Hypoxia and inflammation as a consequence of β-fibril accumulation. A perspective view for new potential therapeutic targets

Amyloidoses are heterogeneous diseases that result from the deposition of toxic insoluble β-sheet fibrillar protein aggregates in different tissues. The cascade of molecular events leading to amyloidoses and to the related clinical manifestations is not completely understood. Nevertheless, it is known that tissue damage associated to this disease involves alteration of tissue architecture, interaction with cell surface receptors, inflammation elicited by the amyloid protein deposition, oxidative stress, and apoptosis. However, another important aspect to consider is that systemic protein massive deposition not only subverts tissue architecture but also determines a progressive cellular hypertrophy and dilation of the extracellular space enlarging the volume of the organ. Such an alteration increases the distance between cells and vessels with a drop in pO2 that, in turn, causes both necrotic cell death and activation of the hypoxia transcription factor HIF-1α. Herewith, we propose the hypothesis that both cell death and hypoxia represent two important events for the pathogenesis of damage and progression of amyloidoses. In fact, molecules released by necrotic cells activate inflammatory cells from one side while binding to HIF-1α-dependent membrane receptors expressed on hypoxic parenchymal cells on the other side. This latter event generates a signaling cascade triggering NFκB activation and chronic inflammation. Finally, we also suggest that this scenario, once proved and detailed, might suggest important targets for new therapeutic interventions

Use of an anatomical mid-sagittal plane for 3-dimensional cephalometry: a preliminary study

Purpose: Cone-beam computed tomography (CBCT) is widely used for 3-dimensional assessments of cranio-maxillo-facial relationships, especially in patients undergoing orthognathic surgery. We have introduced, for reference in CBCT cephalometry, an anatomical mid-sagittal plane (MSP) identified by the nasion, the midpoint between the posterior clinoid processes of the sella turcica, and the basion. The MSP is an updated version of the median plane previously used at our institution for 2D posterior-anterior cephalometry. This study was conducted to test the accuracy of the CBCT measures compared to those obtained using standard posterior-anterior cephalometry.Materials and Methods: Two operators measured the inter-zygomatic distance on 15 CBCT scans using the MSP as a reference plane, and the CBCT measurements were compared with measurements made on patients' posterior-anterior cephalograms. The statistical analysis evaluated the absolute and percentage differences between the 3D and 2D measurements.Results: As demonstrated by the absolute mean difference (roughly 1 mm) and the percentage difference (less than 3%), the MSP showed good accuracy on CBCT compared to the 2D plane, especially for measurements of the left side. However, the CBCT measurements showed a high standard deviation, indicating major variability and low precision.Conclusion: The anatomical MSP can be used as a reliable reference plane for transverse measurements in 3D cephalometry in cases of symmetrical or asymmetrical malocclusion. In patients who suffer from distortions of the skull base, the identification of landmarks might be difficult and the MSP could be unreliable. Becoming familiar with the relevant software could reduce errors and improve reliability

Study of the maxillary yaw on cone beam computed tomography: a preliminary report and comparison between two different dento‐skeletal malocclusions

Objectives: To assess the skeletal and dental maxillary transverse compensation (yaw) on the cone beam computed tomography (CBCT) three-dimensional reconstructed image of the skull in two groups of patients, both clinically affected by a class III malocclusion with deviation of the lower midline.Materials and Methods: An observational retrospective study was designed to analyse differences in two groups of patients, the first one was composed by patients affected by horizontal condylar hyperplasia, the second one by patients affected by dento-skeletal asymmetric class III malocclusion. Each group was composed by 15 patients. Transverse analysis was performed by measuring five landmarks (three bilateral and two uneven) with respect to a mid-sagittal plane; sagittal analysis was performed by measuring the sagittal distance on the mid-sagittal plane between bilateral points. Means were compared through inferential analysis.Results: In the condylar hyperplasia group, all differences between the two sides were not statistically significant, nor for canines' difference (P = .0817), for molars (P = .1105) or for jugular points (.05871). In the class III group, the differences between the two sides were statistically significant for molars (P = .0019) and jugular points (P = .0031) but not for canines (P = .1158). Comparing the two groups, significant differences were found only for incisors' midline deviation (P = .0343) and canine (P = .0177).Conclusion: The study of the yaw on CBCT should be integrated into three-dimensional cephalometry and could help in differentiating the various malocclusion patterns

SIRT1-NOX4 Signaling Axis Regulates Cancer Cachexia

Approximately one third of cancer patients die due to complexities related to cachexia. However, the mechanisms of cachexia and the potential therapeutic interventions remain poorly studied. We observed a significant positive correlation between SIRT1 expression and muscle fiber cross-sectional area in pancreatic cancer patients. Rescuing Sirt1 expression by exogenous expression or pharmacological agents reverted cancer cell-induced myotube wasting in culture conditions and mouse models. RNA-seq and follow-up analyses showed cancer cell-mediated SIRT1 loss induced NF-κB signaling in cachectic muscles that enhanced the expression of FOXO transcription factors and NADPH oxidase 4 (Nox4), a key regulator of reactive oxygen species production. Additionally, we observed a negative correlation between NOX4 expression and skeletal muscle fiber cross-sectional area in pancreatic cancer patients. Knocking out Nox4 in skeletal muscles or pharmacological blockade of Nox4 activity abrogated tumor-induced cachexia in mice. Thus, we conclude that targeting the Sirt1-Nox4 axis in muscles is an effective therapeutic intervention for mitigating pancreatic cancer-induced cachexia

Metabolic Rewiring by Loss of Sirt5 Promotes Kras-induced Pancreatic Cancer Progression.

BACKGROUND & AIMS: SIRT5 plays pleiotropic roles via post-translational modifications, serving as a tumor suppressor, or an oncogene, in different tumors. However, the role SIRT5 plays in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) remains unknown. METHODS: Published datasets and tissue arrays with SIRT5 staining were used to investigate the clinical relevance of SIRT5 in PDAC. Furthermore, to define the role of SIRT5 in the carcinogenesis of PDAC, we generated autochthonous mouse models with conditional Sirt5 knockout. Moreover, to examine the mechanistic role of SIRT5 in PDAC carcinogenesis, SIRT5 was knocked down in PDAC cell lines and organoids, followed by metabolomics and proteomics studies. A novel SIRT5 activator was utilized for therapeutic studies in organoids and patient-derived xenografts. RESULTS: SIRT5 expression negatively regulated tumor cell proliferation and correlated with a favorable prognosis in PDAC patients. Genetic ablation of Sirt5 in PDAC mouse models promoted acinar-to-ductal metaplasia, precursor lesions, and pancreatic tumorigenesis, resulting in poor survival. Mechanistically, SIRT5 loss enhanced glutamine and glutathione metabolism via acetylation-mediated activation of GOT1. A selective SIRT5 activator, MC3138, phenocopied the effects of SIRT5 overexpression and exhibited anti-tumor effects on human PDAC cells. MC3138 also diminished nucleotide pools, sensitizing human PDAC cell lines, organoids, and patient-derived xenografts to gemcitabine. CONCLUSIONS: Collectively, we identify SIRT5 as a key tumor suppressor in PDAC, whose loss promotes tumorigenesis through increased non-canonical utilization of glutamine via GOT1, and that SIRT5 activation is a novel therapeutic strategy to target PDAC

Sirtuins' control of autophagy and mitophagy in cancer

Mammalian cells use a specialized and complex machinery for the removal of altered proteins or dysfunctional organelles. Such machinery is part of a mechanism called autophagy. Moreover, when autophagy is specifically employed for the removal of dysfunctional mitochondria, it is called mitophagy. Autophagy and mitophagy have important physiological implications and roles associated with cellular differentiation, resistance to stresses such as starvation, metabolic control and adaptation to the changing microenvironment. Unfortunately, transformed cancer cells often exploit autophagy and mitophagy for sustaining their metabolic reprogramming and growth to a point that autophagy and mitophagy are recognized as promising targets for ongoing and future antitumoral therapies. Sirtuins are NAD+ dependent deacylases with a fundamental role in sensing and modulating cellular response to external stresses such as nutrients availability and therefore involved in aging, oxidative stress control, inflammation, differentiation and cancer. It is clear, therefore, that autophagy, mitophagy and sirtuins share many common aspects to a point that, recently, sirtuins have been linked to the control of autophagy and mitophagy. In the context of cancer, such a control is obtained by modulating transcription of autophagy and mitophagy genes, by post translational modification of proteins belonging to the autophagy and mitophagy machinery, by controlling ROS production or major metabolic pathways such as Krebs cycle or glutamine metabolism. The present review details current knowledge on the role of sirtuins, autophagy and mitophagy in cancer to then proceed to discuss how sirtuins can control autophagy and mitophagy in cancer cells. Finally, we discuss sirtuins role in the context of tumor progression and metastasis indicating glutamine metabolism as an example of how a concerted activation and/or inhibition of sirtuins in cancer cells can control autophagy and mitophagy by impinging on the metabolism of this fundamental amino acid

Characteristics of the bone components of the temporomandibular joint and its relationship with the vertical skeletal pattern in adolescents. A computed tomography study

Aim: The temporomandibular joint (TMJ) is a joint formed by the mandibular condyle and the glenoid cavity of the temporal bone. Several factors affect the morphology of the TMJ components. A relationship between the characteristics of the bone components of the temporomandibular joint and the craniofacial skeletal characteristics has been reported. Objective: The aim of the present study was to verify the relationship between the characteristics of the bone components of the TMJ and the vertical skeletal pattern in adolescent patients. Method: A total of 45 adolescent patients (16.20 ± 1.91 years of age), 13 males and 32 females, were divided into 3 groups according to their vertical skeletal pattern: 15 normodivergent, 15 hyperdivergent and 15 hypodivergent. The TMJ was evaluated in computed tomography (CT) images, the anteroposterior and lateromedial dimensions of the condyle and the anteroposterior dimension and high of the glenoid cavity were measured. The t-Student test was used to compare the measurements of the right and left sides and between the genders, and the ANOVA test was used to evaluate the correlation between condylar and glenoid cavity measurements with the vertical skeletal pattern and the post-hoc Turkey’s test was used to identify the correlation between groups. Results: No statistical difference was found in the measurements of the condyle and glenoid cavity on the right and left sides, so a mean between both sides was used. A statistically signifcant relationship was observed between the medial-lateral dimension of the condyle and the skeletal pattern (P = 0.000), in the paired comparisons a statistical difference of this dimension was observed between hypodivergent and hyperdivergent. The rest of the variables studied did not present a statistically signifcant difference. Conclusion:The lateromedial dimension of the mandibular condyle is greater in hypodivergent patients and lower hyperdivergent patients. The anteroposterior dimension of the condyle and the measurements of the glenoid cavity did not present a correlation with the vertical skeletal pattern in the adolescent

Dimensions of the mandibular condyle and the glenoid cavity in the different sagittal skeletal patterns in adolescents. A computed tomography study

Aim: The characteristics of the temporomandibular joint (TMJ) are modifed as a consequence of different factors. The sagittal skeletal pattern has been related to the dimensions of the osseous components of the TMJ. Objective: The aim of this study was to evaluate the relationship between the dimension of the mandibular condyle and the glenoid cavity and the sagittal skeletal pattern in adolescents. Methods: 40 adolescent patients, between 11 and 19 years old, 12 males and 28 females, were evaluated. They were divided into three groups according to the ANB angle: 15 Class I (ANB 0 ° - 4 °), 15 Class II (> 4°) and 10 Class III (<0 °). The width and length of the condyle and the width and depth of the glenoid cavity were measured using computed tomography images. By the t-Student test, the means of the measures of the right and left side were compared. Through the ANOVA test, the means of the measurements of the condyle and the glenoid cavity were analyzed according to the vertical skeletal pattern and the post-hoc Bonferroni test was used to identify the group correlations. Results: No signifcant difference was found between the right and left side averages, so the mean between sides was used for the analysis. A correlation was obtained between the depth of the glenoid cavity and the sagittal skeletal pattern (P = 0.009), was deeper in Class III and less in Class II. The rest of the variables studied did not present a statistically signifcant correlation with the sagittal skeletal pattern. Conclusions: The depth of the glenoid cavity is greater in Class III subjects and less deep in those Class II. The dimensions of the condyle and the width of the glenoid cavity did not show a statistically signifcant relationship with the sagittal skeletal pattern in the adolescents studie