Rapid Anti-tTG-IgA Screening Test for Early Diagnosis of Celiac Disease in Pediatric Populations.

A large number of patients with celiac disease (CD) remain undiagnosed because they do not fulfill the criteria for entry into the conventional diagnostic workflow. This study evaluated the clinical utility of anti-tissue transglutaminase IgA antibody lateral flow immunoassays (anti-tTG-IgA LFIA) in the undiagnosed-CD-based pediatric population and the impact of a gluten-free diet (GFD) on screening-detected CD. A total of 576 volunteers were tested for anti-tTG-IgA. Gluten consumption habits, CD related symptoms, and risk factors for CD development were evaluated. Volunteers testing positive for anti-tTG-IgA were referred to the conventional CD diagnostic workflow, and the impact of the GFD on health-related quality of life (HR-QoL) was measured. Among them, 13 had a positive anti-tTG-IgA LFIA test result: 11 had confirmed CD (1.91%), one refused confirmatory tests, and another is undergoing diagnosis. Regarding the CD prevalence, no significant differences were observed among risk (1.89%) and symptomatic (2.65%) groups and the entire tested population (1.55%). Rapid anti-tTG-IgA LFIAs could be of clinical utility in primary care for the early identification of children with CD unidentified by the conventional diagnostic workflow. It could potentially reduce the costs of undiagnosed CD, avoiding unnecessary referrals to gastroenterologists, reducing diagnosis delays and long-term problems, and improving patients' HR-QoL.

To the bone: Prevalence and correlates of depression and anxiety among orthopedic residents in Mexico.

OBJECTIVE: The present study examined among orthopedic residents the relationship between the presence of depressive or anxious symptoms and the degree of perfectionism, perceived work-related distress, and involvement in the care of patient(s) who died. METHOD: A cross-sectional online survey based on self-reported measures was used to collect the data from October 2019 to April 2021. RESULTS: The sample consisted of 642 orthopedic residents (50.6% response rate; 70.9% male; average age 29.8 years old). A total of 12.5 and 18.4% reported depressive or anxious symptoms, respectively. On a scale of 0-100, the mean score of perceived work-related distress was 51.9. A third (33.6%) reported being involved in the care of patient(s) who had died. Higher levels of perceived work-related distress and higher scores on the indecision of action/perfectionism dimension were associated with depressive and anxious symptoms. Being involved in the care of patient(s) who had died was associated with having anxious symptoms (OR = 1.79; 95%CI = 1.18-2.72). CONCLUSIONS: These results highlight the need for the systematic monitoring of the mental health status of orthopedic residents in Mexico, particularly those who report a high level of work-related distress or perfectionism or who have recently experienced the death of a patient.

Gender Differences in Professional Adversities and Mental Health Among Surgical and Nonsurgical Medical Trainees: An Internet-Based Survey.

BACKGROUND: Physicians in training face a variety of stressors throughout their professional development and according to their gender. Among them, surgical trainees appear to be especially at risk for mental health problems. OBJECTIVE: The aim of the present study was to compare demographic features, professional activities and adversities, depression, anxiety, and distress among men and women trainees of surgical and nonsurgical medical specialties. DESIGN AND PARTICIPANTS: A cross-sectional, retrospective, comparative study was conducted on a total of 12,424 trainees (68.7% nonsurgical and 31.3% surgical) from Mexico through an online survey. Demographic features, variables related to professional activities and adversities, depression, anxiety, and distress were evaluated through self-administered measures. Comparative analyses using the Cochran-Mantel-Haenszel test for categorical variables and multivariate analysis of variance including medical residency program and gender as fixed factors to test their interaction effect for continuous variables were used. RESULTS: An important interaction between medical specialty and gender was found. Women trainees from surgical specialties report more frequent psychological and physical aggressions. Women from both specialties had higher distress, significant anxiety, and depression than men. Men from surgical specialties worked more hours per day. CONCLUSIONS: Gender differences are evident in trainees for medical specialties, with a larger impact in surgical fields. Mistreatment of students is a pervasive behavior that affects society as a whole, and actions to improve learning and working environments in all medical specialties, but mostly in surgical fields, are urgently needed.

A better way of life: The role of leisure activities on self-perceived health, perceived stress, confidence in stress management, and satisfaction with social support in psychiatrists and psychiatry trainees in Mexico.

Background: Psychiatrists are at high risk of developing burnout and mental health problems mainly due to their emotionally demanding jobs, difficult working conditions, long working hours, and poor work-life balance. As leisure activities are associated with better physical and mental health, engaging in these activities has been recommended as a measure to improve the wellbeing of healthcare workers. However, it is unclear the extent of which psychiatrists and trainees are involved in leisure activities, what type of activities they prefer, or how these impact their self-perceived health, stress, confidence in stress management, and satisfaction with their social support. Objective: The aim of this study was to identify differences in self-perceived health, perceived stress, confidence in stress management, and satisfaction with social support, between psychiatrists and trainees who engage in different leisure activities, compared with those who do not. Methods: This was a cross-sectional study, including Mexican psychiatrists (n = 355) and trainees (n = 330) who agreed to participate through an online survey. Results: 73.1% of participants engaged in some leisure activity, being solitary-passive activities the most reported. Those who have a leisure activity reported lower stress, greater confidence in stress management, and more satisfaction with their social support. Passive-solitary activities were associated with less perceived stress and better confidence in stress management, while active-solitary and social activities were associated with better satisfaction with social support. Conclusion: Psychiatrists' and trainees' wellbeing benefits from engagement in leisure activities, which should be part of their daily schedules to reduce stress, and potentially improve their mental health.

Self-Perceived Mental Health and Perceived Discrimination in Family Physicians and Residents: A Comparative Study Between Men and Women.

INTRODUCTION: The present study aims to examine sex differences in demographic variables, professional activities and adversities, self-reported mental health problems, and perceived discrimination in a sample of family doctors and family medicine residents in Mexico. METHODS: From a larger sample of medical specialists, an analytic, cross-sectional study was conducted with 566 participants, including 317 (56%) family medicine residents and 249 (44%) family doctors in Mexico through an online survey. Demographic features, professional activities and adversities, mental health, and perceived discrimination were examined. Descriptive and comparative analyses were performed. Cramer's V for chi-square tests and Hedge's g for t test were conducted to determine effect sizes. RESULTS: Both sexes displayed similar percentages of professional adversities (such as attending patients with suicidal behavior or who died not by suicide under their care), and a higher number of women reported seeking specialized support to cope with these deaths (Fisher = 0.04). Men perceived greater discrimination (P = .01), worked more hours per day (P < .001) and were more verbally assaulted (P = .04), whereas women reported mental health problems more frequently (P < .001) particularly depression, anxiety, burnout and sleeping problems. Women also reported worse health status (P < .001) when compared with men. CONCLUSION: Family medicine specialists constitute a vulnerable group for mental health problems and perceived discrimination. Particular attention should be paid to how men and women cope with professional adversities to determine whether additional support is required. Interventions should encourage self-care and promote the well-being of health personnel.

The effect of continuation and maintenance electroconvulsive therapy on cognition: A systematic review of the literature and meta-analysis.

BACKGROUND: Electroconvulsive therapy (ECT) is an effective treatment for depression, mania, and refractory schizophrenia. Its tolerability profile is established for acute treatment, but less is known regarding the effects of longer treatment courses, particularly on cognitive performance. OBJECTIVES: To assess the effect of the long-term ECT on cognition. METHODS: We searched CINAHL, EMBASE, PsychInfo and Pubmed, for the period between January 1, 2010, and June 30, 2022, in English or French, for randomized controlled trials, prospective or retrospective studies of ECT continued for at least 2 months for the treatment of mood or schizophrenic disorders and which measured cognition before and at the end of treatment. Non-peer reviewed records were excluded. The Cochrane Risk of Bias tool was used to assess study quality. Classical meta-analyses, with heterogeneity statistics (tau2, I2) were complemented with three level-meta-analysis and Bayesian Meta-analyses. RESULTS: Nine studies were included in the narrative and quantitative review. Controlled comparison at 6 months (k = 6, n = 334) and at 12 months (k = 3, n = 56), within-subject comparisons at 6 (k = 6, n = 218) and 12 months (k = 4, n = 147) showed no detrimental effect of maintenance or continuation ECT on cognition, with little to no heterogeneity. Bayesian analysis further confirmed that data better supported the no effects hypothesis. LIMITATIONS: Insufficient data resulted in imprecision in estimates. CONCLUSIONS: Continuation and maintenance ECT do not appear detrimental for cognitive performance. However, the low number of studies limit the interpretation of the results.

An Indicator of environmental enrichment to measure physical, social and cognitive activities in human daily life.

BACKGROUND: The concept of environmental enrichment (EE) encompasses complex physical, social, cognitive, motor, and somatosensory stimuli to which individuals are differentially exposed. An indicator of EE comprising these elements would facilitate the study of the impact of EE in diverse clinical settings by allowing an easy and comparable measurement. This study aimed to create and test such an EE indicator based on the Florida Cognitive Activities Scale (FCAS), the Multidimensional Social Integration in Later Life Scale (SILLS), and the International Physical Activity Questionnaire (IPAQ). METHODS: Participants with major depression and control subjects were recruited in this cross-sectional comparative study. Depressive symptom severity was assessed with the Hamilton Depression Rating Scale (HAM-D). The EE indicator was used to evaluate cognitive, social, and physical activity. We divided the sample into three levels of cognitive and social activities to construct an EE indicator and compared the obtained scores between participants with major depression and control subjects. RESULTS: 40 patients suffering from major depression and 50 control subjects were included. Higher HAM-D scores were associated with lower EE levels. Cognitive and social items exhibited adequate reliability. Control subjects reported higher scores in all three activities evaluated, except for some items of physical activities. This indicator of EE clearly differentiated between participants with major depression from control subjects. CONCLUSIONS: FCAS, SILLS, and IPAQ used together are valid to evaluate EE. This EE indicator may be a useful tool during clinical practice. The cross-sectional design and the small sample size are limitations of the present study.

Looking for factors affecting functioning in euthymic patients with bipolar I disorder: the importance of cognitive complaints and BDNF's Val66Met polymorphism.

INTRODUCTION: Functioning in Bipolar Disorder (BD) is affected in a substantial proportion of patients. The impact of demographic, clinical, cognitive, and genetic factors on functioning has been shown individually; however, as a complex phenomenon, a global approach to identify the most relevant as well as possible interactions is needed. METHODS: 102 patients with type I BD in euthymia were invited for evaluation of demographic, clinical, and cognitive characteristics as well as genotype for Val66Met polymorphism of BDNF gene to determine those associated with poor functioning according to the FAST scale cut-off score. Clinical evaluation included assessment of residual affective symptoms and anxiety. Cognitive evaluation included the COBRA scale, verbal memory, and executive functions testing. RESULTS: Residual depressive symptoms, anxiety, cognitive complaints and being a Met carrier were more frequent in the poor functioning group and were entered in a logistic regression model. Being a Met carrier (OR=4.46, CI=1.19-16.67) and cognitive complaints (OR=1.29, CI= 1.13-1.46) were the most important predictors of poor functioning in type I BD. LIMITATIONS: Cross-sectional study, with select population limiting generalizability of findings. CONCLUSIONS: A better understanding of underlying factors affecting cognition, including the possible involvement of BDNF Val66Met polymorphism, its systematic evaluation and a continued search for targeted treatment, along with recognition and attention of residual affective and anxious symptoms might improve psychosocial outcomes such as functioning in this population.

Ten-year course of treated bipolar I disorder: The role of polarity at onset.

INTRODUCTION: Early-stage predictors of illness course are needed in bipolar disorder (BD). Differences among patients with a first depressive versus maniac/hypomanic episode have been stated, although in most studies, memory bias and time from onset to start of specialized treatment might interfere. The aim was to compare the first 10 years of illness course according to polarity at onset. METHODS: 49 type I BD patients admitted for treatment for a first-time affective episode and a following 10-year attendance to the institution were included. A retrospective year by year comparison according to polarity at onset (depressive (DPO) or maniac (MPO)) was performed. Cramer's V and Cohen d were computed to determine effect size. RESULTS: 59.2% (n = 29) started with MPO. Both groups were similar in demographic and social outcome characteristics, clinical features, and treatment variables. Patients with DPO reported more depressive episodes than MPO patients (U = 149.0 p < .001, Cohen's d = 0.87); both groups had a similar number of manic episodes. Only during the first year of follow-up, suicide attempts (SA) were more frequent in patients with DPO while the presence of a psychotic episode and psychiatric hospitalizations were more frequent in the MPO group. CONCLUSION: According to these findings, it can be concluded that illness onset is only indicative of depressive predominant polarity but is not related to other poor prognostic variables after the first year of illness onset, in treated BD. SA in the first year of an affective disorder could represent a marker of BD.

Identifying Risk Factors for Self-reported Mental Health Problems in Psychiatry Trainees and Psychiatrists in Mexico.

OBJECTIVE: The objective was to determine and compare demographic features, professional activities and adversities, physical health conditions, and self-care behaviors related to the most frequently self-reported mental health problems among psychiatrists and psychiatry trainees. METHODS: A cross-sectional, retrospective, comparative study was conducted on a total of 330 (48.2%) psychiatry trainees and 355 (51.8%) psychiatrists from Mexico through an online survey. Demographic features, professional activities and adversities, physical and mental health problems, self-care behaviors, and social support were examined. Comparative analyses and multiple logistic regression models were performed. RESULTS: Major depression, anxiety, and burnout were the most common mental health problems reported with a higher frequency of anxiety disorders in psychiatry trainees. Being a woman, having a physical health problem, and lack of restful sleep were the main risk factors in both groups. Consultation in the government sector and having patients with severe suicidal ideation affected more psychiatry trainees. Perceived discrimination and inadequate eating schedules were risk factors for mental health problems for psychiatrists. CONCLUSION: Psychiatry trainees constitute a vulnerable group for anxiety disorders. Particular attention should be paid to how students cope with the training experience to determine whether additional support is required. These professionals face major stressors leading to a high prevalence of depression, burnout, and anxiety. Encouraging psychiatrists to have better health habits is a step in the right direction, which must be accompanied by tangible organizational avenues to do so and creating a culture that truly promotes self-care.

Probable Case of Vertical Transmission of SARS-CoV-2 in a Newborn in Mexico.

BACKGROUND: Much remains unknown about the transmission of the SARS-CoV-2 virus. Pregnant women are considered part of the risk population, and vertical transmission of other coronaviruses has been suggested; however, this type of transmission in SARS-CoV-2 is believed to be unlikely. CASE REPORT: A newborn delivered in term via cesarean section to an asymptomatic but COVID-19-positive 35-year-old woman started with respiratory distress in the first 30 min of life. A chest radiograph revealed pneumothorax and ground glass opacities. Ventilatory support with continuous positive airway pressure was needed. Given the respiratory failure and the positive test from the mother, the patient was sampled for SARS-CoV-2 (RT-PCR) at minute 30 of life, with a positive result reported at 36 h of life. No complications had been present during pregnancy, and cardiac screening and blood cultures revealed no other etiologies. CONCLUSION: Vertical transmission was highly likely in this case. Clinicians should be alert and report similar cases.

White Matter Abnormalities in Late Onset First Episode Mania: A Diffusion Tensor Imaging Study.

INTRODUCTION: A first manic episode after 50 years of age is uncommon. Late Onset Mania might be indicative of abnormalities in white matter, probably related to vascular, degenerative, or inflammatory processes. OBJECTIVE: To determine if patients with late onset mania have reduced white matter integrity according to Magnetic Resonance Diffusion Tensor Imaging (DTI) and structural MRI. METHODS: Twenty-two patients with late onset mania (>50 years old) and 22 age-paired healthy subjects were included in the study. Fractional anisotropy (FA) was used as a quantitative measure of white matter integrity. Fazekas scale was assessed also to measure white matter abnormalities in the FLAIR sequence. The Frontal Assessment Battery, COGNISTAT and Trail making test A and B were used as cognitive measurements. RESULTS: According to DTI, commissural connections (left corpus callosum), and limbic connections (right and left uncinate fasciculus) were different between the patients and the comparison group. Fractional anisotropy values in the left corpus callosum showed significant correlations with neuropsychological measures, and with the Fazekas scale score. According to Fazekas scale, a pathological score in the FLAIR sequence was significantly more frequent in the patients as compared to the comparison group. CONCLUSIONS: Patients with first episode mania in late life have relevant white matter abnormalities not explained by age, affecting interhemispheric and fronto-limbic networks probably related to executive functioning and emotional processing, at the level of the corpus callosum and the uncinate fasciculus. The etiology of this white matter loss of integrity in patients with late-onset mania is yet to be explored.

PDA-Based Glyconanomicelles for Hepatocellular Carcinoma Cells Active Targeting Via Mannose and Asialoglycoprotein Receptors.

Hepatocellular carcinoma (HCC) is the sixth most common neoplasia and the fourth most common cause of cancer-related mortality worldwide. Sorafenib is the first-line molecular therapy for patients in an advanced stage of HCC. However, the recommended clinical dose of Sorafenib is associated with several complications, which derive from its lack of cell specificity and its very low water solubility. To circumvent these drawbacks, in the present study we developed two sugar-coated polydiacetylene-based nanomicelles-Sorafenib carriers targeting mannose and asialoglycoprotein receptors (MR and ASGPR, respectively). The strategies allowed the inducement of apoptosis and reduction of cell proliferation at a nanomolar, instead of micromolar, range in liver cancer cells. The study showed that, contrary to literature data, Sorafenib included into the pMicMan (Man = mannose) vector (targeting MR) is more efficient than pMicGal (Gal = galactose) (targeting ASGPR). Indeed, pMicMan increased the endosomal incorporation with an increased intracellular Sorafenib concentration that induced apoptosis and reduced cell proliferation at a low concentration range (10-20 nM).

Self-perceived health in psychiatrists and psychiatry trainees. The role of perfectionism and distress / Autopercepción de la salud en psiquiatras y residentes de psiquiatría. El rol del perfeccionismo y el distrés

Abstract Introduction Self-perceived health (SPH) is related to disease and well-being. Psychiatrists report burnout and mental disorders more frequently than other physicians, while personality traits related to perfectionism may influence the perception of well-being and health in these professionals. Objective To compare and determine the association between demographic variables, health conditions, perceived distress, perfectionism, and SPH. Method A cross-sectional, retrospective, comparative study was performed through an online survey. Psychiatrists and psychiatry trainees who were willing and able to participate were included. Demographic variables and self-reports of mental and physical conditions were examined. SPH was rated on a 10-point visual analogue scale and perfectionism through the Multidimensional Perfectionism Scale. Comparative analyses and multiple linear regression models were performed. Results Three hundred and thirty psychiatry trainees and 355 psychiatrists were recruited. Psychiatrists reported more physical conditions (32.4% vs. 15%, p < .001), distress (p < .001), and perfectionism (p < .001). Major depression and anxiety were present over 50% of all participants. A higher SPH was associated with being partnered and having higher distress levels in psychiatry trainees and with the absence of a physical health condition, less concern over errors, and higher personal standards in psychiatrists. Discussion and conclusion Self-oriented perfectionism may have a significant motivational component, accentuated by competitiveness and individualism. Being married and having higher levels of distress in psychiatry trainees appears to create a sense of satisfaction with achievements. The implementation of strategies to prioritize and meet goals is necessary to have an adequate work-life balance without affecting personal satisfaction or the sense of achievement.

Resumen Introducción La autopercepción de la salud (APS) se relaciona con enfermedad y bienestar. Los psiquiatras reportan desgaste emocional y trastornos mentales con mayor frecuencia que otros médicos. El perfeccionismo puede influir en la percepción de la salud en estos profesionistas. Objetivo Comparar y determinar la asociación de variables demográficas, condiciones de salud, distrés y perfeccionismo con la APS. Método Se realizó un estudio transversal, retrospectivo y comparativo mediante una encuesta en línea. Se incluyeron psiquiatras y residentes de psiquiatría que participaron voluntariamente. Se registraron variables demográficas, enfermedades médicas y psiquiátricas (autorreporte). La APS se evaluó con una escala análogo-visual de 10 puntos y el perfeccionismo con la Escala Multidimensional de Perfeccionismo. Se realizaron análisis comparativos y modelos de regresión lineal múltiple. Resultados Se reclutaron 330 residentes y 355 psiquiatras. Los psiquiatras reportaron más enfermedades físicas (32.4% vs. 15%, p < .001), distrés (p < .001) y perfeccionismo (p < .001). Más del 50% de los participantes reportaron ansiedad y depresión. Una mayor APS se asoció con tener pareja y mayor distrés en los residentes, y con la ausencia de una enfermedad física, menor preocupación por errores y mayores estándares personales en los psiquiatras. Discusión y conclusión El perfeccionismo orientado hacía sí mismo puede tener un componente motivacional acentuado por la competitividad y el individualismo. Tener una pareja y presentar mayor distrés en los residentes pudiera crear una sensación de satisfacción por logros. La creación de estrategias para priorizar y alcanzar objetivos es necesaria para tener un equilibrio de vida sin afectar la satisfacción personal y la sensación de logro.

Integrated molecular signaling involving mitochondrial dysfunction and alteration of cell metabolism induced by tyrosine kinase inhibitors in cancer.

Cancer cells have unlimited replicative potential, insensitivity to growth-inhibitory signals, evasion of apoptosis, cellular stress, and sustained angiogenesis, invasiveness and metastatic potential. Cancer cells adequately adapt cell metabolism and integrate several intracellular and redox signaling to promote cell survival in an inflammatory and hypoxic microenvironment in order to maintain/expand tumor phenotype. The administration of tyrosine kinase inhibitor (TKI) constitutes the recommended therapeutic strategy in different malignancies at advanced stages. There are important interrelationships between cell stress, redox status, mitochondrial function, metabolism and cellular signaling pathways leading to cell survival/death. The induction of apoptosis and cell cycle arrest widely related to the antitumoral properties of TKIs result from tightly controlled events involving different cellular compartments and signaling pathways. The aim of the present review is to update the most relevant studies dealing with the impact of TKI treatment on cell function. The induction of endoplasmic reticulum (ER) stress and Ca2+ disturbances, leading to alteration of mitochondrial function, redox status and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) signaling pathways that involve cell metabolism reprogramming in cancer cells will be covered. Emphasis will be given to studies that identify key components of the integrated molecular pattern including receptor tyrosine kinase (RTK) downstream signaling, cell death and mitochondria-related events that appear to be involved in the resistance of cancer cells to TKI treatments.

Molecular Pathways Leading to Induction of Cell Death and Anti-Proliferative Properties by Tacrolimus and mTOR Inhibitors in Liver Cancer Cells.

BACKGROUND/AIMS: Orthotopic liver transplantation (OLT) is the recommended treatment for patients at early stages of hepatocarcinoma (HCC) with portal hypertension and/or increased bilirubinemia, but without vascular-associated diseases. Tumor recurrence, which is the main drawback for the survival of patients submitted to OLT for HCC, has been related to tumor-related variables and the immunosuppressive therapies. We have previously shown that Tacrolimus (FK506) exerts a more potent pro-apoptotic and anti-proliferative effects than the mammalian target of rapamycin (mTOR) inhibitors (Sirolimus and Everolimus) in liver cancer cells. This study identified the role of the immunosuppressant partners such as FK506-binding proteins (FKBPs) in the induction of cell death and arrest of cell proliferation by immunosuppressants in two representative liver cancer cells. METHODS: The regulation of endoplasmic reticulum (ER) stress, apoptosis/autophagy, cell proliferation, and FKBPs expression was determined in Tacrolimus-, Sirolimus- and Everolimus-treated primary human hepatocytes, and hepatoma HepG2 and Huh7 cell lines. The functional repercussion of FKBPs on cell death and proliferation was also addressed using the siRNA technology. The assessed antitumoral properties of the immunosuppressants were associated to microRNAs (miRNAs) pattern. RESULTS: The enhanced pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with increased protein kinase RNA-like endoplasmic reticulum kinase (PERK)-related ER stress, Ser15P-p53/p53 ratio and p21 protein expression that may counterbalance the risk of proliferative upregulation caused by enhanced Thr172P-Cdk4/Cdk4 activation in liver cancer cells. The inhibition of the mTOR pathway by Sirolimus and Everolimus was related to an induction of autophagy; and at a high dose, these drugs impaired translation likely at a very early step of the elongation phase. Tacrolimus and mTOR inhibitors increased the protein expression of FKBP12 and FKBP51 that appeared to play pro-survival role. Interestingly, the administration of immunosuppressants yields a specific pattern of miRNAs. Tacrolimus and mTOR inhibitors decreased miR-92a-1-5p, miR-197-3p, miR-483-3p and miR-720, and increased miR-22-3p, miR-376a-3p, miR-663b, miR-886-5p, miR-1300 and miR-1303 expressions in HepG2 cells. CONCLUSION: The more potent pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with an increased activation of PERK and p53 signaling, and p21 protein expression. FKBP12 and FKBP51 appeared to be the most relevant partners of Tacrolimus and mTOR inhibitors exerting a pro-survival effect in HepG2 cells. The observed effects of immunosuppressants were related to a specific miRNA signature in liver cancer cells.

Differential effectiveness of tyrosine kinase inhibitors in 2D/3D culture according to cell differentiation, p53 status and mitochondrial respiration in liver cancer cells.

Sorafenib and Regorafenib are the recommended first- and second-line therapies in patients with advanced hepatocellular carcinoma (HCC). Lenvatinib and Cabozantinib have shown non-inferior antitumoral activities compared with the corresponding recommended therapies. The clinical trials have established recommended doses for each treatment that lead different blood concentrations in patients for Sorafenib (10 µM), Regorafenib (1 µM), Lenvatinib (0.1 µM), and Cabozantinib (1 µM). However, very low response rates are observed in patients attributed to intrinsic resistances or upregulation of survival signaling. The aim of the study was the comparative dose-response analysis of the drugs (0-100 µM) in well-differentiated (HepG2, Hep3B, and Huh7), moderately (SNU423), and poorly (SNU449) differentiated liver cancer cells in 2D/3D cultures. Cells harbors wild-type p53 (HepG2), non-sense p53 mutation (Hep3B), inframe p53 gene deletion (SNU423), and p53 point mutation (Huh7 and SNU449). The administration of regular used in vitro dose (10 µM) in 3D and 2D cultures, as well as the dose-response analysis in 2D cultures showed Sorafenib and Regorafenib were increasingly effective in reducing cell proliferation, and inducing apoptosis in well-differentiated and expressing wild-type p53 in HCC cells. Lenvatinib and Cabozantinib were particularly effective in moderately to poorly differentiated cells with mutated or lacking p53 that have lower basal oxygen consumption rate (OCR), ATP, and maximal respiration capacity than observed in differentiated HCC cells. Sorafenib and Regorafenib downregulated, and Lenvatinib and Cabozantinib upregulated epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor receptor (c-Met) in HepG2 cells. Conclusions: Sorafenib and Regorafenib were especially active in well-differentiated cells, with wild-type p53 and increased mitochondrial respiration. By contrast, Lenvatinib and Cabozantinib appeared more effective in moderately to poorly differentiated cells with mutated p53 and low mitochondrial respiration. The development of strategies that allow us to deliver increased doses in tumors might potentially enhance the effectiveness of the treatments.

Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer.

Hepatocellular carcinoma (HCC) represents 80% of the primary hepatic neoplasms. It is the sixth most frequent neoplasm, the fourth cause of cancer-related death, and 7% of registered malignancies. Sorafenib is the first line molecular targeted therapy for patients in advanced stage of HCC. The present study shows that Sorafenib exerts free radical scavenging properties associated with the downregulation of nuclear factor E2-related factor 2 (Nrf2)-regulated thioredoxin 1 (Trx1) expression in liver cancer cells. The experimental downregulation and/or overexpression strategies showed that Trx1 induced activation of nitric oxide synthase (NOS) type 3 (NOS3) and S-nitrosation (SNO) of CD95 receptor leading to an increase of caspase-8 activity and cell proliferation, as well as reduction of caspase-3 activity in liver cancer cells. In addition, Sorafenib transiently increased mRNA expression and activity of S-nitrosoglutathione reductase (GSNOR) in HepG2 cells. Different experimental models of hepatocarcinogenesis based on the subcutaneous implantation of HepG2 cells in nude mice, as well as the induction of HCC by diethylnitrosamine (DEN) confirmed the relevance of Trx1 downregulation during the proapoptotic and antiproliferative properties induced by Sorafenib. In conclusion, the induction of apoptosis and antiproliferative properties by Sorafenib were related to Trx1 downregulation that appeared to play a relevant role on SNO of NOS3 and CD95 in HepG2 cells. The transient increase of GSNOR might also participate in the deactivation of CD95-dependent proliferative signaling in liver cancer cells.