CD155/PVR determines acute myeloid leukemia targeting by Delta One T cells.

ABSTRACT: Relapsed or refractory acute myeloid leukemia (AML) remains a major therapeutic challenge. We have recently developed a Vδ1+ γδ T cell-based product for adoptive immunotherapy, named Delta One T (DOT) cells, and demonstrated their cytolytic capacity to eliminate AML cell lines and primary blasts in vitro and in vivo. However, the molecular mechanisms responsible for the broad DOT-cell recognition of AML cells remain poorly understood. Here, we dissected the role of natural killer (NK) cell receptor ligands in AML cell recognition by DOT cells. Screening of multiple AML cell lines highlighted a strong upregulation of the DNAM-1 ligands, CD155/pulmonary vascular resistance (PVR), CD112/nectin-2, as well as the NKp30 ligand, B7-H6, in contrast with NKG2D ligands. CRISPR-mediated ablation revealed key nonredundant and synergistic contributions of PVR and B7-H6 but not nectin-2 to DOT-cell targeting of AML cells. We further demonstrate that PVR and B7-H6 are critical for the formation of robust immunological synapses between AML and DOT cells. Importantly, PVR but not B7-H6 expression in primary AML samples predicted their elimination by DOT cells. These data provide new mechanistic insight into tumor targeting by DOT cells and suggest that assessing PVR expression levels may be highly relevant to DOT cell-based clinical trials.

Cancer germline antigens and tumor-agnostic CD8+ T cell evasion.

Cancer germline antigens (CGAs) are expressed in immune-privileged germline tissues, while epigenetically silenced in somatic tissues. CGAs become re-expressed in tumors and can promote oncogenesis. Tumors prominently exploit mechanisms similar to those in germline tissues to shield from immunosurveillance. We hypothesize that CGAs contribute towards tumor escape from immune effector CD8+ T cells. For illustrative purposes, we assessed the co-presence or -absence of CGAs with these cells in multiple tumor types. Considering a broad array of CD8+ T cell evasive mechanisms, we exemplify the co-occurrence of gene transcripts of eight CGAs with those of adhesion molecules, endothelial cells, and/or the Wnt pathway. We present a novel concept of CGAs and their association with CD8+ T cell evasion, which may be relevant for future immunotherapeutic interventions.

Randomized clinical study of injectable dextrin-based hydrogel as a carrier of a synthetic bone substitute.

OBJECTIVES: This study aimed to improve the performance and mode of administration of a glass-reinforced hydroxyapatite synthetic bone substitute, Bonelike by Biosckin® (BL®), by association with a dextrin-based hydrogel, DEXGEL, to achieve an injectable and moldable device named DEXGEL Bone. METHODS: Twelve participants requiring pre-molar tooth extraction and implant placement were enrolled in this study. BL® granules (250-500 µm) were administered to 6 randomized participants whereas the other 6 received DEXGEL Bone. After 6 months, a bone biopsy of the grafted area was collected for histological and histomorphometric evaluation, prior to implant placement. The performance of DEXGEL Bone and BL® treatments on alveolar preservation were further analyzed by computed tomography and Hounsfield density analysis. Primary implant stability was analyzed by implant stability coefficient technique. RESULTS: The healing of defects was free of any local or systemic complications. Both treatments showed good osseointegration with no signs of adverse reaction. DEXGEL Bone exhibited increased granule resorption (p = 0.029) accompanied by a tendency for more new bone ingrowth (although not statistically significant) compared to the BL® group. The addition of DEXGEL to BL® granules did not compromise bone volume or density, being even beneficial for implant primary stability (p = 0.017). CONCLUSIONS: The hydrogel-reinforced biomaterial exhibited an easier handling, a better defect filling, and benefits in implant stability. CLINICAL RELEVANCE: This study validates DEXGEL Bone safety and performance as an injectable carrier of granular bone substitutes for alveolar ridge preservation. TRIAL REGISTRATION: European Databank on Medical Devices (EUDAMED) No. CIV-PT-18-01-02,705; Registo Nacional de Estudos Clínicos, RNEC, No. 30122.

Catechol-O-methyltransferase activity in individuals with substance use disorders: a case control study.

BACKGROUND: Impulsivity and substance use disorders (SUD) have been both associated with changes in dopaminergic processes. In this study, we intended to evaluate the dopaminergic function in imprisoned SUD offenders through the determination of s-COMT activity. METHODS: The study included 46 male individuals from a Portuguese penal institution. The participants were assessed through a battery of standardised instruments: Psychopathy Checklist-Revised (PCL-R), Barratt Impulsivity Scale Version 11 (BIS-11), and the European version of the Addiction Severity Index (EuropASI). In addition, s-COMT erythrocyte activity was evaluated. RESULTS: Overall, 73.9% (n = 34) of the individuals had Antisocial personality disorder (ASPD) and 58.7% (n = 27) presented SUD. We evidenced, for the first time, that, in individuals with SUD, s-COMT activity was correlated with the severity of drug dependence (EuropASI) (p = 0.009), and with BIS-11 factors self-control (p < 0.0001) and non-planning (p = 0.002). CONCLUSIONS: This study opens new perspectives regarding the pharmacological intervention on substance dependence through the interference on dopamine pathways.

Comparative eye and liver differentially expressed genes reveal monochromatic vision and cancer resistance in the shortfin mako shark (Isurus oxyrinchus).

The shortfin mako, Isurus oxyrinchus is an oceanic pelagic shark found worldwide in tropical and subtropical waters. However, the understanding of its biology at molecular level is still incipient. We sequenced the messenger RNA isolated from eye and liver tissues. De novo transcriptome yielded a total of 705,940 transcripts. A total of 3774 genes were differentially expressed (DEGs), with 1612 in the eye and 2162 in the liver. Most DEGs in the eye were related to structural and signaling functions, including nonocular and ocular opsin genes, whereas nine out of ten most overexpressed genes in the liver were related to tumor suppression, wound healing, and human diseases. Furthermore, DEGs findings provide insights on the monochromatic shark vision and a repertory of cancer-related genes, which may be insightful to elucidate shark resistance to cancer. Therefore, our results provide valuable sequence resources for future functional and population studies.

The multiple facets of psychopathy in attack and defense conflicts.

With respect to De Dreu and Gross's article, we comment on the psychological functions for attack and defense, focusing on associations between individual differences in psychopathic personality traits and the behavioral patterns observed in attack-defense conflicts. We highlight the dimensional nature of psychopathy and formulate hypothetical associations between distinct traits, their different behavioral outcomes, and associated brain mechanisms.

Bridging Autism Spectrum Disorders and Schizophrenia through inflammation and biomarkers - pre-clinical and clinical investigations.

In recent years, evidence supporting a link between inflammation and neuropsychiatric disorders has been mounting. Autism spectrum disorders (ASD) and schizophrenia share some clinical similarities which we hypothesize might reflect the same biological basis, namely, in terms of inflammation. However, the diagnosis of ASD and schizophrenia relies solely on clinical symptoms, and to date, there is no clinically useful biomarker to diagnose or monitor the course of such illnesses.The focus of this review is the central role that inflammation plays in ASD and schizophrenia. It spans from pre-clinical animal models to clinical research and excludes in vitro studies. Four major areas are covered: (1) microglia, the inflammatory brain resident myeloid cells, (2) biomarkers, including circulating cytokines, oxidative stress markers, and microRNA players, known to influence cellular processes at brain and immune levels, (3) effect of anti-psychotics on biomarkers and other predictors of response, and (4) impact of gender on response to immune activation, biomarkers, and response to anti-psychotic treatments.

Dynamic modeling of bone metastasis, microenvironment and therapy: Integrating parathyroid hormone (PTH) effect, anti-resorptive and anti-cancer therapy.

Bone is a common site for the development of metastasis, as its microenvironment provides the necessary conditions for the growth and proliferation of cancer cells. Several mathematical models to describe the bone remodeling process and how osteoclasts and osteoblasts coupled action ensures bone homeostasis have been proposed and further extended to include the effect of cancer cells. The model proposed here includes the influence of the parathyroid hormone (PTH) as capable of triggering and regulating the bone remodeling cycle. It also considers the secretion of PTH-related protein (PTHrP) by cancer cells, which stimulates the production of receptor activator of nuclear factor kappa-B ligand (RANKL) by osteoblasts that activates osteoclasts, increasing bone resorption and the subsequent release of growth factors entrapped in the bone matrix, which induce tumor growth, giving rise to a self-perpetuating cycle known as the vicious cycle of bone metastases. The model additionally describes how the presence of metastases contributes to the decoupling between bone resorption and formation. Moreover, the effects of anti-cancer and anti-resorptive treatments, through chemotherapy and the administration of bisphosphonates or denosumab, are also included, along with their corresponding pharmacokinetics (PK) and pharmacodynamics (PD). The simulated models, available at http://sels.tecnico.ulisboa.pt/software/, are able to describe bone remodeling cycles, the growth of bone metastases and how treatment can effectively reduce tumor burden on bone and prevent loss of bone strength.

Metabolic profile and psychological variables after bariatric surgery: association with weight outcomes.

PURPOSE: This study aims to examine associations between metabolic profile and psychological variables in post-bariatric patients and to investigate if metabolic and psychological variables, namely high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), glycated hemoglobin (HbA 1c), impulsivity, psychological distress, depressive and eating disorder symptoms are independently associated with percentage of excess weight loss (%EWL) after bariatric surgery. METHODS: One hundred and fifty bariatric patients (BMI = 33.04 ± 5.8 kg/m(2)) who underwent to bariatric surgery for more than 28.63 ± 4.9 months were assessed through a clinical interview, a set of self-report measures and venous blood samples. Pearson's correlations were used to assess correlations between %EWL, metabolic and psychological variables. Multiple linear regression was conducted to investigate which metabolic and psychological variables were independently associated with %EWL, while controlling for type of surgery. RESULTS: Higher TG blood levels were associated with higher disordered eating, psychological distress and depression scores. HDL-C was associated with higher depression scores. Both metabolic and psychological variables were associated with %EWL. Regression analyses showed that, controlling for type of surgery, higher % EWL is significantly and independently associated with less disordered eating symptoms and lower TG and HbA_1c blood concentrations (R (2) aj = 0.383, F (4, 82) = 14.34, p < 0.000). CONCLUSION: An association between metabolic and psychological variables, particularly concerning TG blood levels, disordered eating and psychological distress/depression was found. Only higher levels of disordered eating, TG and HbA_1c showed and independent correlation with less weight loss. Targeting maladaptive eating behaviors may be a reasonable strategy to avoid weight regain and optimize health status post-operatively.

The role of maternal attachment in the experience of labor pain: a prospective study.

OBJECTIVE: To examine the influence of attachment dimensions and sociodemographic and physical predictors in the experience of labor pain. METHODS: Eighty-one pregnant women were assessed during their third trimester of pregnancy and during labor. The perceived intensity of pain in the early stages of labor (3 cm of cervical dilatation) and before the administration of patient-controlled epidural analgesia was measured using a visual analog scale. Pain was also assessed indirectly based on anesthetic doses. Attachment was assessed using the Adult Attachment Scale-Revised. RESULTS: Attachment anxiety and avoidance were positively and significantly correlated with labor pain and anesthetic consumption. In the multivariate models, attachment anxiety was a significant predictor of higher pain at 3 cm of cervical dilatation (ß = 0.36, p = .042) and before the administration of patient-controlled epidural analgesia (ß = 0.51, p = .002). Older age (ß = 0.31, p = .005), a shorter duration of labor (ß= -0.41, p = .001), and attachment avoidance (ß = 0.41, p = .004) were significant predictors of higher anesthetic use. CONCLUSIONS: The study findings suggest that perceived labor pain and anesthetic use are strongly associated with attachment, rather than demographic and physical factors. These data support the importance of understanding the experience of labor pain within an attachment theoretical framework.

A case of choking phobia: towards a conceptual approach.

Choking phobia, also known as phagophobia or swallowing phobia is an uncommon clinical entity that has been underappreciated and is included in the new DSM-5 and upcoming ICD-11 diagnostic category of avoidant/restrictive food intake disorder. Phenomenologically distinct from other eating disorders, it is characterized by the phobic stimulus of swallowing that results in the avoidance of food or drinks, and ultimately to low weight, social withdrawal, anxiety and depression states. Its prevalence and long-term course on the general population still needs to be determined, probably reflecting years of indefiniteness regarding its nosology and by the absence of a clear set of diagnostic criteria. We present a clinical case of choking phobia in a 32-year-old male patient after an episode of choke when eating chicken. An early diagnosis and distinction from other eating disorders is important for proper treatment and fundamental for prognosis. We also make a thorough revision on literature in clinical features, differential diagnosis and treatment approaches, suggesting a conceptual approach for choking phobia as a clinical spectrum settled by different degrees of phobic subtypes, which may depend on a varied number of clinical variables.

Zieve's Syndrome: An Underdiagnosed Cause of Non-immune Hemolytic Anemia.

Zieve's syndrome is an underdiagnosed condition characterized by the triad of jaundice, hemolytic anemia, and hyperlipidemia in the setting of chronic alcohol use. It may be accompanied by acute alcoholic hepatitis. The distinction between the coexistence of acute alcoholic hepatitis with Zieve's syndrome and Zieve's syndrome in isolation is crucial, given the different treatments and prognoses in these situations. A 35-year-old woman presented with complaints of abdominal discomfort, nausea, and vomiting in the previous week. She was a heavy drinker with resultant cirrhosis, splenomegaly, and esophageal varices. An ancillary test showed hemolytic anemia, moderately elevated transaminases, hyperbilirubinemia, and coagulopathy. A negative direct Coombs test established the anemia as non-immune, supporting the diagnosis of Zieve's syndrome despite the absence of hyperlipidemia. Maddrey's discriminant function score was 92 points, so she was treated with supportive measures, as well as corticosteroids in the setting of acute alcoholic hepatitis. The patient showed a favorable clinical and analytical evolution and was discharged home one month following admission with her hemoglobin levels stabilized. Previous literature focused on the distinction between Zieve's syndrome and acute alcoholic hepatitis but they may coexist.

Combining inflammatory miRNA molecules as diagnostic biomarkers for depression: a clinical study.

Background: Inflammation has been implicated in core features of depression pathophysiology and treatment resistance. Therefore, new challenges in the discovery of inflammatory mediators implicated in depression have emerged. MicroRNAs (miRNAs) have been found aberrantly expressed in several pathologies, increasing their potential as biomarkers and therapeutical targets. In this study, the aim was to assess the changes and biomarker potential of inflammation-related miRNAs in depression patients. Methods: Depression diagnosis was performed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). 40 healthy controls and 32 depression patients were included in the study. The levels of inflammatory cytokines were measured in plasma, and expression levels of cytokines and inflammation-related miRNAs were evaluated in peripheral blood mononuclear cells (PBMCs). Results: Depression patients were found to have a pro-inflammatory profile in plasma, with significantly higher levels of TNF-α and CCL2 compared with controls. In PBMCs of depression patients, TNF-α and IL-6 expression levels were significantly up and downregulated, respectively. Moreover, miR-342 levels were found upregulated, while miR-146a and miR-155 were significantly downregulated. miR-342 expression levels were positively correlated with TNF-α. Importantly, when analyzed as a diagnostic panel, receiver operating characteristics (ROC) analysis of miR-342, miR-146a, miR-155 in combination, showed to be highly specific and sensitive in distinguishing between depression patients and healthy controls. Conclusion: In summary, these findings suggest that inflammation-related miRNAs are aberrantly expressed in depression patients. Moreover, we show evidences on the potential of the combination of dysregulated miRNAs as a powerful diagnostic tool for depression.

Seascape Genomics and Phylogeography of the Sailfish (Istiophorus platypterus).

Permeable phylogeographic barriers characterize the vast open ocean, boosting gene flow and counteracting population differentiation and speciation of widely distributed and migratory species. However, many widely distributed species consists of distinct populations throughout their distribution, evidencing that our understanding of how the marine environment triggers population and species divergence are insufficient. The sailfish is a circumtropical and highly migratory billfish that inhabits warm and productive areas. Despite its ecological and socioeconomic importance as a predator and fishery resource, the species is threatened by overfishing, requiring innovative approaches to improve their management and conservation status. Thus, we presented a novel high-quality reference genome for the species and applied a seascape genomics approach to understand how marine environmental features may promote local adaptation and how it affects gene flow between populations. We delimit two populations between the Atlantic and Indo-Western Pacific oceans and detect outlier loci correlated with sea surface temperature, salinity, oxygen, and chlorophyll concentrations. However, the most significant explanatory factor that explains the differences between populations was isolation by distance. Despite recent population drops, the sailfish populations are not inbred. For billfishes in general, genome-wide heterozygosity was found to be relatively low compared to other marine fishes, evidencing the need to counteract overfishing effects. In addition, in a climate change scenario, management agencies must implement state-of-the-art sequencing methods, consider our findings in their management plans, and monitor genome-wide heterozygosity over time to improve sustainable fisheries and the long-term viability of its populations.

Biomarkers for rhythmic and discrete dynamic primitives in locomotion.

Rehabilitation can promote brain plasticity and improve motor control after central nervous system injuries. Our working model is that motor control is encoded using dynamic primitives: submovements, oscillations, and mechanical impedances. We hypothesize that therapies focusing on these primitives can achieve greater motor recovery. At the observational level, these primitives lead to discrete and rhythmic movements. Here, we propose two novel biomarkers to evaluate rhythmic and discrete movements in gait based on the feet forward position: the smoothness of their relative position, using the mean-squared jerk ratio (MSJR), to assess rhythmicity; and the angle between principal components of consecutive trajectories (dPCA), to detect discrete movements amidst rhythmic motion. We applied these methods to kinematic data collected with healthy individuals during experiments employing the MIT-Skywalker: level-ground walking at five speeds, with and without imposed ankle stiffness; walking at constant speed on ascending, descending, and laterally tilted slopes; and performing sidesteps. We found a decrease in MSJR as speed increases, related to increased rhythmicity, even with imposed stiffness. Rhythmicity seems unaffected by the terrain perturbations imposed. Finally, dPCA successfully detects sidesteps, discrete events amidst rhythmic movement. These biomarkers appear to accurately assess rhythmic and discrete movements during walking and can potentially improve clinical evaluation and rehabilitation of neurological patients.

Multivariable passive ankle impedance in stroke patients: A preliminary study.

Multivariable ankle mechanical impedance was estimated in four stroke survivors, in coupled dorsi- plantarflexion and inversion-eversion. We applied external torque perturbation with an ankle robot and used multi-input, multi-output stochastic system identification methods to estimate impedance, in both paretic and nonparetic limbs. Subjects were instructed to remain at rest throughout the four trials performed on each leg. Impedance projected onto the directions of maximum and minimum stiffness was fit to a 2nd order linear model, including inertia, viscosity and stiffness. For most trials, stiffness and damping in dorsi-plantarflexion are increased on the paretic side. However, for two subjects, overall impedance is not increased in the absence of sustained involuntary tonic contraction, registering values comparable to the non-paretic side. Thus, we speculate that the intrinsic properties of the paretic ankle remained unaffected at the evaluated pose. Spasticity (hyperflexive stretch reflex) would have systematically increased stiffness and damping, even in the absence of involuntary contraction. Hence, we speculate that these two subjects did not exhibit spasticity, while the remaining two subjects did, since impedance was increased, with no involuntary tonic muscle contraction. Regarding inversion-eversion, impedance in this direction remained unaffected by stroke. We evaluated two volunteers before and after the application of botulinum toxin. Surprisingly, ankle stiffness was not reduced, but anisotropy was normalized.

Long-term outcomes of primary cardiovascular prevention: A retrospective study at a referral center in Portugal.

INTRODUCTION AND OBJECTIVES: Lifestyle changes are frequently insufficient to reduce cardiovascular (CV) risk in patients with dyslipidemia. This study aims to characterize the long-term evolution of lipid profile and CV risk of patients under primary prevention. METHODS: A retrospective study was performed of outpatients at a Portuguese cardiovascular risk clinic with ≥2 CV risk factors, followed for ≥2 years between 1995 and 2015. Statin therapy had been initiated early, in accordance with the clinic's practice. After written informed consent was obtained, sociodemographic and clinical characteristics were collected from medical charts, at baseline and last visit. Changes in lipid profile and CV risk scores were estimated. Associations between HDL-C or LDL-C changes and gender, age, observation time and treatments were assessed through bivariate analysis and multiple linear regression models. RESULTS: Out of 516 participants with mean follow-up of 11.4±4.3 years, 56.6% were female and 91.5% received statins. Lipid profile showed statistically significant improvement, including median changes in LDL-C and HDL-C of -77.0 mg/dl and +19 mg/dl, respectively. CV risk also showed statistically significant improvements according to all scores. Statin therapy resulted in a mean HDL-C increase of 7.4 mg/dl (independently of gender and other treatments) and a mean LDL-C reduction of 51.8 mg/dl (irrespective of age and other treatments). CONCLUSION: Results from this long-term real-life study indicate that primary prevention, specifically early and continuous therapy with intermediate-intensity statins as an add-on to lifestyle interventions, was important in obtaining consistent and adequate metabolic correction in patients with additional risk factors.

Diving into the vertical dimension of elasmobranch movement ecology.

Knowledge of the three-dimensional movement patterns of elasmobranchs is vital to understand their ecological roles and exposure to anthropogenic pressures. To date, comparative studies among species at global scales have mostly focused on horizontal movements. Our study addresses the knowledge gap of vertical movements by compiling the first global synthesis of vertical habitat use by elasmobranchs from data obtained by deployment of 989 biotelemetry tags on 38 elasmobranch species. Elasmobranchs displayed high intra- and interspecific variability in vertical movement patterns. Substantial vertical overlap was observed for many epipelagic elasmobranchs, indicating an increased likelihood to display spatial overlap, biologically interact, and share similar risk to anthropogenic threats that vary on a vertical gradient. We highlight the critical next steps toward incorporating vertical movement into global management and monitoring strategies for elasmobranchs, emphasizing the need to address geographic and taxonomic biases in deployments and to concurrently consider both horizontal and vertical movements.

COVID-19 Suicide Survivors-A Hidden Grieving Population.

Present time has been dominated by the COVID-19 pandemic. People are grieving several non-death related situations: the loss of a job, of a status, of a role, of their life. Restrictive measures and uncertainty about the future makes individuals vulnerable to feelings of hopelessness and helplessness. Mental health support has been hindered and teams are reinventing themselves to reach people in need. Nevertheless, decompensation of previous psychiatric disorders, increasing levels of depression and anxiety, economical handicaps and fear of the infection, are prompting several cases of COVID-19 related suicides worldwide. Every suicide affects between 5 and 80 individuals, which are known as suicide survivors. Suicide grief is particularly challenging, with rates of complicated grief as high as 40%. Suicide survivors are at increased risk of developing depression, anxiety disorders and of suicidal behaviors. Moreover, feelings of guilt and shame, as well as social stigma, are major obstacles for them to reach form help. This article aims to review the existing literature on COVID-19 related suicides, complicated grief in suicide survivors and highlight modifiable risk factors for both conditions, as well as propose some public health measures to reduce the impact of the pandemic context on self-inflicted harm and its consequences on families, friends and the community. Obstacles to access to mental health support need to be overcome through the use of technology. Technicians should actively approach populations more vulnerable to develop suicidal ideation. Social media have the obligation to provide accurate an non-sensationalistic information. Families and friends should maintain social proximity, despite the need for physical distancing. When a suicide death occurs, police forces and health staff should be prepared to share the news with the family using an empathic and humane approach and providing psychological support. Funerals, memorials and other services should be held as much as possible. Closer contacts should be signalized and closely followed in order to detect the need for specific interventions. Help seeking behaviors should be promoted. Additionally, people should be educated on suicide and its impacts, in order to reduce stigma.

Putative shared mechanisms in autism spectrum disorders and attention deficit hyperactivity disorder, a systematic review of the role of oxidative stress.

Oxidative stress is now believed to play a crucial role for neurodevelopment disorders such as autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD). To review the most recent literature regarding the role of oxidative stress for the pathophysiology of ASD and ADHD, we conducted a systematic search of the relevant literature and further discuss the clinical and research implications of this knowledge. A systematic search in PubMed database retrieved 132 articles, of which 33 were included in the review. This review found relevant evidence concerning the role of oxidative status in ASD and ADHD, albeit with some contradictory findings. In order to overcome the incongruities found, more studies are needed in the study of neurodevelopmental disorders, with more thorough study designs and particular attention to the accuracy of the diagnostic tools used for the cases included.