Autophagy sustains mitochondrial respiration and determines resistance to BRAFV600E inhibition in thyroid carcinoma cells.

BRAFV600E is the most prevalent mutation in thyroid cancer and correlates with poor prognosis and therapy resistance. Although selective inhibitors of BRAFV600E have been developed, more advanced tumors such as anaplastic thyroid carcinomas show a poor response in clinical trials. Therefore, the study of alternative survival mechanisms is needed. Since metabolic changes have been related to malignant progression, in this work we explore metabolic dependencies of thyroid tumor cells to exploit them therapeutically. Our results show that respiration of thyroid carcinoma cells is highly dependent on fatty acid oxidation and, in turn, fatty acid mitochondrial availability is regulated through macroautophagy/autophagy. Furthermore, we show that both lysosomal inhibition and the knockout of the essential autophagy gene, ATG7, lead to enhanced lipolysis; although this effect is not essential for survival of thyroid carcinoma cells. We also demonstrate that following inhibition of either autophagy or fatty acid oxidation, thyroid tumor cells compensate oxidative phosphorylation deficiency with an increase in glycolysis. In contrast to lipolysis induction, upon autophagy inhibition, glycolytic boost in autophagy-deficient cells is essential for survival and, importantly, correlates with a higher sensitivity to the BRAFV600E selective inhibitor, vemurafenib. In agreement, downregulation of the glycolytic pathway results in enhanced mitochondrial respiration and vemurafenib resistance. Our work provides new insights into the role of autophagy in thyroid cancer metabolism and supports mitochondrial targeting in combination with vemurafenib to eliminate BRAFV600E-positive thyroid carcinoma cells.Abbreviations: AMP: adenosine monophosphate; ATC: anaplastic thyroid carcinoma; ATG: autophagy related; ATP: adenosine triphosphate; BRAF: B-Raf proto-oncogene, serine/threonine kinase; Cas9: CRISPR-associated protein; CREB: cAMP responsive element binding protein; CRISPR: clustered regularly interspaced short palindromic repeats; 2DG: 2-deoxyglucose; FA: fatty acid; FAO: fatty acid oxidation; FASN: fatty acid synthase; FCCP: trifluoromethoxy carbonyl cyanide phenylhydrazone; LAMP1: lysosomal associated membrane protein 1; LIPE/HSL: lipase E, hormone sensitive type; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation; PRKA/PKA: protein kinase cAMP-activated; PTC: papillary thyroid carcinoma; SREBF1/SREBP1: sterol regulatory element binding transcription factor 1.

Borderline, where are you? A psychometric approach to the personality domains in the International Classification of Diseases, 11th Revision (ICD-11).

The inclusion of the borderline pattern in the International Classification of Diseases, 11th Revision (ICD-11) dimensional classification of personality disorders (PDs) has caused controversy. Unease about leaving out these clinically challenging patients seems to conflict with the need of an evidence-based and credible diagnostic system. However, the accommodation of borderline within the new diagnostic system has not yet been studied in depth. To this end, we examine in a sample of 1799 general population and clinical subjects the joint structure of the five initial ICD-11 domains and the borderline pattern. Regression and item-level factor analyses reveal that borderline criteria do not form a separate construct and are indissociable from negative affectivity. Furthermore, borderline adds nothing to the remaining domains when it comes to predict PD severity. The borderline pattern appears as largely superfluous and even misguiding, unless their criteria are properly integrated within the structure of personality pathology. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A Double-Track Pathway to Fast Strategy in Humans and Its Personality Correlates.

The fast-slow paradigm of life history (LH) focuses on how individuals grow, mate, and reproduce at different paces. This paradigm can contribute substantially to the field of personality and individual differences provided that it is more strictly based on evolutionary biology than it has been so far. Our study tested the existence of a fast-slow continuum underlying indicators of reproductive effort-offspring output, age at first reproduction, number and stability of sexual partners-in 1,043 outpatients with healthy to severely disordered personalities. Two axes emerged reflecting a double-track pathway to fast strategy, based on restricted and unrestricted sociosexual strategies. When rotated, the fast-slow and sociosexuality axes turned out to be independent. Contrary to expectations, neither somatic effort-investment in status, material resources, social capital, and maintenance/survival-was aligned with reproductive effort, nor a clear tradeoff between current and future reproduction was evident. Finally, we examined the association of LH axes with seven high-order personality pathology traits: negative emotionality, impulsivity, antagonism, persistence-compulsivity, subordination, and psychoticism. Persistent and disinhibited subjects appeared as fast-restricted and fast-unrestricted strategists, respectively, whereas asocial subjects were slow strategists. Associations of LH traits with each other and with personality are far more complex than usually assumed in evolutionary psychology.

Dicer ablation in Kiss1 neurons impairs puberty and fertility preferentially in female mice.

Kiss1 neurons, producing kisspeptins, are essential for puberty and fertility, but their molecular regulatory mechanisms remain unfolded. Here, we report that congenital ablation of the microRNA-synthesizing enzyme, Dicer, in Kiss1 cells, causes late-onset hypogonadotropic hypogonadism in both sexes, but is compatible with pubertal initiation and preserved Kiss1 neuronal populations at the infantile/juvenile period. Yet, failure to complete puberty and attain fertility is observed only in females. Kiss1-specific ablation of Dicer evokes disparate changes of Kiss1-cell numbers and Kiss1/kisspeptin expression between hypothalamic subpopulations during the pubertal-transition, with a predominant decline in arcuate-nucleus Kiss1 levels, linked to enhanced expression of its repressors, Mkrn3, Cbx7 and Eap1. Our data unveil that miRNA-biosynthesis in Kiss1 neurons is essential for pubertal completion and fertility, especially in females, but dispensable for initial reproductive maturation and neuronal survival in both sexes. Our results disclose a predominant miRNA-mediated inhibitory program of repressive signals that is key for precise regulation of Kiss1 expression and, thereby, reproductive function.

Aortic Aneurysm as a Cause of Dysphonia in a Patient Who Smokes.

Vocal cord paralysis secondary to a cardiovascular disease is known as Cardiovocal or Ortner's syndrome. The most common cause of Ortner's syndrome is atrial dilation due to mitral valvulopathy. Other causes include aneurysms of the thoracic aorta, patent ductus arteriosus, aneurysm of the ductus arteriosus, defects of the interatrial or interventricular septum, among others. Hoarseness might be the only symptom that leads a given individual to consult with a physician. Here we present the case of a 77-year-old male patient with history of diabetes mellitus type 1 and hypertension, whose illness started about a year ago when he presented progressive dysphonia associated with dry cough after food intake without another concomitant symptom. CT studies reported the presence of an aortic aneurism compressing the left recurrent nerve. Patient refused surgical treatment. As of this writing, he remains symptomatic.

Psychometric Analysis of the Barber Suggestibility Scale in a Clinical Population.

The aim of the study was to administer the Barber suggestibility scale to a clinical population in Spain and to examine its psychometric properties therein. The reliability and factor structure of the adapted scale was compared with that of the original (American) scale and with data from two other versions (British and Puerto Rican samples). Sex differences in suggestibility were also analyzed. The Barber suggestibility scale was administered (without preliminaries) to a sample of 283 patients (130 women, 153 men) with a range of diagnoses: anxiety disorder (33.9%), substance-related and addictive disorder (25.8%), mood disorder (12.7%), somatic symptom disorder (4.6%), trauma- and stress-related disorder (3.5%), and other disorders (19.5%). Results indicated a higher degree of suggestibility among women, with the effect size being low (d = 0.26) for the objective subscale and moderate (d = 0.55) for the subjective subscale. Therefore, normative scores were reported by sex for both subscales. As a whole, the present clinical sample showed higher suggestibility than has been reported previously for nonclinical populations (p < 0.001; d = 1.56). Reliability indices (Cronbach's alpha and split-half/Spearman-Brown) for the present adaptation in a clinical population indicated acceptable internal consistency (range 0.70-0.82). Applied to a clinical sample the Barber suggestibility scale showed a three-factor structure for the objective subscale and a more complex structure for the subjective subscale. These results suggest that the Barber suggestibility scale is a suitable instrument for assessing the degree of suggestibility in persons with a clinical disorder.

Peer counselling versus role-playing: Two training methods of therapeutic skills in clinical psychology.

BACKGROUND: Training programmes for clinical psychologists should include evidence-based teaching methods that enable trainees to learn therapeutic skills. Here we compared the perceived utility of role-playing vs. peer counselling. In peer counselling, one student recounts a personal experience to the other, who thus has the opportunity to act as the therapist in relation to a real situation. Given that sharing such personal experiences may provoke discomfort in students, we also examined this aspect. METHOD: Trainees (n=202) were given both role-play and peer counselling activities as a way of practising empathy and active listening. After completing the skills training programme they completed a questionnaire to assess the extent to which each method had helped them to develop their self-awareness and to acquire these therapeutic skills. RESULTS: In general, peer counselling was considered more useful than role-playing for enhancing self-awareness and personal growth, as well as for learning these professional skills. Regarding the discomfort experienced by students, our data suggest that any initial reluctance to share personal experiences is outweighed by the personal and professional benefits obtained. CONCLUSIONS: Our results indicate that experiential learning involving emotionally charged situations is an effective way of teaching therapeutic skills to clinical and health psychology trainees.