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Simple Summary: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related morbidity and mortality. In the last decade, a breakthrough in the treatment landscape of HCC has been experienced. The unprecedented number of therapeutic options for advanced stages has made the selection of sequence strategies more complex and the need for biomarkers of treatment response or tumor escape more urgent. The understanding of molecular events leading to drug resistance has identified noncoding RNAs as promising therapeutic targets. Preclinical studies testing the combined efficacy of noncoding RNAs and clinically available drugs represent a crucial step to prevent/limit the onset of drug resistance in advanced cases. The incidence of hepatocellular carcinoma (HCC) is increasing, and 40% of patients are diagnosed at advanced stages. Over the past 5 years, the number of clinically available treatments has dramatically increased for HCC, making patient management particularly complex. Immune checkpoint inhibitors (ICIs) have improved the overall survival of patients, showing a durable treatment benefit over time and a different response pattern with respect to tyrosine kinase inhibitors (TKIs). Although there is improved survival in responder cases, a sizeable group of patients are primary progressors or are ineligible for immunotherapy. Indeed, patients with nonviral etiologies, such as nonalcoholic steatohepatitis (NASH), and alterations in specific driver genes might be less responsive to immunotherapy. Therefore, improving the comprehension of mechanisms of drug resistance and identifying biomarkers that are informative of the best treatment approach are required actions to improve patient survival. Abundant evidence indicates that noncoding RNAs (ncRNAs) are pivotal players in cancer. Molecular mechanisms through which ncRNAs exert their effects in cancer progression and drug resistance have been widely investigated. Nevertheless, there are no studies summarizing the synergistic effect between ncRNA-based strategies and TKIs or ICIs in the preclinical setting. This review aims to provide up-to-date information regarding the possible use of ncRNAs as therapeutic targets in association with molecular-targeted agents and immunotherapies and as predictive tools for the selection of optimized treatment options in advanced HCCs. [ABSTRACT FROM AUTHOR]

Background: Research has shown that potential perpetrators and individuals high in psychopathic traits tend to body language cues to target a potential new victim. However, whether targeting occurs also by tending to vocal cues has not been examined. Thus, the role of voice in interpersonal violence merits investigation. Objective: In two studies, we examined whether perpetrators could differentiate female speakers with and without sexual and physical assault histories (presented as rating the degree of ‘vulnerability’ to victimization). Methods: Two samples of male listeners (sample one N = 105, sample two, N = 109) participated. Each sample rated 18 voices (9 survivors and 9 controls). Listener sample one heard spontaneous speech, and listener sample two heard the second sentence of a standardized passage. Listeners’ self-reported psychopathic traits and history of previous perpetration were measured. Results: Across both samples, history of perpetration (but not psychopathy) predicted accuracy in distinguishing survivors of assault. Conclusions: These findings highlight the potential role of voice in prevention and intervention. Gaining a further understanding of what voice cues are associated with accuracy in discerning survivors can also help us understand whether or not specialized voice training could have a role in self-defense practices. [ABSTRACT FROM AUTHOR]

Foreign body ingestion in the upper digestive tract is a relatively common emergency. Less than 1% have to be treated surgically. We report the case of a 68-year-old man who ingested a dental prosthesis, probably during a seizure, and thus unknowingly, and presented two days later to the emergency department complaining of a mild dysphagia. A chest radiograph showed the presence of a removable dental prosthesis in the upper esophageal tract. The patient was brought to the operating room where a multidisciplinary equipe was assembled. Two attempts of retrieval with a flexible and a rigid endoscope failed because the removable dental prosthesis was stuck in the right pyriform sinus. Therefore, the surgeon performed an uncommon right cervicotomy and retrieved the foreign body through a right-side esophagotomy. The surgical approach depends on the nature and location of the foreign body. Urgent treatment is required whenever the patient develops dyspnea or dysphagia because of the high risk of inhalation and asphyxia. Removal of any esophageal foreign body has to be performed within 12–24 h. Repeated attempts to retrieve large dental prosthesis using an endoscope may result in esophageal perforation therefore when such risk of complication is too high, a surgical approach becomes inevitable. In our opinion, surgery remains the extrema ratio after a failed endoscopic retrieval attempt but can be lifesaving despite high risk of complications. [ABSTRACT FROM AUTHOR]

Nonverbal markers of childhood trauma have been identified in the literature. Yet, the relationship between childhood trauma and the voice is still largely unexplored. We report preliminary findings from a study (N = 48) that investigated whether self-reported childhood trauma is related to acoustic measures on sustained phonation before and after childhood trauma recall. Childhood trauma and minimization/denial of trauma were measured using the Childhood Trauma Questionnaire. Measures of voice (fundamental frequency, related to pitch, and perturbation, or "unsteadiness" in voice sustained phonation) were obtained using voice analysis software lingWAVES. Self-reported trait and state anxiety were also measured, using the State and Trait Anxiety Inventory. Results showed that voice fundamental frequency at baseline was related to self-reported minimization of childhood trauma. Childhood trauma and minimization of childhood trauma were significantly related to voice perturbation measures recorded after trauma recall, accounting for baseline voice measures and self-reported anxiety. These preliminary results indicate the importance of studying voice as a potential nonverbal marker of childhood trauma. [ABSTRACT FROM AUTHOR]

This article addresses the notable yet unexplored similarities between dialogical self theory (DST) in psychotherapy and the therapeutic approaches of vocal psychotherapy, a voice-based model of music psychotherapy developed by Diane Austin. Particularly - to address the similitudes and also the differences between these two domains - we aim at stressing the importance of musicality in voicing what DST calls I-positions (which can be compared to “parts of the self”) and stimulating them to engage in musical dialogue in vocal psychotherapy. Diane Austin’s techniques such as “vocal holding” and “free associative singing” can offer a unique and important perspective on DST. In vocal psychotherapy, the “dialogical” interplay is brought to a profound and musical level and it offers traumatized parts of the psyche a unique way to voice their existence and eventually become integrated into a more complete self. [ABSTRACT FROM AUTHOR]

Research shows that negative experiences in childhood have a long-lasting impact on one’s psychological outcomes and one’s physiology. The voice is a crucial means of expression, and its complex physiology is believed to be reflective of emotional and mental states. Parenting practices (particularly those contributing to insecure attachment) and traumatic experiences in childhood may thus also influence vocal characteristics. Except for literature on psychogenic voice disorders, the relationship between such experiences and the ‘normal’ voice is generally unexplored; we propose that a potential relationship is most likely to emerge in singers, for whom the voice is a more central part of their sense of self. In this paper, we test the hypothesis that vocal characteristics relate to attachment and trauma history. Study 1: 25 singers (age 18–35) completed an attachment history questionnaire (ECR-R) and the Singing Voice Handicap Index. Voice range profile and perturbation measures were recorded and analyzed for voice quality assessment. Study 2: 26 singers (age 19–33) completed the attachment history questionnaire, the Childhood Trauma Questionnaire, and the State and Trait Anxiety Inventory. They were also administered the Test of Self-Conscious Affect to assess shame and guilt proneness. Voice range profile, perturbation, and spectrogram measures were recorded and analyzed. The results indicated that anxious attachment, shame, and emotional neglect can predict vocal acoustic measures of intensity and, to some extent, perturbation. This suggests the need to address attachment, shame, and trauma history patterns in the aspiring performer. [ABSTRACT FROM PUBLISHER]

The drug discovery and development process is still long, costly, and highly risky. The principal attrition factor is undetected toxicity, with hepatic and cardiac toxicities playing a critical role and being the main responsible of safetyrelated drug withdrawals from the market. Multi Organs-on-Chip (MOoC) represent a disruptive solution to study drug-related effects on several organs simultaneously and to efficiently predict drug toxicity in preclinical trials. Specifically focusing on drug safety, different technological features are applied here to develop versatile MOoC platforms encompassing two culture chambers for generating and controlling the type of communication between a metabolically competent liver model and a functional 3D heart model. The administration of the drug Terfenadine, a cardiotoxic compound liver-metabolized into the noncardiotoxic Fexofenadine, proves that liver metabolism and a fine control over drug diffusion are fundamental to elicit a physio-pathological cardiac response. From these results, an optimized LivHeart platform is developed to house a liver model and a cardiac construct that can be mechanically trained to achieve a beating microtissue, whose electrophysiology can be directly recorded in vitro. The platform is proved able to predict off-target cardiotoxicity of Terfenadine after liver metabolism both in terms of cell viability and functionality. [ABSTRACT FROM AUTHOR]

Background: Metabolic reprogramming is a well-known marker of cancer, and it represents an early event during hepatocellular carcinoma (HCC) development. The recent approval of several molecular targeted agents has revolutionized the management of advanced HCC patients. Nevertheless, the lack of circulating biomarkers still affects patient stratification to tailored treatments. In this context, there is an urgent need for biomarkers to aid treatment choice and for novel and more effective therapeutic combinations to avoid the development of drug-resistant phenotypes. This study aims to prove the involvement of miR-494 in metabolic reprogramming of HCC, to identify novel miRNA-based therapeutic combinations and to evaluate miR-494 potential as a circulating biomarker. Methods: Bioinformatics analysis identified miR-494 metabolic targets. QPCR analysis of glucose 6-phosphatase catalytic subunit (G6pc) was performed in HCC patients and preclinical models. Functional analysis and metabolic assays assessed G6pc targeting and miR-494 involvement in metabolic changes, mitochondrial dysfunction, and ROS production in HCC cells. Live-imaging analysis evaluated the effects of miR-494/G6pc axis in cell growth of HCC cells under stressful conditions. Circulating miR-494 levels were assayed in sorafenib-treated HCC patients and DEN-HCC rats. Results: MiR-494 induced the metabolic shift of HCC cells toward a glycolytic phenotype through G6pc targeting and HIF-1A pathway activation. MiR-494/G6pc axis played an active role in metabolic plasticity of cancer cells, leading to glycogen and lipid droplets accumulation that favored cell survival under harsh environmental conditions. High miR-494 serum levels associated with sorafenib resistance in preclinical models and in a preliminary cohort of HCC patients. An enhanced anticancer effect was observed for treatment combinations between antagomiR-494 and sorafenib or 2-deoxy-glucose in HCC cells. Conclusions: MiR-494/G6pc axis is critical for the metabolic rewiring of cancer cells and associates with poor prognosis. MiR-494 deserves attention as a candidate biomarker of likelihood of response to sorafenib to be tested in future validation studies. MiR-494 represents a promising therapeutic target for combination strategies with sorafenib or metabolic interference molecules for the treatment of HCC patients who are ineligible for immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Problems in learning that sights, sounds, or situations that were once associated with danger have become safe (extinction learning) may explain why some individuals suffer prolonged psychological distress following traumatic experiences. Although simple learning models have been unable to provide a convincing account of why this learning fails, it has recently been proposed that this may be explained by individual differences in beliefs about the causal structure of the environment. Methods: Here, we tested two competing hypotheses as to how differences in causal inference might be related to trauma-related psychopathology, using extinction learning data collected from clinically well-characterised individuals with varying degrees of post-traumatic stress (N = 56). Model parameters describing individual differences in causal inference were related to multiple post-traumatic stress disorder (PTSD) and depression symptom dimensions via network analysis. Results: Individuals with more severe PTSD were more likely to assign observations from conditioning and extinction stages to a single underlying cause. Specifically, greater re-experiencing symptom severity was associated with a lower likelihood of inferring that multiple causes were active in the environment. Conclusions: We interpret these results as providing evidence of a primary deficit in discriminative learning in participants with more severe PTSD. Specifically, a tendency to attribute a greater diversity of stimulus configurations to the same underlying cause resulted in greater uncertainty about stimulus-outcome associations, impeding learning both that certain stimuli were safe, and that certain stimuli were no longer dangerous. In the future, better understanding of the role of causal inference in trauma-related psychopathology may help refine cognitive therapies for these disorders. [ABSTRACT FROM AUTHOR]