Metabolic Pathways as a Novel Landscape in Pancreatic Ductal Adenocarcinoma

Metabolism plays a fundamental role in both human physiology and pathology, including pancreatic ductal adenocarcinoma (PDAC) and other tumors. Anabolic and catabolic processes do not only have energetic implications but are tightly associated with other cellular activities, such as DNA duplication, redox reactions, and cell homeostasis. PDAC displays a marked metabolic phenotype and the observed reduction in tumor growth induced by calorie restriction with in vivo models supports the crucial role of metabolism in this cancer type. The aggressiveness of PDAC might, therefore, be reduced by interventions on bioenergetic circuits. In this review, we describe the main metabolic mechanisms involved in PDAC growth and the biological features that may favor its onset and progression within an immunometabolic context. We also discuss the need to bridge the gap between basic research and clinical practice in order to offer alternative therapeutic approaches for PDAC patients in the more immediate future

Earthquake source kinematics of moderate earthquakes from the inversion of apparent source time functions

We present an approach to infer the slip and rupture velocity distributions on the fault plane from the non-linear inversion of the apparent source time functions, obtained from the empirical Green???s function deconvolution method. The main advantage of this technique is that it allows overcoming, in the forward modelling, the limitations related to the computation of the Green???s function, as the choice of a correct and reliable earth propagation model. We perform a parameter resolution and uncertainty study, which is based on the analysis of the misfit function in the neighbourhood of the best-fitting model. In this paper, we present the results obtained by applying the technique to synthetic and real records from an Mw 4 event which occurred during the 2009 L???Aquila (central Italy) aftershock sequence. Results show a heterogeneous slip distribution, characterized by two main high slip patches located NW of the hypocentre and an average slip of 3.7 cm, corresponding to a seismic model of about 0.82 × 10^15 Nm

HDAC6 Inhibition Extinguishes Autophagy in Cancer: Recent Insights

Autophagy is an essential intracellular catabolic mechanism involved in the degradation and recycling of damaged organelles regulating cellular homeostasis and energy metabolism. Its activation enhances cellular tolerance to various stresses and is known to be involved in drug resistance. In cancer, autophagy has a dual role in either promoting or blocking tumorigenesis, and recent studies indicate that epigenetic regulation is involved in its mechanism of action in this context. Specifically, the ubiquitin-binding histone deacetylase (HDAC) enzyme HDAC6 is known to be an important player in modulating autophagy. Epigenetic modulators, such as HDAC inhibitors, mediate this process in different ways and are already undergoing clinical trials. In this review, we describe current knowledge on the role of epigenetic modifications, particularly HDAC-mediated modifications, in controlling autophagy in cancer. We focus on the controversy surrounding their ability to promote or block tumor progression and explore the impact of HDAC6 inhibitors on autophagy modulation in cancer. In light of the fact that targeted drug therapy for cancer patients is attracting ever increasing interest within the research community and in society at large, we discuss the possibility of using HDAC6 inhibitors as adjuvants and/or in combination with conventional treatments to overcome autophagy-related mechanisms of resistance

Histone lysine demethylase inhibition reprograms prostate cancer metabolism and mechanics

Objective: Aberrant activity of androgen receptor (AR) is the primary cause underlying development and progression of prostate cancer (PCa) and castration-resistant PCa (CRPC). Androgen signaling regulates gene transcription and lipid metabolism, facilitating tumor growth and therapy resistance in early and advanced PCa. Although direct AR signaling inhibitors exist, AR expression and function can also be epigenetically regulated. Specifically, lysine (K)-specific demethylases (KDMs), which are often overexpressed in PCa and CRPC phenotypes, regulate the AR transcriptional program.Methods: We investigated LSD1/UTX inhibition, two KDMs, in PCa and CRPC using a multi-omics approach. We first performed a mitochondrial stress test to evaluate respiratory capacity after treatment with MC3324, a dual KDM-inhibitor, and then carried out lipidomic, proteomic, and metabolic analyses. We also investigated mechanical cellular properties with acoustic force spectroscopy. Results: MC3324 induced a global increase in H3K4me2 and H3K27me3 accompanied by significant growth arrest and apoptosis in androgen -responsive and-unresponsive PCa systems. LSD1/UTX inhibition downregulated AR at both transcriptional and non-transcriptional level, showing cancer selectivity, indicating its potential use in resistance to androgen deprivation therapy. Since MC3324 impaired metabolic activity, by modifying the protein and lipid content in PCa and CRPC cell lines. Epigenetic inhibition of LSD1/UTX disrupted mitochondrial ATP production and mediated lipid plasticity, which affected the phosphocholine class, an important structural element for the cell membrane in PCa and CRPC associated with changes in physical and mechanical properties of cancer cells.Conclusions: Our data suggest a network in which epigenetics, hormone signaling, metabolite availability, lipid content, and mechano-metabolic process are closely related. This network may be able to identify additional hotspots for pharmacological intervention and un-derscores the key role of KDM-mediated epigenetic modulation in PCa and CRPC.(c) 2022 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

The Rorschach Test Evaluation in Chronic Childhood Migraine: A Preliminary Multicenter Case–Control Study

ObjectAbout 1.2–3.2% of children at 7 years of age with increasing age up to 4–19% in adolescents are suffering from migraine without aura (MwA). The aim of the present study is investigating the personality style associated with children and adolescents affected by MwA, administrating the Rorschach test, and comparing with typical developing healthy controls (TD).Methods137 patients (74 males), aged 7.3–17.4 years (mean age 11.4, SD 3.02 years), affected by MwA according to the IHs-3 criteria. The Rorschach variables were treated as numerical variables and statistically tested with t-Student’s analysis.ResultsNo statistical differences were found between the MwA and TD for age (p = 0.55), and gender (p = 0.804). From the comparison between the two samples, MwA group shows lower W responses (p < 0.001), good quality W responses (p < 0.001), high frequency of detailed responses (p < 0.001), the presence of even minor form of good quality responses (p < 0.001), increased presence of animals answers (A%) (p < 0.001), more frequent trivial answers (Ban%) (p < 0.001).DiscussionRorschach interpretation pinpointed many interesting and, perhaps, peculiar aspects in our MwA population such as a trend predisposition for: analytical reasoning rather than synthetic, ease/practicality rather than creativity, oppositionality rather than external adaptation to the environment that may be interpreted as effect of general maladaptivity

Sensitivity to Immune Checkpoint Blockade in Advanced Non-Small Cell Lung Cancer Patients with EGFR Exon 20 Insertion Mutations

Besides platinum-based chemotherapy, no established treatment option exists for advanced non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 (Ex20ins) insertion mutations. We sought to determine the clinical outcome of patients with this EGFR mutation subtype in the immunotherapy era. Thirty NSCLCs with EGFR Ex20ins mutations were identified, of whom 15 had received immune checkpoint blockade (ICB) treatment as monotherapy (N = 12), in combination with chemotherapy (N = 2) or with another immunotherapeutic agent (N = 1). The response rate was observed in 1 out of 15 patients (6.7%), median progression-free survival (PFS) was 2.0 months and median overall survival (OS) was 5.3 months. A trend towards an inferior outcome in terms of PFS and OS was observed for patients receiving ICB treatment in the first versus second line setting (PFS: 1.6 months versus 2.7 months, respectively, p = 0.16—OS: 2.0 months versus 8.1 months, respectively, p = 0.09). Median OS from the time of diagnosis of advanced disease was shorter for patients treated with ICB versus those who did not receive immunotherapy (12.9 months versus 25.2 months, respectively, p = 0.08), which difference remained associated with a worse survival outcome at multivariate analysis (p = 0.04). Treatment with ICB is poorly effective in NSCLCs with EGFR Ex20ins mutations, especially when given in the first-line setting. This information is crucial in order to select the optimal treatment strategy for patients with this subtype of EGFR mutation