promotes Glutamatergic Receptor-Mediated Synaptic Transmission and Signaling in the Mouse Central Nervous System.

NX210c is a disease-modifying dodecapeptide derived from the subcommissural organ-spondin that is under preclinical and clinical development for the treatment of neurological disorders. Here, using whole-cell patch-clamp recordings, we demonstrate that NX210c increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)- and GluN2A-containing N-methyl-D-aspartate receptor (GluN2A-NMDAR)-mediated excitatory postsynaptic currents in the brain. Accordingly, using extracellular field excitatory postsynaptic potential recordings, an enhancement of synaptic transmission was shown in the presence of NX210c in two different neuronal circuits. Furthermore, the modulation of synaptic transmission and GluN2A-NMDAR-driven signaling by NX210c restored memory in mice chronically treated with the NMDAR antagonist phencyclidine. Overall, by promoting glutamatergic receptor-related neurotransmission and signaling, NX210c represents an innovative therapeutic opportunity for patients suffering from CNS disorders, injuries, and states with crippling synaptic dysfunctions.

Chronic pain patients in the Brazilian private healthcare system: a claim database study with the experts' perspective / Pacientes com dor crônica no sistema de saúde suplementar brasileiro: um estudo de banco de dados com a perspectiva dos especialistas

Objective: This study aimed to describe the demands and costs from chronic pain patients over the private Brazilian healthcare system. Methods: This was a retrospective claim database study to assess the resource utilization of pain patients in the private setting. We used a four-year follow-up period to assess inpatient, outpatient, and procedures reported. Further, we promoted a forum of discussion with five pain experts and healthcare managers to address the management of chronic pain and assistance models.Results: We identified 79,689 patients with chronic pain. The orthopedist was the main medical specialist consulted with a total number of 38,879 visits performed. The ophthalmologist, cardiologist, gynecologist, and general practitioner were also frequently consulted (rheumatologist was seldom consulted). Among non-medical specialists, the physical therapist was consulted 87,574 times by 12,342 patients (15% of the entire cohort), Among chronic pain patients, 96% performed at least one exam and 86% of the patients presented at least one ER visit during the follow-up period. In 4 years, we estimate that pain patients costed more than 3 billion reais to the private health care system. According to the experts' opinions, a fragmented healthcare system and the lack of patient centered interdisciplinary approaches contributes to a high ineffective pain management leading to a high use of resources. Conclusion: There is an urgent need to change the chronic pain care model in the Brazilian private setting. Qualification in pain management, a multidisciplinary patient centered care, integrated approaches, pain centers, and patients' education may help changing this scenario.

Objetivo: O objetivo do estudo foi descrever as demandas e custos dos pacientes com dor crônica no sistema privado de saúde brasileiro. Métodos: Neste estudo retrospectivo do banco de dados administrativo, avaliamos a utilização de recursos de pacientes com dor no ambiente privado. Em um período de quatro anos, avaliamos internações, visitas ambulatoriais e procedimentos. Adicionalmente, promovemos um fórum de discussão com cinco especialistas em dor e gerentes de saúde para abordar o manejo da dor e os modelos de assistência. Resultados: Identificamos 79.689 pacientes com dor crônica. O ortopedista foi o principal especialista médico consultado, com 38.879 visitas realizadas. O oftalmologista, o cardiologista, o ginecologista e o clínico geral também foram consultados com frequência (o reumatologista foi raramente consultado). Entre os especialistas não médicos, o fisioterapeuta foi consultado 87.574 vezes por 12.342 pacientes (15% de toda a coorte). Entre os pacientes, 96% realizaram pelo menos um exame e 86% apresentaram pelo menos uma consulta de emergência durante o período. Em 4 anos, estimamos um custo de mais de 3 bilhões de reais para o sistema privado de saúde. De acordo com as opiniões dos especialistas, um sistema de saúde fragmentado e a falta de abordagens centradas no paciente contribuem para um manejo ineficaz da dor, resultando em um alto uso de recursos. Conclusão: Há necessidade de mudar o modelo de manejo da dor crônica no sistema privado brasileiro. Qualificação dos profissionais, atendimento multidisciplinar centrado no paciente, abordagens integradas, centros de dor e educação dos pacientes podem ajudar a mudar esse cenário.

Esophagojejunostomy after total gastrectomy: A systematic review and meta-analysis comparing hand-sewn and stapled anastomosis.

This review aims to evaluate the surgical outcomes of hand-sewn esophageal anastomosis compared to mechanical anastomosis to reconstruct total gastrectomy. A systematic review and meta-analysis of comparative studies evaluating hand-sewn and stapled anastomosis were performed. A total of 12 studies were selected, comprising 1761 individuals. The results indicate that the hand-sewn and stapled esophageal anastomosis have similar surgical outcomes. Stapled anastomosis has a shorter operation time.

THE PROGNOSIS OF THE DIFFERENT ESOPHAGEAL NEUROENDOCRINE CARCINOMA SUBTYPES: A POPULATION-BASED STUDY.

BACKGROUND: Neuroendocrine neoplasms are extremely rare and account for 0.4% to 2% of all malignant esophageal neoplasms. The burden of the neuroendocrine histological type on the patients' prognosis and survival is poorly debated. This study aimed to compare the survival rates of primary neuroendocrine neoplasms compared with adenocarcinoma and squamous cell carcinoma of the esophagus. METHODS: This is a retrospective cohort from the Surveillance, Epidemiology, and End Results Program database. Overall survival and cancer-specific survival were evaluated with Kaplan-Meier curves and logrank tests. Proportional Cox regression models were used to evaluate variables related to overall survival. RESULTS: After eligibility criteria, 66,528 patients were selected. The mean follow-up was 22.6 months (SD 35.6). Adenocarcinoma was predominant (62%), followed by squamous cell carcinoma (36%). Large cell carcinoma, small cell carcinoma, and mixed adenoneuroendocrine carcinoma each account for less than 1% each. On the long-term overall survival analysis, esophageal adenocarcinoma showed a better prognosis than all the other histologic types (P-value for logrank test <0.001). With adenocarcinoma as a reference, HR was 1.32 for large cell carcinoma (95%CI 1.2 to 1.45) and 1.37 for small cell carcinoma (95%CI 1.23 to 1.53). The HR was 1.22 for squamous cell carcinoma (95%CI: 1.2 to 1.24); and 1.3 for adenoneuroendocrine carcinoma (95%CI 1.01 to 1.66). For multivariate Cox regression analysis, besides age and stage, the neuroendocrine subtypes large cell carcinoma and small cell carcinoma were considered independent prognostic variables. CONCLUSION: In the esophagus, large cell carcinoma and small cell carcinoma show poorer long-term survival rates than squamous cell carcinoma and adenocarcinoma.

O prognóstico dos diferentes subtipos de carcinomas de esôfago neuroendócrinos: um estudo de base populacional / The prognosis of the different esophageal neuroendocrine carcinoma subtypes: a population-based study

ABSTRACT Background Neuroendocrine neoplasms are extremely rare and account for 0.4% to 2% of all malignant esophageal neoplasms. The burden of the neuroendocrine histological type on the patients' prognosis and survival is poorly debated. This study aimed to compare the survival rates of primary neuroendocrine neoplasms compared with adenocarcinoma and squamous cell carcinoma of the esophagus. Methods This is a retrospective cohort from the Surveillance, Epidemiology, and End Results Program database. Overall survival and cancer-specific survival were evaluated with Kaplan-Meier curves and logrank tests. Proportional Cox regression models were used to evaluate variables related to overall survival. Results After eligibility criteria, 66,528 patients were selected. The mean follow-up was 22.6 months (SD 35.6). Adenocarcinoma was predominant (62%), followed by squamous cell carcinoma (36%). Large cell carcinoma, small cell carcinoma, and mixed adenoneuroendocrine carcinoma each account for less than 1% each. On the long-term overall survival analysis, esophageal adenocarcinoma showed a better prognosis than all the other histologic types (P-value for logrank test <0.001). With adenocarcinoma as a reference, HR was 1.32 for large cell carcinoma (95%CI 1.2 to 1.45) and 1.37 for small cell carcinoma (95%CI 1.23 to 1.53). The HR was 1.22 for squamous cell carcinoma (95%CI: 1.2 to 1.24); and 1.3 for adenoneuroendocrine carcinoma (95%CI 1.01 to 1.66). For multivariate Cox regression analysis, besides age and stage, the neuroendocrine subtypes large cell carcinoma and small cell carcinoma were considered independent prognostic variables. Conclusion In the esophagus, large cell carcinoma and small cell carcinoma show poorer long-term survival rates than squamous cell carcinoma and adenocarcinoma.

RESUMO Contexto As neoplasias neuroendócrinas são extremamente raras e representam 0,4% a 2% de todas as neoplasias malignas do esôfago. A determinação prognóstica e avaliação de sobrevida para o tipo histológico neuroendócrino é pouco debatida. Este estudo teve como objetivo comparar as taxas de sobrevida de neoplasias neuroendócrinas primárias comparadas com adenocarcinoma e carcinoma espinocelular de esôfago. Métodos Este é um estudo coorte retrospectivo do banco de dados do Surveillance, Epidemiology, and End Results Program. A sobrevida global e a sobrevida específica do câncer foram avaliadas com curvas de Kaplan-Meier e testes de logrank. Modelos de regressão de Cox proporcional foram utilizados para avaliar as variáveis relacionadas à sobrevida global. Resultados Após critérios de elegibilidade, foram selecionados 66,528 pacientes. O seguimento médio foi de 22,6 meses (DP 35,6). O adenocarcinoma foi predominante (62%), seguido pelo carcinoma espinocelular (36%). Carcinoma de grandes células, carcinoma de pequenas células e carcinoma adenoneuroendócrino misto representam menos de 1% cada. Na análise de sobrevida global, o adenocarcinoma de esôfago apresentou um prognóstico melhor do que todos os outros tipos histológicos (P valor para teste de logrank < 0,001). Com adenocarcinoma como referência, HR foi de 1,32 para carcinoma de grandes células (IC95% 1,2 a 1,45) e 1,37 para carcinoma de pequenas células (IC95% 1,23 a 1,53). O HR foi de 1,22 para carcinoma espinocelular (IC95%: 1,2 a 1,24); e 1,3 para carcinoma adenoneuroendócrino (IC95% 1,01 a 1,66). Para a análise multivariada da regressão de Cox, além da idade e do estadiamento, os subtipos neuroendócrinos carcinoma de grandes células e carcinoma de pequenas células foram considerados variáveis prognósticas independentes. Conclusão No esôfago, o carcinoma de grandes células e o carcinoma de pequenas células apresentam menores taxas de sobrevida a longo prazo do que o carcinoma espinocelular e o adenocarcinoma.

Muscle cells of sporadic amyotrophic lateral sclerosis patients secrete neurotoxic vesicles.

BACKGROUND: The cause of the motor neuron (MN) death that drives terminal pathology in amyotrophic lateral sclerosis (ALS) remains unknown, and it is thought that the cellular environment of the MN may play a key role in MN survival. Several lines of evidence implicate vesicles in ALS, including that extracellular vesicles may carry toxic elements from astrocytes towards MNs, and that pathological proteins have been identified in circulating extracellular vesicles of sporadic ALS patients. Because MN degeneration at the neuromuscular junction is a feature of ALS, and muscle is a vesicle-secretory tissue, we hypothesized that muscle vesicles may be involved in ALS pathology. METHODS: Sporadic ALS patients were confirmed to be ALS according to El Escorial criteria and were genotyped to test for classic gene mutations associated with ALS, and physical function was assessed using the ALSFRS-R score. Muscle biopsies of either mildly affected deltoids of ALS patients (n = 27) or deltoids of aged-matched healthy subjects (n = 30) were used for extraction of muscle stem cells, to perform immunohistology, or for electron microscopy. Muscle stem cells were characterized by immunostaining, RT-qPCR, and transcriptomic analysis. Secreted muscle vesicles were characterized by proteomic analysis, Western blot, NanoSight, and electron microscopy. The effects of muscle vesicles isolated from the culture medium of ALS and healthy myotubes were tested on healthy human-derived iPSC MNs and on healthy human myotubes, with untreated cells used as controls. RESULTS: An accumulation of multivesicular bodies was observed in muscle biopsies of sporadic ALS patients by immunostaining and electron microscopy. Study of muscle biopsies and biopsy-derived denervation-naïve differentiated muscle stem cells (myotubes) revealed a consistent disease signature in ALS myotubes, including intracellular accumulation of exosome-like vesicles and disruption of RNA-processing. Compared with vesicles from healthy control myotubes, when administered to healthy MNs the vesicles of ALS myotubes induced shortened, less branched neurites, cell death, and disrupted localization of RNA and RNA-processing proteins. The RNA-processing protein FUS and a majority of its binding partners were present in ALS muscle vesicles, and toxicity was dependent on the expression level of FUS in recipient cells. Toxicity to recipient MNs was abolished by anti-CD63 immuno-blocking of vesicle uptake. CONCLUSIONS: ALS muscle vesicles are shown to be toxic to MNs, which establishes the skeletal muscle as a potential source of vesicle-mediated toxicity in ALS.

The impact of venous resection in pancreatoduodectomy: A systematic review and meta-analysis.

BACKGROUND: Vein resection pancreatoduodenectomy (VRPD) may be performed in selected pancreatic cancer patients. However, the main risks and benefits related to VRPD remain controversial. OBJECTIVE: This review aimed to evaluate the risks and survival benefits that the VRPD may add when compared with standard pancreatoduodenectomy (PD). METHODS: A systematic review and meta-analysis of studies comparing VRPD and PD were performed. RESULTS: VRPD was associated with a higher risk for postoperative mortality (risk difference: -0.01; 95% confidence interval [CI] -0.02 to -0.00) and complications (risk difference: -0.05; 95% CI -0.09 to -0.01) than PD. The length of hospital stay was not different between the groups (mean difference [MD]: -0.65; 95% CI -2.11 to 0.81). In the VRPD, the operating time was 69 minutes higher on average (MD: -69.09; 95% CI -88.4 to -49.78), with a higher blood loss rate (MD: -314.04; 95% CI -423.86 to -195.22). In the overall survival evaluation, the hazard ratio for mortality during follow-up on the group of VRPD was higher compared to the PD group (hazard ratio: 1.13; 95% CI 1.03-1.23). CONCLUSION: VRPD is associated with a higher risk of short-term complications and mortality and a lower probability of survival than PD. Knowing the risks and potential benefits of surgery can help clinicians to properly manage pancreatic cancer patients with venous invasion. The decision for surgery with major venous resection should be shared with the patients after they are informed of the risks and prognosis.

Sphingolipids metabolism alteration in the central nervous system: Amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases.

Sphingolipids are complex lipids. They play a structural role in neurons, but are also involved in regulating cellular communication, and neuronal differentiation and maturation. There is increasing evidence to suggest that dysregulated metabolism of sphingolipids is linked to neurodegenerative processes in amyotrophic lateral sclerosis (ALS), Parkinson's disease and Gaucher's disease. In this review, we provide an overview of the role of sphingolipids in the development and maintenance of the nervous system. We describe the implications of altered metabolism of sphingolipids in the pathophysiology of certain neurodegenerative diseases, with a primary focus on ALS. Finally, we provide an update of potential treatments that could be used to target the metabolism of sphingolipids in neurodegenerative diseases.

Drug repositioning in neurodegeneration: An overview of the use of ambroxol in neurodegenerative diseases.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults. While it is primarily characterized by the death of upper and lower motor neurons, there is a significant metabolic component involved in the progression of the disease. Two-thirds of ALS patients have metabolic alterations that are associated with the severity of symptoms. In ALS, as in other neurodegenerative diseases, the metabolism of glycosphingolipids, a class of complex lipids, is strongly dysregulated. We therefore assume that this pathway constitutes an interesting avenue for therapeutic approaches. We have shown that the glucosylceramide degrading enzyme, glucocerebrosidase (GBA) 2 is abnormally increased in the spinal cord of the SOD1G86R mouse model of ALS. Ambroxol, a chaperone molecule that inhibits GBA2, has been shown to have beneficial effects by slowing the development of the disease in SOD1G86R mice. Currently used in clinical trials for Parkinson's and Gaucher disease, ambroxol could be considered as a promising therapeutic treatment for ALS.

Longitudinal transcriptomic analysis of altered pathways in a CHMP2Bintron5-based model of ALS-FTD.

Amyotrophic lateral sclerosis and frontotemporal dementia are two neurodegenerative diseases with currently no cure. These two diseases share a clinical continuum with overlapping genetic causes. Mutations in the CHMP2B gene are found in patients with ALS, FTD and ALS-FTD. To highlight deregulated mechanisms occurring in ALS-FTD linked to the CHMP2B gene, we performed a whole transcriptomic study on lumbar spinal cord from CHMP2Bintron5 mice, a model that develops progressive motor alterations associated with dementia symptoms reminiscent of both ALS and FTD. To gain insight into the transcriptomic changes taking place during disease progression this study was performed at three stages: asymptomatic, symptomatic and end stage. We showed that before appearance of motor symptoms, the major disrupted mechanisms were linked with the immune system/inflammatory response and lipid metabolism. These processes were progressively replaced by alterations of neuronal electric activity as motor symptoms appeared, alterations that could lead to motor neuron dysfunction. To investigate overlapping alterations in gene expression between two ALS-causing genes, we then compared the transcriptome of symptomatic CHMP2Bintron5 mice with the one of symptomatic SOD1G86R mice and found the same families deregulated providing further insights into common underlying dysfunction of biological pathways, disrupted or disturbed in ALS. Altogether, this study provides a database to explore potential new candidate genes involved in the CHMP2Bintron5-based pathogenesis of ALS, and provides molecular clues to further understand the functional consequences that diseased neurons expressing CHMP2B mutant may have on their neighbor cells.

Ambroxol Hydrochloride Improves Motor Functions and Extends Survival in a Mouse Model of Familial Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a multifactorial and fatal neurodegenerative disease. Growing evidence connects sphingolipid metabolism to the pathophysiology of ALS. In particular, levels of ceramides, glucosylceramides, and gangliosides are dysregulated in the central nervous system and at the neuromuscular junctions of both animal models and patients. Glucosylceramide is the main precursor of complex glycosphingolipids that is degraded by lysosomal (GBA1) or non-lysosomal (GBA2) glucocerebrosidase. Here, we report that GBA2, but not GBA1, activity is markedly increased in the spinal cord, of SOD1G86R mice, an animal model of familial ALS, even before disease onset. We therefore investigated the effects of ambroxol hydrochloride, a known GBA2 inhibitor, in SOD1G86R mice. A presymptomatic administration of ambroxol hydrochloride, in the drinking water, delayed disease onset, protecting neuromuscular junctions, and the number of functional spinal motor neurons. When administered at disease onset, ambroxol hydrochloride delayed motor function decline, protected neuromuscular junctions, and extended overall survival of the SOD1G86R mice. In addition, ambroxol hydrochloride improved motor recovery and muscle re-innervation after transient sciatic nerve injury in non-transgenic mice and promoted axonal elongation in an in vitro model of motor unit. Our study suggests that ambroxol hydrochloride promotes and protects motor units and improves axonal plasticity, and that this generic compound is a promising drug candidate for ALS.