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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.

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.

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., (© 2023. The Author(s).)

Objectives/hypothesis: This exploratory pilot study aimed to probe the relationship between past experiences of trauma in people who self-identify as "laryngoresponders" compared to those who do not. It also explored the communicative context of past traumatic events in laryngoresponders versus non-laryngoresponders., Study Design: Prospective, within-subjects experimental design., Methods: 29 vocally healthy cisgender women (ages 19 to 56) completed a battery of validated self-report measures relating to their past traumatic experiences. Participants also completed two original self-report measures designed to provide insight about (1) where stress tends to manifest in their body and (2) communicative settings of participants' past trauma., Results: Six participants (21%) self-identified a predictable laryngeal and/or vocal response to acute stress and thus comprise the laryngoresponders group. Laryngoresponders exhibited worse scores on 75% of all trauma-related variables compared to non-laryngoresponders, and Emotional Neglect was disproportionately represented in laryngoresponders. Participants with a reported history of childhood Emotional Neglect (83% of laryngoresponders, 35% of nonlaryngoresponders) reported quantitatively "less ideal" communication experiences in the context of past traumatic experiences., Conclusions: Other investigators identify the larynx as a "vulnerable body pathway" for some women. This pilot study of adult women without voice complaints revealed several commonalities amongst self-reported laryngoresponders, and compels further exploration of the voice-trauma relationship., Competing Interests: DECLARATION OF COMPETING INTEREST None., (Copyright © 2022 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The novel coronavirus has a high mortality rate (over 1% for patients older than 50 years). This can only be partially ascribed to other comorbidities. A possible explanation is a factor that assures a prompt response to SARS-CoV-2 in younger people, independent from the novelty of the virus itself. A factor is believed to stimulate the immune system and provide immunity against more antigens. The only external stimulation received by healthy people is vaccination (eg, the diphtheria, tetanus, and pertussis [DTP] vaccine). One hypothesis is that vaccination helps develop specific immunity but generates sprouting immunity against antigens in transit. The underlying immunological phenomena are the "bystander effect" and "trained immunity." The developed immunity gives protection for years until it naturally fades out. After the fifth decade of life, the immune system is almost incompetent when a viral infection occurs, and thus, at this stage, the novel coronavirus can enter the body and cause acute respiratory distress syndrome., Objective: The initial aim is to demonstrate that blood monocytes and natural killer cells show overpowering hyperactivity, while CD4+ and CD8+ T cells experience impediments to their defensive functions in patients with severe SARS-CoV-2 infection. The secondary objectives are to correlate clinical data and vaccination history with laboratory immune patterns in order to identify protective factors. Subsequently, we are also interested in characterizing the phenotypes and state of the degree of activation of peripheral blood mononuclear cells, including monocytes, natural killer cells, and CD4+ and CD8+ T cells, in healthy subjects vaccinated with the Pfizer vaccine., Methods: Data will be collected using the following 3 approaches: (1) an experimental analysis to study the innate immune response and to identify genetic profiles; (2) an epidemiological analysis to identify the patients' vaccination history; and (3) a clinical analysis to detect the immunological profile., Results: The protocol was approved by the Ethics Committee on April 16, 2020, and the study started on April 27, 2020. As of February 2021, enrollment has been completed. Immunological analysis is ongoing, and we expect to complete this analysis by December 2022., Conclusions: We will recognize different populations of patients, each one with a specific immunological pattern in terms of cytokines, soluble factor serum levels, and immune cell activity. Anamnestic data, such as preceding vaccinations and comorbidities, biochemical findings like lymphocyte immunophenotyping, and pre-existing persistent cytomegalovirus infection, allow depicting the risk profile of severe COVID-19. Proof of the roles of these immunological phenomena in the development of COVID-19 can be the basis for the implementation of therapeutic immunomodulatory treatments., Trial Registration: ClinicalTrials.gov NCT04375176; https://clinicaltrials.gov/ct2/show/NCT04375176., International Registered Report Identifier (irrid): DERR1-10.2196/29892., (©Giuseppe Ietto, Lorenzo Mortara, Daniela Dalla Gasperina, Domenico Iovino, Lorenzo Azzi, Andreina Baj, Walter Ageno, Angelo Paolo Genoni, Francesco Acquati, Matteo Gallazzi, Giorgia Spina, Grace Coco, Federica Pierin, Douglas Noonan, Andrea Vigezzi, Elisa Monti, Valentina Iori, Federica Masci, Caterina Franchi, Salomone Di Saverio, Giulio Carcano. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 25.01.2022.)

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.

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.