Use of Telehealth Among Cancer Survivors: A Scoping Review.

Background: Long-term cancer survivors have specific needs that are frequently neglected. Telehealth, as a new form of health care, can benefit this growing population. Objective: To identify, analyze, and synthesize the existing evidence on the use of telehealth in the care of cancer survivors after the end of treatment. Methods: A scoping review was conducted in the databases PubMed, CINAHL, COCHRANE, SCIELO, DIALNET, and LILACS and reference institutions in cancer. Results: The initial search yielded 406 publications with 59 articles meeting the eligibility criteria. There are different types of telehealth (video calls, phone calls, websites, mobile applications, and short message services) used for the care of cancer survivors. Most telehealth interventions focus on improving the physical and mental spheres of quality of life in the extended survival phase (from 1 to 3 years postdiagnosis), with only two articles (3%) on long-term cancer survivors (>5 years postdiagnosis). Survivors are satisfied with telehealth interventions, noting the importance of improving comprehensibility, personalization of the platforms, and the lack of excessive information included. Conclusions: Telehealth is a feasible modality for cancer survival care. The scarcity of interventions aimed at long-term survivors stands out, as does the general neglect of the social and spiritual spheres of quality of life. Implications for Practice: Telehealth platforms must adapt their content, format, and items to the preferences reported by the survivors.

Chronic Pain and Psychological Distress Among Undocumented Latinx Immigrants in the USA.

BACKGROUND: Undocumented immigration is often accompanied by multiple and complex stressors, which over time may increase the risk for chronic pain. OBJECTIVE: This study aimed to identify the prevalence of chronic pain and its association with psychological distress among undocumented Latinx immigrants in the USA. DESIGN/PARTICIPANTS: We used respondent-driven sampling to collect and analyze data from clinical interviews with 254 undocumented Latinx immigrants, enabling inference to a population of 22,000. MAIN MEASURES: Chronic pain was assessed using the World Health Organization Composite International Diagnostic Interview (CIDI) Chronic Conditions Module. For all analyses, inferential statistics accounted for design effects and sample weights to produce weighted estimates. We conducted logistic regression analyses to assess the association between chronic pain and psychological distress after controlling for age, years in the USA, and history of trauma. RESULTS: A total of 28% of undocumented Latinx immigrants reported having chronic pain, and 20% of those had clinically significant psychological distress. Significant differences in the prevalence of chronic pain were reported across age groups, years in the USA, and trauma history. After controlling for relevant covariates, chronic pain was significantly associated with psychological distress (OR = 1.06, 95% CI [1.02, 1.09]), age (OR = 1.05, 95% CI [1.02; 1.09]), and history of trauma (OR = 1.10 per additional traumatic event, 95% CI [1.02; 1.19]; C-statistic = 0.79). CONCLUSION: Among undocumented Latinx immigrants, chronic pain is significantly associated with psychological distress, older age, and trauma history. Given that undocumented immigrants have restricted access to healthcare and are at high risk for chronic pain, developing alternatives to facilitate access to chronic pain interventions and risk-reduction prevention are needed.

Synthetic and Natural Derivatives of Cannabidiol.

The non-psychoactive component of Cannabis Sativa, cannabidiol (CBD), has centered the attention of a large body of research in the last years. Recent clinical trials have led to the FDA approval of CBD for the treatment of children with drug-resistant epilepsy. Even though it is not yet in clinical phases, its use in sleep-wake pathological alterations has been widely demonstrated.Despite the outstanding current knowledge on CBD therapeutic effects in numerous in vitro and in vivo disease models, diverse questions still arise from its molecular pharmacology. CBD has been shown to modulate a wide variety of targets including the cannabinoid receptors, orphan GPCRs such as GPR55 and GPR18, serotonin, adenosine, and opioid receptors as well as ligand-gated ion channels among others. Its pharmacology is rather puzzling and needs to be further explored in the disease context.Also, the metabolism and interactions of this phytocannabinoid with other commercialized drugs need to be further considered to elucidate its clinical potential for the treatment of specific pathologies.Besides CBD, natural and synthetic derivatives of this chemotype have also been reported exhibiting diverse functional profiles and providing a deeper understanding of the potential of this scaffold.In this chapter, we analyze the knowledge gained so far on CBD and its analogs specially focusing on its molecular targets and metabolic implications. Phytogenic and synthetic CBD derivatives may provide novel approaches to improve the therapeutic prospects offered by this promising chemotype.

Emerging Roles of Cannabinoids and Synthetic Cannabinoids in Clinical Experimental Models.

In recent years, an increasing number of investigations has demonstrated the therapeutic potential of molecules targeting the endocannabinoid system. Cannabinoids of endogenous, phytogenic, and synthetic nature have been assessed in a wide variety of disease models ranging from neurological to metabolic disorders. Even though very few compounds of this type have already reached the market, numerous preclinical and clinical studies suggest that cannabinoids are suitable drugs for the clinical management of diverse pathologies.In this chapter, we will provide an overview of the endocannabinoid system under certain physiopathological conditions, with a focus on neurological, oncologic, and metabolic disorders. Cannabinoids evaluated as potential therapeutic agents in experimental models with an emphasis in the most successful chemical entities and their perspectives towards the clinic will be discussed.

Relevance of Peroxisome Proliferator Activated Receptors in Multitarget Paradigm Associated with the Endocannabinoid System.

Cannabinoids have shown to exert their therapeutic actions through a variety of targets. These include not only the canonical cannabinoid receptors CB1R and CB2R but also related orphan G protein-coupled receptors (GPCRs), ligand-gated ion channels, transient receptor potential (TRP) channels, metabolic enzymes, and nuclear receptors. In this review, we aim to summarize reported compounds exhibiting their therapeutic effects upon the modulation of CB1R and/or CB2R and the nuclear peroxisome proliferator-activated receptors (PPARs). Concomitant actions at CBRs and PPARα or PPARγ subtypes have shown to mediate antiobesity, analgesic, antitumoral, or neuroprotective properties of a variety of phytogenic, endogenous, and synthetic cannabinoids. The relevance of this multitargeting mechanism of action has been analyzed in the context of diverse pathologies. Synergistic effects triggered by combinatorial treatment with ligands that modulate the aforementioned targets have also been considered. This literature overview provides structural and pharmacological insights for the further development of dual cannabinoids for specific disorders.

Preclinical Investigation in Neuroprotective Effects of the GPR55 Ligand VCE-006.1 in Experimental Models of Parkinson's Disease and Amyotrophic Lateral Sclerosis.

Cannabinoids act as pleiotropic compounds exerting, among others, a broad-spectrum of neuroprotective effects. These effects have been investigated in the last years in different preclinical models of neurodegeneration, with the cannabinoid type-1 (CB1) and type-2 (CB2) receptors concentrating an important part of this research. However, the issue has also been extended to additional targets that are also active for cannabinoids, such as the orphan G-protein receptor 55 (GPR55). In the present study, we investigated the neuroprotective potential of VCE-006.1, a chromenopyrazole derivative with biased orthosteric and positive allosteric modulator activity at GPR55, in murine models of two neurodegenerative diseases. First, we proved that VCE-006.1 alone could induce ERK1/2 activation and calcium mobilization, as well as increase cAMP response but only in the presence of lysophosphatidyl inositol. Next, we investigated this compound administered chronically in two neurotoxin-based models of Parkinson's disease (PD), as well as in some cell-based models. VCE-006.1 was active in reversing the motor defects caused by 6-hydroxydopamine (6-OHDA) in the pole and the cylinder rearing tests, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity detected in the substantia nigra. Similar cytoprotective effects were found in vitro in SH-SY5Y cells exposed to 6-OHDA. We also investigated VCE-006.1 in LPS-lesioned mice with similar beneficial effects, except against glial reactivity and associated inflammatory events, which remained unaltered, a fact confirmed in BV2 cells treated with LPS and VCE-006.1. We also analyzed GPR55 in these in vivo models with no changes in its gene expression, although GPR55 was down-regulated in BV2 cells treated with LPS, which may explain the lack of efficacy of VCE-006.1 in such an assay. Furthermore, we investigated VCE-006.1 in two genetic models of amyotrophic lateral sclerosis (ALS), mutant SOD1, or TDP-43 transgenic mice. Neither the neurological decline nor the deteriorated rotarod performance were prevented with this compound, and the same happened with the elevated microglial and astroglial reactivities, albeit modest spinal motor neuron preservation was achieved in both models. We also analyzed GPR55 in these in vivo models and found no changes in both TDP-43 transgenic and mSOD1 mice. Therefore, our findings support the view that targeting the GPR55 may afford neuroprotection in experimental PD, but not in ALS, thus stressing the specificities for the development of cannabinoid-based therapies in the different neurodegenerative disorders.

Discovery of Homobivalent Bitopic Ligands of the Cannabinoid CB2 Receptor*.

Single chemical entities with potential to simultaneously interact with two binding sites are emerging strategies in medicinal chemistry. We have designed, synthesized and functionally characterized the first bitopic ligands for the CB2 receptor. These compounds selectively target CB2 versus CB1 receptors. Their binding mode was studied by molecular dynamic simulations and site-directed mutagenesis.

Prevalence of fibromyalgia and associated factors in Spain.

OBJECTIVES: The prevalence of fibromyalgia (FM) differs depending on the population studied. The main objective of the EPISER2016 study was to estimate the prevalence of FM in adults in Spain. The secondary objective was to evaluate the association with sociodemographic and anthropometric characteristics and smoking. METHODS: This is a population-based cross-sectional multicentre study. The random selection was based on multistage stratified cluster sampling. The final sample comprised 4916 persons aged ≥20 years. Participants were contacted by telephone for completion of a screening survey. Investigating rheumatologists evaluated positive results (review of medical records and/or telephone interview, with medical visit if needed) to confirm the diagnosis. Prevalence and 95% confidence interval were calculated, taking into account the sample design. Weighing was applied based on age, sex, and geographic origin. Predictive models were constructed to analyse which sociodemographic, anthropometric and lifestyle variables in the call centre questionnaire were associated with the presence of FM. RESULTS: 602 subjects (12.25%) had a positive screening result for FM, of which 24 were missing (3.99%). A total of 141 cases of FM were recorded. The estimated prevalence was 2.45% (95% CI, 2.06-2.90). Female sex was the variable most associated with FM, with an odds ratio (OR) of 10.156 (95% CI, 5.068-20.352). Peak prevalence was at 60-69 years (p=0.009, OR=6.962). FM was 68% more frequent in obese individuals (OR, 1.689; 95% CI, 1.036-2.755). CONCLUSIONS: The prevalence of FM in adults in Spain barely changed between 2000 and 2016 and it is similar to that observed in Europe as a whole.

Myocardial Injury After Noncardiac Surgery: Incidence, Predictive Factors, and Outcome in High-Risk Patients Undergoing Thoracic Surgery: An Observational Study.

OBJECTIVE: The authors aimed to evaluate the incidence of myocardial injury after noncardiac surgery (MINS), its relationship with perioperative variables, and its prognostic implications for 30-day mortality in high-risk thoracic surgery patients. DESIGN: Observational study including cardiovascular high-risk patients undergoing routine postoperative troponin monitoring during the first 2 postoperative days. MINS was diagnosed based on at least 1 troponin I determination ≥0.04 ng/mL with no evidence of a nonischemic etiology. SETTING: Tertiary university hospital. PARTICIPANTS: Adult patients with cardiac risk factors, defined as patients ≥65 years old or patients <65 years old with known cardiovascular pathology (history of cardiac, cerebral, or peripheral vascular pathology) who underwent elective thoracic surgery. MEASUREMENT AND MAIN RESULTS: Forty-eight patients (27.3%) (95% confidence interval [CI] 20.8%-34.5%) of 177 had diagnostic criteria for MINS. On univariate analysis, an association was found between MINS and smoking (odds ratio [OR] 2.17, 95% CI 1.26-3.76), lobectomy (OR 1.30, 95% CI 1.03-1.66), pneumonectomy (OR 6.72, 95% CI 1.35-33.9), use of vasoactive drugs (OR 1.94, 95% CI 1.03-3.65), and pericardial incision (OR 6.72, 95% CI 1.35-33.9). On multivariate logistic regression analysis, only smoker status and type of surgery were independent risk factors for MINS. No association was found between MINS and 30-day mortality. CONCLUSIONS: Based on the findings, the elevated incidence of MINS after thoracic surgery, the independent relationship with the extent of lung resection, and the fact that MINS was not associated with greater mortality suggest that nonischemic causes may contribute to troponin elevation after thoracic surgeries.

Structural Insights into ß-arrestin/CB1 Receptor Interaction: NMR and CD Studies on Model Peptides.

Activation of the cannabinoid CB1 receptor induces different cellular signaling cascades through coupling to different effector proteins (G-proteins and ß-arrestins), triggering numerous therapeutic effects. Conformational changes and rearrangements at the intracellular domain of this GPCR receptor that accompany ligand binding dictate the signaling pathways. The GPCR-binding interface for G proteins has been extensively studied, whereas ß-arrestin/GPCR complexes are still poorly understood. To gain knowledge in this direction, we designed peptides that mimic the motifs involved in the putative interacting region: ß-arrestin1 finger loop and the transmembrane helix 7-helix 8 (TMH7-H8) elbow located at the intracellular side of the CB1 receptor. According to circular dichroism and NMR data, these peptides form a native-like, helical conformation and interact with each other in aqueous solution, in the presence of trifluoroethanol, and using zwitterionic detergent micelles as membrane mimics. These results increase our understanding of the binding mode of ß-arrestin and CB1 receptor and validate minimalist approaches to structurally comprehend complex protein systems.

GPR6 Structural Insights: Homology Model Construction and Docking Studies.

GPR6 is an orphan G protein-coupled receptor that has been associated with the cannabinoid family because of its recognition of a sub-set of cannabinoid ligands. The high abundance of GPR6 in the central nervous system, along with high constitutive activity and a link to several neurodegenerative diseases make GPR6 a promising biological target. In fact, diverse research groups have demonstrated that GPR6 represents a possible target for the treatment of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, and Huntington's disease. Several patents have claimed the use of a wide range of pyrazine derivatives as GPR6 inverse agonists for the treatment of Parkinson's disease symptoms and other dyskinesia syndromes. However, the full pharmacological importance of GPR6 has not yet been fully explored due to the lack of high potency, readily available ligands targeting GPR6. The long-term goal of the present study is to develop such ligands. In this paper, we describe our initial steps towards this goal. A human GPR6 homology model was constructed using a suite of computational techniques. This model permitted the identification of unique GPR6 structural features and the exploration of the GPR6 binding crevice. A subset of patented pyrazine analogs were docked in the resultant GPR6 inactive state model to validate the model, rationalize the structure-activity relationships from the reported patents and identify the key residues in the binding crevice for ligand recognition. We will take this structural knowledge into the next phase of GPR6 project, in which scaffold hopping will be used to design new GPR6 ligands.

Design and structural characterisation of monomeric water-soluble α-helix and ß-hairpin peptides: State-of-the-art.

Peptides are not only useful models for the structural understanding of protein folding and stability but also provide promising therapeutic avenues for the treatment of numerous diseases, and as biomaterials. The field has been very active over the last decades, but the complex conformational behaviour of peptides still poses challenges to the characterisation and rational design of defined structures. In this context, we aim to provide a comprehensive overview of linear water-soluble monomeric peptides able to form the two simplest structural motifs: α-helices and ß-hairpins. For both structures, we describe the geometry features, and the main contributions to stability: intrinsic propensities, position dependence of specific residues, particular capping motifs and side chain interactions. They should be considered to design α-helical or ß-hairpin peptides. Solvent influence on peptide stability and selected in silico design approaches are also discussed. Moreover, we provide guidelines for structural characterisation of α-helical and ß-hairpin-forming peptides by NMR and circular dichroism. We also highlight recently reported designed peptides and current strategies developed to improve their stability, bioactivity and bioavailability. The information gathered herein may aid peptide design and characterisation of stable α-helical and ß-hairpin motifs in the search of biological constructs or improved peptide therapeutics.

Structural Insights into CB1 Receptor Biased Signaling.

The endocannabinoid system has emerged as a promising target for the treatment of numerous diseases, including cancer, neurodegenerative disorders, and metabolic syndromes. Thus far, two cannabinoid receptors, CB1 and CB2, have been discovered, which are found predominantly in the central nervous system (CB1) or the immune system (CB2), among other organs and tissues. CB1 receptor ligands have been shown to induce a complex pattern of intracellular effects. The binding of a ligand induces distinct conformational changes in the receptor, which will eventually translate into distinct intracellular signaling pathways through coupling to specific intracellular effector proteins. These proteins can mediate receptor desensitization, trafficking, or signaling. Ligand specificity and selectivity, complex cellular components, and the concomitant expression of other proteins (which either regulate the CB1 receptor or are regulated by the CB1 receptor) will affect the therapeutic outcome of its targeting. With an increased interest in G protein-coupled receptors (GPCR) research, in-depth studies using mutations, biological assays, and spectroscopic techniques (such as NMR, EPR, MS, FRET, and X-ray crystallography), as well as computational modelling, have begun to reveal a set of concerted structural features in Class A GPCRs which relate to signaling pathways and the mechanisms of ligand-induced activation, deactivation, or activity modulation. This review will focus on the structural features of the CB1 receptor, mutations known to bias its signaling, and reported studies of CB1 receptor ligands to control its specific signaling.

Towards A Molecular Understanding of The Cannabinoid Related Orphan Receptor GPR18: A Focus on Its Constitutive Activity.

The orphan G-protein coupled receptor (GPCR), GPR18, has been recently proposed as a potential member of the cannabinoid family as it recognizes several endogenous, phytogenic, and synthetic cannabinoids. Potential therapeutic applications for GPR18 include intraocular pressure, metabolic disorders, and cancer. GPR18 has been reported to have high constitutive activity, i.e., activation/signaling occurs in the absence of an agonist. This activity can be reduced significantly by the A3.39N mutation. At the intracellular (IC) ends of (transmembrane helices) TMH3 and TMH6 in GPCRs, typically, a pair of oppositely charged amino acids form a salt bridge called the "ionic lock". Breaking of this salt bridge creates an IC opening for coupling with G protein. The GPR18 "ionic lock" residues (R3.50/S6.33) can form only a hydrogen bond. In this paper, we test the hypothesis that the high constitutive activity of GPR18 is due to the weakness of its "ionic lock" and that the A3.39N mutation strengthens this lock. To this end, we report molecular dynamics simulations of wild-type (WT) GPR18 and the A3.39N mutant in fully hydrated (POPC) phophatidylcholine lipid bilayers. Results suggest that in the A3.39N mutant, TMH6 rotates and brings R3.50 and S6.33 closer together, thus strengthening the GPR18 "ionic lock".

Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12.

GPR3, GPR6, and GPR12 are three orphan receptors that belong to the Class A family of G-protein-coupled receptors (GPCRs). These GPCRs share over 60% of sequence similarity among them. Because of their close phylogenetic relationship, GPR3, GPR6, and GPR12 share a high percentage of homology with other lipid receptors such as the lysophospholipid and the cannabinoid receptors. On the basis of sequence similarities at key structural motifs, these orphan receptors have been related to the cannabinoid family. However, further experimental data are required to confirm this association. GPR3, GPR6, and GPR12 are predominantly expressed in mammalian brain. Their high constitutive activation of adenylyl cyclase triggers increases in cAMP levels similar in amplitude to fully activated GPCRs. This feature defines their physiological role under certain pathological conditions. In this review, we aim to summarize the knowledge attained so far on the understanding of these receptors. Expression patterns, pharmacology, physiopathological relevance, and molecules targeting GPR3, GPR6, and GPR12 will be analyzed herein. Interestingly, certain cannabinoid ligands have been reported to modulate these orphan receptors. The current debate about sphingolipids as putative endogenous ligands will also be addressed. A special focus will be on their potential role in the brain, particularly under neurological conditions such as Parkinson or Alzheimer's disease. Reported physiological roles outside the central nervous system will also be covered. This critical overview may contribute to a further comprehension of the physiopathological role of these orphan GPCRs, hopefully attracting more research towards a future therapeutic exploitation of these promising targets.

Post-translational modifications of vertebrate striated muscle myosin heavy chains.

Post-translational modifications (PTMs) play a crucial role in regulating the function of many sarcomeric proteins, including myosin. Myosins comprise a family of motor proteins that play fundamental roles in cell motility in general and muscle contraction in particular. A myosin molecule consists of two myosin heavy chains (MyHCs) and two pairs of myosin light chains (MLCs); two MLCs are associated with the neck region of each MyHC's N-terminal head domain, while the two MyHC C-terminal tails form a coiled-coil that polymerizes with other MyHCs to form the thick filament backbone. Myosin undergoes extensive PTMs, and dysregulation of these PTMs may lead to abnormal muscle function and contribute to the development of myopathies and cardiovascular disorders. Recent studies have uncovered the significance of PTMs in regulating MyHC function and showed how these PTMs may provide additional modulation of contractile processes. Here, we discuss MyHC PTMs that have been biochemically and/or functionally studied in mammals' and rodents' striated muscle. We have identified hotspots or specific regions in three isoforms of myosin (MYH2, MYH6, and MYH7) where the prevalence of PTMs is more frequent and could potentially play a significant role in fine-tuning the activity of these proteins.

The CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls.

Cereblon/CRBN is a substrate-recognition component of the Cullin4A-DDB1-Roc1 E3 ubiquitin ligase complex. Destabilizing mutations in the human CRBN gene cause a form of autosomal recessive non-syndromic intellectual disability (ARNSID) that is modelled by knocking-out the mouse Crbn gene. A reduction in excitatory neurotransmission has been proposed as an underlying mechanism of the disease. However, the precise factors eliciting this impairment remain mostly unknown. Here we report that CRBN molecules selectively located on glutamatergic neurons are necessary for proper memory function. Combining various in vivo approaches, we show that the cannabinoid CB1 receptor (CB1R), a key suppressor of synaptic transmission, is overactivated in CRBN deficiency-linked ARNSID mouse models, and that the memory deficits observed in these animals can be rescued by acute CB1R-selective pharmacological antagonism. Molecular studies demonstrated that CRBN interacts physically with CB1R and impairs the CB1R-Gi/o-cAMP-PKA pathway in a ubiquitin ligase-independent manner. Taken together, these findings unveil that CB1R overactivation is a driving mechanism of CRBN deficiency-linked ARNSID and anticipate that the antagonism of CB1R could constitute a new therapy for this orphan disease.

Description of a bivalent cannabinoid ligand with hypophagic properties.

A series of bivalent cannabinoid ligands is proposed. The synthesis of double amides based on the rimonabant structure separated by an alkyl chain and the evaluation of their affinities for cannabinoid receptors are reported. The data of 4d confirmed that a bivalent structure is a suitable scaffold for CB1 cannabinoid receptor binding. The compound 4d was selected for in vitro and in vivo pharmacological evaluations. Moreover, intraperitoneal administration of 4d to food-deprived rats resulted in a dose-dependent inhibition of feeding that was maintained up to 240 min.

Viewpoint on the Second Transatlantic GPCR Symposium for Early Career Investigators.

The second Transatlantic Early Career Investigator (ECI) G Protein-Coupled Receptor (GPCR) Symposium was an online scientific meeting geared at young GPCR investigators, with the primary goal of expanding opportunities for sharing research and networking among trainees in North America and Europe. Here, we discuss the format of our meeting, its impact, and the challenges and opportunities facing meetings like it in the future.