Lineage-Restricted Regulation of SCD and Fatty Acid Saturation by MITF Controls Melanoma Phenotypic Plasticity.

Phenotypic and metabolic heterogeneity within tumors is a major barrier to effective cancer therapy. How metabolism is implicated in specific phenotypes and whether lineage-restricted mechanisms control key metabolic vulnerabilities remain poorly understood. In melanoma, downregulation of the lineage addiction oncogene microphthalmia-associated transcription factor (MITF) is a hallmark of the proliferative-to-invasive phenotype switch, although how MITF promotes proliferation and suppresses invasion is poorly defined. Here, we show that MITF is a lineage-restricted activator of the key lipogenic enzyme stearoyl-CoA desaturase (SCD) and that SCD is required for MITFHigh melanoma cell proliferation. By contrast MITFLow cells are insensitive to SCD inhibition. Significantly, the MITF-SCD axis suppresses metastasis, inflammatory signaling, and an ATF4-mediated feedback loop that maintains de-differentiation. Our results reveal that MITF is a lineage-specific regulator of metabolic reprogramming, whereby fatty acid composition is a driver of melanoma phenotype switching, and highlight that cell phenotype dictates the response to drugs targeting lipid metabolism.

Magnetically modified-mitoxantrone mesoporous organosilica drugs: an emergent multimodal nanochemotherapy for breast cancer.

BACKGROUND: Chemotherapy, the mainstay treatment for metastatic cancer, presents serious side effects due to off-target exposure. In addition to the negative impact on patients' quality of life, side effects limit the dose that can be administered and thus the efficacy of the drug. Encapsulation of chemotherapeutic drugs in nanocarriers is a promising strategy to mitigate these issues. However, avoiding premature drug release from the nanocarriers and selectively targeting the tumour remains a challenge. RESULTS: In this study, we present a pioneering method for drug integration into nanoparticles known as mesoporous organosilica drugs (MODs), a distinctive variant of periodic mesoporous organosilica nanoparticles (PMOs) in which the drug is an inherent component of the silica nanoparticle structure. This groundbreaking approach involves the chemical modification of drugs to produce bis-organosilane prodrugs, which act as silica precursors for MOD synthesis. Mitoxantrone (MTO), a drug used to treat metastatic breast cancer, was selected for the development of MTO@MOD nanomedicines, which demonstrated a significant reduction in breast cancer cell viability. Several MODs with different amounts of MTO were synthesised and found to be efficient nanoplatforms for the sustained delivery of MTO after biodegradation. In addition, Fe3O4 NPs were incorporated into the MODs to generate magnetic MODs to actively target the tumour and further enhance drug efficacy. Importantly, magnetic MTO@MODs underwent a Fenton reaction, which increased cancer cell death twofold compared to non-magnetic MODs. CONCLUSIONS: A new PMO-based material, MOD nanomedicines, was synthesised using the chemotherapeutic drug MTO as a silica precursor. MTO@MOD nanomedicines demonstrated their efficacy in significantly reducing the viability of breast cancer cells. In addition, we incorporated Fe3O4 into MODs to generate magnetic MODs for active tumour targeting and enhanced drug efficacy by ROS generation. These findings pave the way for the designing of silica-based multitherapeutic nanomedicines for cancer treatment with improved drug delivery, reduced side effects and enhanced efficacy.

New Insights into Endogenous Retrovirus-K Transcripts in Amyotrophic Lateral Sclerosis.

Retroviral reverse transcriptase activity and the increased expression of human endogenous retroviruses (HERVs) are associated with amyotrophic lateral sclerosis (ALS). We were interested in confirming HERVK overexpression in the ALS brain, its use as an accessory diagnostic marker for ALS, and its potential interplay with neuroinflammation. Using qPCR to analyze HERVK expression in peripheral blood mononuclear cells (PBMCs) and in postmortem brain samples from ALS patients, no significant differences were observed between patients and control subjects. By contrast, we report alterations in the expression patterns of specific HERVK copies, especially in the brainstem. Out of 27 HERVK copies sampled, the relative expression of 17 loci was >1.2-fold changed in samples from ALS patients. In particular, the relative expression of two HERVK copies (Chr3-3 and Chr3-5) was significantly different in brainstem samples from ALS patients compared with controls. Further qPCR analysis of inflammation markers in brain samples revealed a significant increase in NLRP3 levels, while TNFA, IL6, and GZMB showed slight decreases. We cannot confirm global HERVK overexpression in ALS, but we can report the ALS-specific overexpression of selected HERVK copies in the ALS brain. Our data are compatible with the requirement for better patient stratification and support the potential importance of particular HERVK copies in ALS.

Clinical competency development with handmade simulator in highly realistic paediatric dentistry scenarios.

INTRODUCTION: The use of simulation is extremely useful in pregraduate students. However, there is a very small number of simulators adapted to paediatric dentistry. A paediatric simulator was created to use in simulated scenarios for paediatric dentistry using an actress in the role of mother. The objectives of the present study were three. First, to analyse the perception of clinical competencies acquired by the students. Second, to examine the realism perceived by the students. Finally, to analyse the influence on the perception of clinical competencies after the integration of a handmade simulator in the Paediatric Dentistry III course. MATERIALS AND METHODS: Eight clinical scenarios were carried out with a modified Erler Zimmer simulator for children, a professional actress in the role of the mother and two students (in the roles of dentist and assistant) on a paediatric dentistry case of pulpal pathology. The educational intervention was evaluated on 114 students by means of questionnaires with Likert-type answers applied pre- and post-simulation. RESULTS: The perception of clinical competence in the students increased an average of 0.956 points in relation with the initial clinical evaluation, finding a strong correlation between the perception of subsequent competence and all the perceived realism, with significant statistical differences in all cases. The realism of the simulated participant (professional actress) was the best rated by the students, although not significantly. The realism of the mannequin was positively and strongly correlated with the perceived realism of the cabinet. CONCLUSION: Simulation using a handmade mannequin with a professional actress in a simulated dental office increased the perception of clinical competence in 4th year dental students and raised the level of overall realism perceived by the student.

Accuracy and Survival Outcomes after National Implementation of Sentinel Lymph Node Biopsy in Early Stage Endometrial Cancer.

BACKGROUND: Sentinel lymph node (SLN) biopsy has recently been accepted to evaluate nodal status in endometrial cancer at early stage, which is key to tailoring adjuvant treatments. Our aim was to evaluate the national implementation of SLN biopsy in terms of accuracy to detect nodal disease in a clinical setting and oncologic outcomes according to the volume of nodal disease. PATIENTS AND METHODS: A total of 29 Spanish centers participated in this retrospective, multicenter registry including patients with endometrial adenocarcinoma at preoperative early stage who had undergone SLN biopsy between 2015 and 2021. Each center collected data regarding demographic, clinical, histologic, therapeutic, and survival characteristics. RESULTS: A total of 892 patients were enrolled. After the surgery, 12.9% were suprastaged to FIGO 2009 stages III-IV and 108 patients (12.1%) had nodal involvement: 54.6% macrometastasis, 22.2% micrometastases, and 23.1% isolated tumor cells (ITC). Sensitivity of SLN biopsy was 93.7% and false negative rate was 6.2%. After a median follow up of 1.81 years, overall surivial and disease-free survival were significantly lower in patients who had macrometastases when compared with patients with negative nodes, micrometastases or ITC. CONCLUSIONS: In our nationwide cohort we obtained high sensitivity of SLN biopsy to detect nodal disease. The oncologic outcomes of patients with negative nodes and low-volume disease were similar after tailoring adjuvant treatments. In total, 22% of patients with macrometastasis and 50% of patients with micrometastasis were at low risk of nodal metastasis according to their preoperative risk factors, revealing the importance of SLN biopsy in the surgical management of patients with early stage EC.

A meta-analysis of cognitive interventions for patients with recent onset psychosis: are they effective for improving functioning?

The increasing popularity of cognitive interventions for patients with psychosis calls for further exploration on how these interventions may benefit functional outcomes. We conducted a meta-analysis of randomized controlled trials (RCTs) to examine the effectiveness of cognitive interventions (i.e. Cognitive Remediation, Cognitive Training, Social Cognition, and their combination) on functioning of patients with recent onset psychosis, established as the period within the first five years from the first episode. The following databases were searched: Proquest, PUBMED/MEDLINE, PsycINFO, WOS, Scopus for research published until January 2022. In total, 12 studies were eligible. The total number of participants was 759, of which 32.2% in the intervention and 30.8% in the control group were female. We extracted data to calculate the standardized mean change from pre-test to post-test comparing the intervention with the control conditions. Overall, there was no effect of any of the cognitive intervention types on functioning. None of the examined factors (intervention type, length, and modality; control condition, follow-up time; cognitive functions; medication; symptoms) seemed to moderate these findings. Our results indicate that cognitive interventions as standalone interventions do not appear to improve functioning in patients with recent onset psychosis. Given the small number of eligible studies, further RCTs with larger and more refined samples are needed to test whether these interventions should be applied as single interventions with these patients.

Efficacy of technology-based interventions in psychosis: a systematic review and network meta-analysis.

BACKGROUND: Technology-based interventions (TBIs) are a useful approach when attempting to provide therapy to more patients with psychosis. METHODS: Randomized controlled trials of outcomes of TBIs v. face-to-face interventions in psychosis were identified in a systematic search conducted in PubMed/Ovid MEDLINE. Data were extracted independently by two researchers, and standardized mean changes were pooled using a three-level model and network meta-analysis. RESULTS: Fifty-eight studies were included. TBIs complementing treatment as usual (TAU) were generally superior to face-to-face interventions (g = 0.16, p ≤ 0.0001) and to specific outcomes, namely, neurocognition (g = 0.13, p ≤ 0.0001), functioning (g = 0.25, p = 0.006), and social cognition (g = 0.32, p ≤ 0.05). Based on the network meta-analysis, the effect of two TBIs differed significantly from zero; these were the TBIs cognitive training for the neurocognitive outcome [g = 0.16; 95% confidence interval (CI) 0.09-0.23] and cognitive behavioral therapy for quality of life (g = 1.27; 95% CI 0.46-2.08). The variables educational level, type of medication, frequency of the intervention, and contact during the intervention moderated the effectiveness of TBIs over face-to-face interventions in neurocognition and symptomatology. CONCLUSIONS: TBIs are effective for the management of neurocognition, symptomatology, functioning, social cognition, and quality of life outcomes in patients with psychosis. The results of the network meta-analysis showed the efficacy of some TBIs for neurocognition, symptomatology, and quality of life. Therefore, TBIs should be considered a complement to TAU in patients with psychosis.

Paradoxical activation of AMPK by glucose drives selective EP300 activity in colorectal cancer.

Coordination of gene expression with nutrient availability supports proliferation and homeostasis and is shaped by protein acetylation. Yet how physiological/pathological signals link acetylation to specific gene expression programs and whether such responses are cell-type-specific is unclear. AMP-activated protein kinase (AMPK) is a key energy sensor, activated by glucose limitation to resolve nutrient supply-demand imbalances, critical for diabetes and cancer. Unexpectedly, we show here that, in gastrointestinal cancer cells, glucose activates AMPK to selectively induce EP300, but not CREB-binding protein (CBP). Consequently, EP300 is redirected away from nuclear receptors that promote differentiation towards ß-catenin, a driver of proliferation and colorectal tumorigenesis. Importantly, blocking glycogen synthesis permits reactive oxygen species (ROS) accumulation and AMPK activation in response to glucose in previously nonresponsive cells. Notably, glycogen content and activity of the ROS/AMPK/EP300/ß-catenin axis are opposite in healthy versus tumor sections. Glycogen content reduction from healthy to tumor tissue may explain AMPK switching from tumor suppressor to activator during tumor evolution.

Comparison among three predictive models for cancer-associated thromboembolism in a hispanic population.

In this study we aimed to evaluate and compare the overall performance of the Khorana, PROTECHT, and CONKO scores as predictive scores for the occurrence of venous thromboembolism (VTE) among ambulatory Hispanic patients with solid tumors. We included all outpatients with newly diagnosed solid tumors receiving systemic chemotherapy in Hospital San Juan Dios, San José, Costa Rica, from January to December 2021. For each patient the Khorana, PROTECHT, and CONKO scores were calculated at the beginning of treatment. The sixth-month cumulative incidence of VTE was estimated using the Fine & Gray competing risk model. The receiver operating characteristic (ROC) curve was used to assess the performance of each predictive tool through the analysis of the c-statistic, sensitivity, and specificity. A total of 708 patients were included in the research. After a median follow-up of 8.13 months, the cumulative VTE incidence at six months was 4.45% (95%CI: 3.25-6.91%) for the overall population. At the conventional positivity threshold of 3 points, these scores classified from 17.7 to 32.5% of all patients as high-risk for VTE. Patients belonging to the high-risk category of the Khorana, PROTECHT, and CONKO scores had significantly higher risk of VTE in comparison to low-risk patients (Khorana score: Hazard Ratio (HR): 2.66; 95%CI:1.20-5.89; p = 0.042; PROTECHT score: HR: 3.44; 95%CI:1.63-7.21; p = 0.001; CONKO score HR: 3.68; 95%CI:1.72-7.85; p = 0.001). The c-statistic of the ROC curve was: 0.62 (95%CI: 0.52-0.72), 0.62 (95%CI: 0.52-0.73), and 0.65 (95%CI: 0.56-0.76) for the Khorana, PROTECHT, and CONKO scores, respectively; with similar sensitivity (range: 67-70%) and specificity (range: 52-62%) among them. For Hispanic patients with solid tumors the Khorana, PROTECHT, and CONKO scores accurately categorize their risk of VTE. However, the overall discriminatory performance of these models remains poor (c-statistic from 0.62 to 0.65) for predicting all patients at risk for thromboembolic events.

Central sensitization negatively influences the level of disability in female patients with anterior knee pain.

PURPOSE: To define the prevalence of Central Sensitization (CS) in patients with Anterior Knee Pain (AKP) and determine whether there is an association between CS and the magnitude of pain, disability, quality-of-life and psychological impairment. METHODS: The data of a total of 44 AKP female patients with a mean age of 27.7 years (15-50) recruited consecutively from hospital outpatient knee clinics were prospectively included in this study. The patients had no antecedents of knee trauma or surgery and no history of injury or disease of the nervous system. There were also 50 healthy female controls with a mean age of 26.1 years (16-46). CS was evaluated using the Central Sensitization Inventory (CSI). Quality-of-life was evaluated using the EuroQoL-5D questionnaire. Self-reporting of clinical pain intensity was obtained using the Visual Analogue Scale. The Kujala Knee Scale and IKDC form were used to evaluate disability. Anxiety and depression were evaluated using the Hospital Anxiety and Depression Subscale (HAD). Kinesiophobia was measured with the Tampa Scale for Kinesiophobia (TSK-11) and catastrophizing by means of the Pain Catastrophizing Scale (PCS). RESULTS: Sixteen AKP patients (36%), and 2 (4%) of the healthy controls presented with central sensitization (p < 0.01). AKP patients with CS have a greater degree of disability based on the Kujala Scale and higher levels of anxiety and depression than AKP patients without CS. The score of AKP patients in the CSI correlated weakly with disability and quality of life and moderately with anxiety and depression. However, no association was seen between CSI score and pain intensity, nor with catastrophizing and kinesiophobia. A multivariate logistic regression analysis showed that only depression was statistically significant in the prediction of the presence of CS (odds ratio 1.45; 95% CI 1.07 to 1.96). CONCLUSIONS: AKP patients have a significantly higher prevalence of CS in comparison with what has been reported for the general population. This finding suggests the presence of altered pain modulation in a subgroup of AKP patients. LEVEL OF EVIDENCE: Level III.

Vaccination against SARS-CoV-2 and its relationship with public interest in mental health: a study between 2020-2022 in Spain.

The possible relationship between vaccination against SARS-CoV-2 (COVID-19) and mental health has been largely unexplored. We investigated variations in public interest in mental health issues between the different periods of the vaccination campaign against SARS-CoV-2 in Spain and before the initiation of the campaign. Using Google Trends, we explored the relative search volume (RSV) for the terms 'anxiety', 'depression', 'stress', 'insomnia', and 'suicide' between 03/01/2020 and 01/15/2022. The RSV was compared for these terms with respect to four periods: the pre-vaccination pandemic period; the period running from initiation of vaccination until 50% of the population was fully vaccinated (FV); the period running from 50% FV to 70% FV; and the period after 70% FV. Differences in the RSV indices were observed between the studied periods for 'anxiety'(F = 6.07; p = 0.001; ƞ2 = 0.16), 'stress' (F = 7.77; p < 0.001; ƞ2 = 0.19), and 'insomnia' (F = 3.80; p = 0.013; ƞ2 = 0.11). A lower RSV was found for 'anxiety', 'stress', and 'insomnia' after 70% FV compared to the two previous vaccination periods. A lower RSV was also found for 'stress' after achieving the milestone of 70% FV in relation to the period prior to initiation of the campaign. In conclusion, there is less need for information on specific mental health topics in the period after 70% FV. In Spain, reaching this vaccination milestone may have had a positive impact on anxiety, stress, and insomnia levels in the population, as reflected in fewer web searches for information on these psychopathological processes. The promotion of the COVID-19 vaccination campaign could take into account the changes observed in this preliminary study with respect to public interest in stress, anxiety, and insomnia once a large percentage of the population has been vaccinated.

Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice.

The interaction of the activating transcription factor 6 (ATF6), a key effector of the unfolded protein response (UPR) in the endoplasmic reticulum, with the neuronal calcium sensor Downstream Regulatory Element Antagonist Modulator (DREAM) is a potential therapeutic target in neurodegeneration. Modulation of the ATF6-DREAM interaction with repaglinide (RP) induced neuroprotection in a model of Huntington's disease. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no cure, characterized by the progressive loss of motoneurons resulting in muscle denervation, atrophy, paralysis, and death. The aim of this work was to investigate the potential therapeutic significance of DREAM as a target for intervention in ALS. We found that the expression of the DREAM protein was reduced in the spinal cord of SOD1G93A mice compared to wild-type littermates. RP treatment improved motor strength and reduced the expression of the ALS progression marker collagen type XIXα1 (Col19α1 mRNA) in the quadriceps muscle in SOD1G93A mice. Moreover, treated SOD1G93A mice showed reduced motoneuron loss and glial activation and increased ATF6 processing in the spinal cord. These results indicate that the modulation of the DREAM-ATF6 interaction ameliorates ALS symptoms in SOD1G93A mice.

Clinical results of lumbar sympathetic blocks in lower limb complex regional pain syndrome using infrared thermography as a support tool.

AIM: To describe the clinical outcomes for a group of complex regional pain syndrome patients using infrared thermography as an intraprocedural support tool when undertaking fluoroscopy-guided lumbar sympathetic blocks. SUBJECTS: 27 patients with lower limb complex regional pain syndrome accompanied by severe pain and persistent functional impairment. METHODS: A series of three fluoroscopic-guided lumbar sympathetic blocks with local anesthetic and corticoids using infrared thermography as an intraprocedural support tool were performed. Clinical variables were collected at baseline, prior to each block, and one, three, and six months after blocks in a standardized checklist assessing each of the clinical categories of complex regional pain syndrome stipulated in the Budapest criteria. RESULTS: 23.75% of the blocks required more than one chance to achieve the desired thermal pattern and therefore to be considered as successful. A decrease in pain measured on a visual analogic scale was observed at all time points compared to pre-blockade data, but only 37% of the cases were categorized as responders, representing a ≥ 30% decrease in VAS, with the disappearance of pain at rest. An improvement of most of the clinical variables recorded was observed, such as tingling, edema, perception of thermal asymmetry, difference in coloring and sweating. There was a significant decrease of neuropathic pain and improvement of functional limitation. Logistic regression analysis showed the main variable to explain the probability of being a responder was immobilization time (odds ratio of 0.89). CONCLUSION: A series of fluoroscopy-guided lumbar sympathetic blocks controlled by infrared thermography in the treatment of lower limb CRPS showed a responder rate of 37%.

Neuropsychological functioning and suicidal behaviours in patients with first-episode psychosis: A systematic review.

INTRODUCTION: Suicidal behaviour is particularly frequent in patients with psychosis. Therefore, prevention is a key objective of mental health policies. The aim of the current work is to systematically review the association between neurocognitive functioning and suicidal behaviour in patients with first-episode psychosis (FEP). MATERIAL AND METHODS: Of the 3051 studies reviewed, only 7 met the inclusion criteria. Documents in English from their earliest date of coverage until January 2022 were searched for in the following databases: PubMed, Science Direct, Web of Science, Cochrane Library, PsycINFO (ProQuest), and Springerlink. We used the PICO strategy to collect and categorize the data from each selected manuscript. RESULTS: Overall, the results showed that the risk of suicidal behaviour is higher for FEP patients in the presence of a number of factors: poorer general neuropsychological functioning (except for working memory), poorer social cognition, more depressive symptoms, longer duration of untreated psychosis, higher awareness of the illness, poorer premorbid adjustment, and more frequent cannabis use. DISCUSSION: Comprehensive general neuropsychology and assessment of social cognition, together with routine clinical record keeping, may help to identify FEP patients at a greater risk of attempting suicide.

GPCR-mediated glucose sensing system regulates light-dependent fungal development and mycotoxin production.

Microorganisms sense environmental fluctuations in nutrients and light, coordinating their growth and development accordingly. Despite their critical roles in fungi, only a few G-protein coupled receptors (GPCRs) have been characterized. The Aspergillus nidulans genome encodes 86 putative GPCRs. Here, we characterise a carbon starvation-induced GPCR-mediated glucose sensing mechanism in A. nidulans. This includes two class V (gprH and gprI) and one class VII (gprM) GPCRs, which in response to glucose promote cAMP signalling, germination and hyphal growth, while negatively regulating sexual development in a light-dependent manner. We demonstrate that GprH regulates sexual development via influencing VeA activity, a key light-dependent regulator of fungal morphogenesis and secondary metabolism. We show that GprH and GprM are light-independent negative regulators of sterigmatocystin biosynthesis. Additionally, we reveal the epistatic interactions between the three GPCRs in regulating sexual development and sterigmatocystin production. In conclusion, GprH, GprM and GprI constitute a novel carbon starvation-induced glucose sensing mechanism that functions upstream of cAMP-PKA signalling to regulate fungal development and mycotoxin production.

Nonrestorative treatment of initial caries lesion in primary teeth: a systematic review and network meta-analysis.

OBJECTIVE: To identify the best available approach to avoid initial caries lesions progression in primary teeth. MATERIALS AND METHODS: Search was performed in MEDLINE/Pubmed, Web of Science, Embase and CENTRAL databases until March 2021. Studies compared treatment options to avoid the initial caries lesion progression with at least 12 months of follow-up were included. Network meta-analyses were conducted considering the non-progression of caries lesions as an outcome. RESULTS: Potentially eligible studies were screened (n = 2820) and eleven were included. Six studies evaluated the use of fluoride varnish, resin infiltration, sealing, and toothbrushing/flossing on proximal initial caries lesions. When considering occlusal surfaces, only two studies evaluating the ozone gas, fluoride varnish, resin infiltration, and sealants were included. For buccal/lingual surfaces, three studies evaluating toothbrushing, CPP-ACP paste, fluoride varnish, and resin infiltration were included. For all types of surfaces, the resin infiltration showed the best probability to avoid the progression of initial caries lesions. CONCLUSION: The limited number of included studies, most with a high risk of bias and lack of hard outcomes, such as frank cavitation, makes it not feasible to recommend a specific management approach for initial caries lesion control in primary teeth with a high certainty of evidence. PROSPERO: #CRD42016037781.

Hemizygous Granzyme A Mice Expressing the hSOD1G93A Transgene Show Slightly Extended Lifespan.

Granzyme A (gzmA), a serine protease involved in the modulation of the inflammatory immune response, is found at an elevated level in the serum from ALS patients. However, the influence of gzmA on the progression of ALS remains unclear. The aim of our work was to assess whether the absence of gzmA in an ALS murine model could help slow down the progression of the disease. Homozygous and hemizygous gzmA-deficient mice expressing the hSOD1G93A transgene were generated, and survival of these mice was monitored. Subsequently, gene and protein expression of inflammatory and oxidative stress markers was measured in the spinal cord and quadriceps of these mice. We observed the longest lifespan in gzmA+/- mice. GzmA gene and protein expression was downregulated in the spinal cord and serum from gmzA+/- mice, confirming that the increased survival of hemizygous mice is correlated with lower levels of gzmA. In addition, mRNA and protein levels of glutathione reductase (GSR), involved in oxidative stress, were found downregulated in the spinal cord and quadriceps of gmzA+/- mice, together with lower IL-1ß and IL-6 mRNA levels in hemyzigous mice. In summary, our findings indicate for the first time that reduced levels, but not the absence, of gzmA could slightly ameliorate the disease progression in this animal model.

Glucose-induced ß-catenin acetylation enhances Wnt signaling in cancer.

Nuclear accumulation of ß-catenin, a widely recognized marker of poor cancer prognosis, drives cancer cell proliferation and senescence bypass and regulates incretins, critical regulators of fat and glucose metabolism. Diabetes, characterized by elevated blood glucose levels, is associated with increased cancer risk, partly because of increased insulin growth factor 1 signaling, but whether elevated glucose directly impacts cancer-associated signal-transduction pathways is unknown. Here, we show that high glucose is essential for nuclear localization of ß-catenin in response to Wnt signaling. Glucose-dependent ß-catenin nuclear retention requires lysine 354 and is mediated by alteration of the balance between p300 and sirtuins that trigger ß-catenin acetylation. Consequently ß-catenin accumulates in the nucleus and activates target promoters under combined glucose and Wnt stimulation, but not with either stimulus alone. Our results reveal a mechanism by which high glucose enhances signaling through the cancer-associated Wnt/ß-catenin pathway and may explain the increased frequency of cancer associated with obesity and diabetes.

Inflammasome in ALS Skeletal Muscle: NLRP3 as a Potential Biomarker.

Since NLRP3 inflammasome plays a pivotal role in several neurodegenerative disorders, we hypothesized that levels of inflammasome components could help in diagnosis or prognosis of amyotrophic lateral sclerosis (ALS). Gene and protein expression was assayed by RT-PCR and Western blot. Spearman's correlation coefficient was used to determine the linear correlation of transcriptional expression levels with longevity throughout disease progression in mice models. Kaplan-Meier analysis was performed to evaluate MCC950 effects (NLRP3 inhibitor) on lifespan of SOD1G93A mice. The results showed significant alterations in NLRP3 inflammasome gene and protein levels in the skeletal muscle of SOD1G93A mice. Spearman's correlation coefficient revealed a positive association between Nlrp3 transcriptional levels in skeletal muscle and longevity of SOD1G93A mice (r = 0.506; p = 0.027). Accordingly, NLRP3 inactivation with MCC950 decreased the lifespan of mice. Furthermore, NLRP3 mRNA levels were significantly elevated in the blood of ALS patients compared to healthy controls (p = 0.03). In conclusion, NLRP3 could be involved in skeletal muscle pathogenesis of ALS, either through inflammasome or independently, and may play a dual role during disease progression. NLRP3 gene expression levels could be used as a biomarker to improve diagnosis and prognosis in skeletal muscle from animal models and also to support diagnosis in clinical practice with the blood of ALS patients.

Gene therapy for overexpressing Neuregulin 1 type I in skeletal muscles promotes functional improvement in the SOD1G93A ALS mice.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motoneurons (MNs), with no effective treatment currently available. The molecular mechanisms that are involved in MN death are complex and not fully understood, with partial contributions of surrounding glial cells and skeletal muscle to the disease. Neuregulin 1 (NRG1) is a trophic factor highly expressed in MNs and neuromuscular junctions. Recent studies have suggested a crucial role of the isoform I (NRG1-I) in the collateral reinnervation process in skeletal muscle, and NRG1-III in the preservation of MNs in the spinal cord, opening a window for developing novel therapies for neuromuscular diseases like ALS. In this study, we overexpressed NRG1-I widely in the skeletal muscles of the SOD1G93A transgenic mouse. The results show that NRG1 gene therapy activated the survival pathways in muscle and spinal cord, increasing the number of surviving MNs and neuromuscular junctions and reducing the astroglial reactivity in the spinal cord of the treated SOD1G93A mice. Furthermore, NRG1-I overexpression preserved motor function and delayed the onset of clinical disease. In summary, our data indicates that NRG1 plays an important role on MN survival and muscle innervation in ALS, and that viral-mediated overexpression of NRG1 isoforms may be considered as a promising approach for ALS treatment.