Advancing Animal Models of Human Type 1 Diabetes.

Multiple rodent models have been developed to study the basis of type 1 diabetes (T1D). However, nonobese diabetic (NOD) mice and derivative strains still provide the gold standard for dissecting the basis of the autoimmune responses underlying T1D. Here, we review the developmental origins of NOD mice, and how they and derivative strains have been used over the past several decades to dissect the genetic and immunopathogenic basis of T1D. Also discussed are ways in which the immunopathogenic basis of T1D in NOD mice and humans are similar or differ. Additionally reviewed are efforts to "humanize" NOD mice and derivative strains to provide improved models to study autoimmune responses contributing to T1D in human patients.

Using a standalone ear-EEG device for focal-onset seizure detection.

BACKGROUND: Seizure detection is challenging outside the clinical environment due to the lack of comfortable, reliable, and practical long-term neurophysiological monitoring devices. We developed a novel, discreet, unobstructive in-ear sensing system that enables long-term electroencephalography (EEG) recording. This is the first study we are aware of that systematically compares the seizure detection utility of in-ear EEG with that of simultaneously recorded intracranial EEG. In addition, we present a similar comparison between simultaneously recorded in-ear EEG and scalp EEG. METHODS: In this foundational research, we conducted a clinical feasibility study and validated the ability of the ear-EEG system to capture focal-onset seizures against 1255 hrs of simultaneous ear-EEG data along with scalp or intracranial EEG in 20 patients with refractory focal epilepsy (11 with scalp EEG, 8 with intracranial EEG, and 1 with both). RESULTS: In a blinded, independent review of the ear-EEG signals, two epileptologists were able to detect 86.4% of the seizures that were subsequently identified using the clinical gold standard EEG modalities, with a false detection rate of 0.1 per day, well below what has been reported for ambulatory monitoring. The few seizures not detected on the ear-EEG signals emanated from deep within the mesial temporal lobe or extra-temporally and remained very focal, without significant propagation. Following multiple sessions of recording for a median continuous wear time of 13 hrs, patients reported a high degree of tolerance for the device, with only minor adverse events reported by the scalp EEG cohort. CONCLUSIONS: These preliminary results demonstrate the potential of using ear-EEG to enable routine collection of complementary, prolonged, and remote neurophysiological evidence, which may permit real-time detection of paroxysmal events such as seizures and epileptiform discharges. This study suggests that the ear-EEG device may assist clinicians in making an epilepsy diagnosis, assessing treatment efficacy, and optimizing medication titration.

Exploring Predictors of Ketamine Response in Adolescent Treatment-Resistant Depression.

Objective: Ketamine has proved effective as a rapid-acting antidepressant agent, but treatment is not effective for everyone (approximately a quarter to a half of patients). Some adult studies have begun to investigate predictors of ketamine's antidepressant response, but no studies have examined this in adolescents with depression. Methods: We conducted a secondary data analysis of adolescents who participated in a randomized, single-dose, midazolam-controlled crossover trial of ketamine for adolescents with treatment-resistant depression. We examined the relationship between 19 exploratory demographic and clinical variables and depression symptom improvement (using the Montgomery-Åsberg Depression Rating Scale [MADRS]) at 1 and 7 days postinfusion. Results: Subjects who had fewer medication trials of both antidepressant medications and augmentation treatments were more likely to experience depression symptom improvement with ketamine. Subjects with shorter duration of their current depressive episode were more likely to experience depression symptom improvement with ketamine. Subjects currently being treated with selective serotonin reuptake inhibitor medications, and not being treated with serotonin-norepinephrine reuptake inhibitor medications, also experienced greater symptom improvement with ketamine. When receiving the midazolam control, less severe depressive symptoms, as measured by the Children's Depression Rating Scale (CDRS) (but not MADRS), and a comorbid attention-deficit/hyperactivity disorder diagnosis were associated with increased response. Conclusions: Findings should be viewed as preliminary and exploratory given the small sample size and multiple secondary analyses. Identifying meaningful predictors of ketamine response is important to inform future therapeutic use of this compound, however, considerably more research is warranted before such clinical guidance is established. The trial was registered in clinicaltrials.gov with the identifier NCT02579928.

HLA-DQ8 Supports Development of Insulitis Mediated by Insulin-Reactive Human TCR-Transgenic T Cells in Nonobese Diabetic Mice.

In an effort to improve HLA-"humanized" mouse models for type 1 diabetes (T1D) therapy development, we previously generated directly in the NOD strain CRISPR/Cas9-mediated deletions of various combinations of murine MHC genes. These new models improved upon previously available platforms by retaining ß2-microglobulin functionality in FcRn and nonclassical MHC class I formation. As proof of concept, we generated H2-Db/H2-Kd double knockout NOD mice expressing human HLA-A*0201 or HLA-B*3906 class I variants that both supported autoreactive diabetogenic CD8+ T cell responses. In this follow-up work, we now describe the creation of 10 new NOD-based mouse models expressing various combinations of HLA genes with and without chimeric transgenic human TCRs reactive to proinsulin/insulin. The new TCR-transgenic models develop differing levels of insulitis mediated by HLA-DQ8-restricted insulin-reactive T cells. Additionally, these transgenic T cells can transfer insulitis to newly developed NSG mice lacking classical murine MHC molecules, but expressing HLA-DQ8. These new models can be used to test potential therapeutics for a possible capacity to reduce islet infiltration or change the phenotype of T cells expressing type 1 diabetes patient-derived ß cell autoantigen-specific TCRs.

Behavioral and physiological effects of ocean acidification and warming on larvae of a continental shelf bivalve.

The negative impacts of ocean warming and acidification on bivalve fisheries are well documented but few studies investigate parameters relevant to energy budgets and larval dispersal. This study used laboratory experiments to assess developmental, physiological and behavioral responses to projected climate change scenarios using larval Atlantic surfclams Spisula solidissima solidissima, found in northwest Atlantic Ocean continental shelf waters. Ocean warming increased feeding, scope for growth, and biomineralization, but decreased swimming speed and pelagic larval duration. Ocean acidification increased respiration but reduced immune performance and biomineralization. Growth increased under ocean warming only, but decreased under combined ocean warming and acidification. These results suggest that ocean warming increases metabolic activity and affects larval behavior, while ocean acidification negatively impacts development and physiology. Additionally, principal component analysis demonstrated that growth and biomineralization showed similar response profiles, but inverse response profiles to respiration and swimming speed, suggesting alterations in energy allocation under climate change.

The Relationship Between Acute Dissociative Effects Induced by Ketamine and Treatment Response in Adolescent Patients with Treatment-Resistant Depression.

Objective: Ketamine has proven effective as a rapid-acting antidepressant agent. Several adult studies have investigated the association between ketamine's acute dissociative effects and depression response, but no studies have examined the association in adolescents with treatment-resistant depression (TRD). Methods: We conducted a secondary data analysis of 16 adolescent participants who participated in a randomized, single-dose, midazolam-controlled crossover trial of ketamine in adolescents with depression. We examined the association between the acute dissociative symptoms (measured at 60 minutes following start of infusion using the Clinician-Administered Dissociative States Scale [CADSS], and its three subscales: depersonalization, derealization, amnesia) and response and depression symptom improvement at 1'day (using the Montgomery-Åsberg Depression Rating Scale). Results: Within the ketamine group, there were no significant associations between dissociation symptoms or CADSS subscale scores and magnitude of depression symptom improvement or likelihood of ketamine response. When receiving midazolam, there was no significant association between overall dissociation symptoms and magnitude or likelihood of response of depressive symptoms. Higher levels of symptoms on the 'depersonalization' CADSS subscale when receiving midazolam were associated with less improvement in depression symptoms at 1 day following infusion. Conclusions: In contrast to some adult literature, the current data do not show a relationship between acute dissociative effects and antidepressant response to ketamine in pediatric patients with TRD. Interpretation may be limited by the small sample size, reducing the power to detect small or medium associations. Future research should utilize larger samples to more definitively measure the magnitude of association between acute dissociative symptoms and later antidepressant response to ketamine and to assess the relationship to trial design (e.g., crossover vs. parallel trial, comparison condition utilized and number of infusions) within both adult and pediatric populations. ClinicalTrials.gov identifier: NCT02579928.

Dome1-JAK-STAT signaling between parasite and host integrates vector immunity and development.

Ancestral signaling pathways serve critical roles in metazoan development, physiology, and immunity. We report an evolutionary interspecies communication pathway involving a central Ixodes scapularis tick receptor termed Dome1, which acquired a mammalian cytokine receptor motif exhibiting high affinity for interferon-gamma (IFN-γ). Host-derived IFN-γ facilitates Dome1-mediated activation of the Ixodes JAK-STAT pathway. This accelerates tick blood meal acquisition and development while upregulating antimicrobial components. The Dome1-JAK-STAT pathway, which exists in most Ixodid tick genomes, regulates the regeneration and proliferation of gut cells-including stem cells-and dictates metamorphosis through the Hedgehog and Notch-Delta networks, ultimately affecting Ixodes vectorial competence. We highlight the evolutionary dependence of I. scapularis on mammalian hosts through cross-species signaling mechanisms that dually influence arthropod immunity and development.

Nfkbid Overexpression in Nonobese Diabetic Mice Elicits Complete Type 1 Diabetes Resistance in Part Associated with Enhanced Thymic Deletion of Pathogenic CD8 T Cells and Increased Numbers and Activity of Regulatory T Cells.

Type 1 diabetes (T1D) in both humans and NOD mice is caused by T cell-mediated autoimmune destruction of pancreatic ß cells. Increased frequency or activity of autoreactive T cells and failures of regulatory T cells (Tregs) to control these pathogenic effectors have both been implicated in T1D etiology. Due to the expression of MHC class I molecules on ß cells, CD8 T cells represent the ultimate effector population mediating T1D. Developing autoreactive CD8 T cells normally undergo extensive thymic negative selection, but this process is impaired in NOD mice and also likely T1D patients. Previous studies identified an allelic variant of Nfkbid, a NF-κB signal modulator, as a gene strongly contributing to defective thymic deletion of autoreactive CD8 T cells in NOD mice. These previous studies found ablation of Nfkbid in NOD mice using the clustered regularly interspaced short palindromic repeats system resulted in greater thymic deletion of pathogenic CD8 AI4 and NY8.3 TCR transgenic T cells but an unexpected acceleration of T1D onset. This acceleration was associated with reductions in the frequency of peripheral Tregs. In this article, we report transgenic overexpression of Nfkbid in NOD mice also paradoxically results in enhanced thymic deletion of autoreactive CD8 AI4 T cells. However, transgenic elevation of Nfkbid expression also increased the frequency and functional capacity of peripheral Tregs, in part contributing to the induction of complete T1D resistance. Thus, future identification of a pharmaceutical means to enhance Nfkbid expression might ultimately provide an effective T1D intervention approach.

Host CLIC4 expression in the tumor microenvironment is essential for breast cancer metastatic competence.

The TGF-ß-regulated Chloride Intracellular Channel 4 (CLIC4) is an essential participant in the formation of breast cancer stroma. Here, we used data available from the TCGA and METABRIC datasets to show that CLIC4 expression was higher in breast cancers from younger women and those with early-stage metastatic disease. Elevated CLIC4 predicted poor outcome in breast cancer patients and was linked to the TGF-ß pathway. However, these associations did not reveal the underlying biological contribution of CLIC4 to breast cancer progression. Constitutive ablation of host Clic4 in two murine metastatic breast cancer models nearly eliminated lung metastases without reducing primary tumor weight, while tumor cells ablated of Clic4 retained metastatic capability in wildtype hosts. Thus, CLIC4 was required for host metastatic competence. Pre- and post-metastatic proteomic analysis identified circulating pro-metastatic soluble factors that differed in tumor-bearing CLIC4-deficient and wildtype hosts. Vascular abnormalities and necrosis increased in primary tumors from CLIC4-deficient hosts. Transcriptional profiles of both primary tumors and pre-metastatic lungs of tumor-bearing CLIC4-deficient hosts were consistent with a microenvironment where inflammatory pathways were elevated. Altogether, CLIC4 expression in human breast cancers may serve as a prognostic biomarker; therapeutic targeting of CLIC4 could reduce primary tumor viability and host metastatic competence.

Efficacy of Intravenous Ketamine in Adolescent Treatment-Resistant Depression: A Randomized Midazolam-Controlled Trial.

Objective: Adolescent depression is prevalent and is associated with significant morbidity and mortality. Although intravenous ketamine has shown efficacy in adult treatment-resistant depression, its efficacy in pediatric populations is unknown. The authors conducted an active-placebo-controlled study of ketamine's safety and efficacy in adolescents. Methods: In this proof-of-concept randomized, double-blind, single-dose crossover clinical trial, 17 adolescents (ages 13-17) with a diagnosis of major depressive disorder received a single intravenous infusion of either ketamine (0.5 mg/kg over 40 minutes) or midazolam (0.045 mg/kg over 40 minutes), and the alternate compound 2 weeks later. All participants had previously tried at least one antidepressant medication and met the severity criterion of a score >40 on the Children's Depression Rating Scale-Revised. The primary outcome measure was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 24 hours after treatment. Results: A single ketamine infusion significantly reduced depressive symptoms 24 hours after infusion compared with midazolam (MADRS score: midazolam, mean=24.13, SD=12.08, 95% CI=18.21, 30.04; ketamine, mean=15.44, SD=10.07, 95% CI=10.51, 20.37; mean difference=-8.69, SD=15.08, 95% CI=-16.72, -0.65, df=15; effect size=0.78). In secondary analyses, the treatment gains associated with ketamine appeared to remain 14 days after treatment, the latest time point assessed, as measured by the MADRS (but not as measured by the Children's Depression Rating Scale-Revised). A significantly greater proportion of participants experienced a response to ketamine during the first 3 days following infusion as compared with midazolam (76% and 35%, respectively). Ketamine was associated with transient, self-limited dissociative symptoms that affected participant blinding, but there were no serious adverse events. Conclusions: In this first randomized placebo-controlled clinical trial of intravenous ketamine in adolescents with depression, the findings suggest that it is well tolerated acutely and has significant short-term (2-week) efficacy in reducing depressive symptoms compared with an active placebo.Reprinted from Am J Psychiatry 2021; 178:352-362 with permission from American Psychiatric Association Publishing.

Nuclear pore protein NUP210 depletion suppresses metastasis through heterochromatin-mediated disruption of tumor cell mechanical response.

Mechanical signals from the extracellular microenvironment have been implicated in tumor and metastatic progression. Here, we identify nucleoporin NUP210 as a metastasis susceptibility gene for human estrogen receptor positive (ER+) breast cancer and a cellular mechanosensor. Nup210 depletion suppresses lung metastasis in mouse models of breast cancer. Mechanistically, NUP210 interacts with LINC complex protein SUN2 which connects the nucleus to the cytoskeleton. In addition, the NUP210/SUN2 complex interacts with chromatin via the short isoform of BRD4 and histone H3.1/H3.2 at the nuclear periphery. In Nup210 knockout cells, mechanosensitive genes accumulate H3K27me3 heterochromatin modification, mediated by the polycomb repressive complex 2 and differentially reposition within the nucleus. Transcriptional repression in Nup210 knockout cells results in defective mechanotransduction and focal adhesion necessary for their metastatic capacity. Our study provides an important role of nuclear pore protein in cellular mechanosensation and metastasis.

Clinical trial of raltegravir, an integrase inhibitor, in HAM/TSP.

OBJECTIVE: Human T-cell lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive myelopathy. A high proviral load (PVL) is one of the main risk factors for HAM/TSP. Recently, it was shown that raltegravir could inhibit cell-free and cell-to-cell transmission of HTLV-1 in vitro. Given the substantial clinical experience in human immunodeficiency virus infection and its excellent safety profile, this agent may be an attractive therapeutic option for HAM/TSP patients. METHODS: Sixteen subjects with HAM/TSP received raltegravir 400 mg orally twice daily in an initial 6-month treatment phase, followed by a 9-month post-treatment phase. HTLV-1 PVLs were assessed using droplet digital PCR from the PBMCs every 3 months, and from the CSF at baseline, month 6, and month 15. We also evaluated the ability of raltegravir to regulate abnormal immune responses in HAM/TSP patients. RESULTS: While a downward trend was observed in PBMC and/or CSF PVLs of some patients, raltegravir overall did not have any impact on the PVL in this HAM/TSP patient cohort. Clinically, all patients' neurological scores and objective measurements remained relatively stable, with some expected variability. Immunologic studies showed alterations in the immune profiles of a subset of patients including decreased CD4+ CD25+ T cells and spontaneous lymphoproliferation. INTERPRETATION: Raltegravir was generally well tolerated in this HAM/TSP patient cohort. A subset of patients exhibited a mild decrease in PVL as well as variations in their immune profiles after taking raltegravir. These findings suggest that raltegravir may be a therapeutic option in select HAM/TSP patients. CLINICAL TRIAL REGISTRATION NUMBER: NCT01867320.

Meta-Analysis: Hemodynamic Responses to Sub-anesthetic Doses of Ketamine in Patients With Psychiatric Disorders.

Ketamine, a medication traditionally used as an anesthetic, has increasingly been recognized as an effective treatment for psychiatric disorders. At sub-anesthetic doses (defined here as ≤ 0.5 mg/kg), ketamine treatment has been studied in patients with treatment-resistant depression (TRD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and social anxiety disorder (SAD). Transient increases in hemodynamic activity have been reported during and after ketamine treatment, which may be desirable properties in some anesthesia settings, but are generally undesirable in psychiatric settings. While ketamine doses used in psychiatry are lower than those used in anesthesia, there are published instances of early termination of psychiatric ketamine infusions due to elevations in blood pressure and heart rate. No unifying study has been conducted to examine the impact of sub-anesthetic ketamine doses on hemodynamic parameters [systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR)] in psychiatric populations and to evaluate these changes across adult age groups. Here, data from 15 articles comprising a total N = 2,252 ketamine or esketamine treatments in adult participants were used to conduct a meta-analysis of treatment-induced hemodynamic changes. Ketamine/esketamine produced modest but significant increases in the variables of interest with an average SBP increase of 12.61 mm Hg (95% CI 10.40-14.82 mm Hg, z = 11.18, p < 0.0001), average DBP increase of 8.49 mm Hg (95% CI 6.89-10.09 mmHg, z = 10.41, p < 0.0001), and average heart rate increase of 4.09 beats per minute (95% CI 0.55-7.63 BPM), z = 2.27, p = 0.0235). Stratified subgroup analysis indicated no significant differences between ketamine and esketamine effects on blood pressure. Further analysis indicated that there was no significant effect of age on ketamine-induced changes in SBP, DBP, and HR. Taken together these data show that sub-anesthetic ketamine and esketamine induce small but significant increases in hemodynamic parameters that are transient in nature in adult psychiatric populations. While these data are reassuring, it is important for each treatment case to fully explore potential cardiovascular risks prior to initiating treatment.

Efficacy of Intravenous Ketamine in Adolescent Treatment-Resistant Depression: A Randomized Midazolam-Controlled Trial.

OBJECTIVE: Adolescent depression is prevalent and is associated with significant morbidity and mortality. Although intravenous ketamine has shown efficacy in adult treatment-resistant depression, its efficacy in pediatric populations is unknown. The authors conducted an active-placebo-controlled study of ketamine's safety and efficacy in adolescents. METHODS: In this proof-of-concept randomized, double-blind, single-dose crossover clinical trial, 17 adolescents (ages 13-17) with a diagnosis of major depressive disorder received a single intravenous infusion of either ketamine (0.5 mg/kg over 40 minutes) or midazolam (0.045 mg/kg over 40 minutes), and the alternate compound 2 weeks later. All participants had previously tried at least one antidepressant medication and met the severity criterion of a score >40 on the Children's Depression Rating Scale-Revised. The primary outcome measure was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 24 hours after treatment. RESULTS: A single ketamine infusion significantly reduced depressive symptoms 24 hours after infusion compared with midazolam (MADRS score: midazolam, mean=24.13, SD=12.08, 95% CI=18.21, 30.04; ketamine, mean=15.44, SD=10.07, 95% CI=10.51, 20.37; mean difference=-8.69, SD=15.08, 95% CI=-16.72, -0.65, df=15; effect size=0.78). In secondary analyses, the treatment gains associated with ketamine appeared to remain 14 days after treatment, the latest time point assessed, as measured by the MADRS (but not as measured by the Children's Depression Rating Scale-Revised). A significantly greater proportion of participants experienced a response to ketamine during the first 3 days following infusion as compared with midazolam (76% and 35%, respectively). Ketamine was associated with transient, self-limited dissociative symptoms that affected participant blinding, but there were no serious adverse events. CONCLUSIONS: In this first randomized placebo-controlled clinical trial of intravenous ketamine in adolescents with depression, the findings suggest that it is well tolerated acutely and has significant short-term (2-week) efficacy in reducing depressive symptoms compared with an active placebo.

Glutamate Systems in DSM-5 Anxiety Disorders: Their Role and a Review of Glutamate and GABA Psychopharmacology.

Serotonin reuptake inhibitors and benzodiazepines are evidence-based pharmacological treatments for Anxiety Disorders targeting serotonin and GABAergic systems, respectively. Although clearly effective, these medications fail to improve anxiety symptoms in a significant proportion of patients. New insights into the glutamate system have directed attention toward drugs that modulate glutamate as potential alternative treatments for anxiety disorders. Here we summarize the current understanding of the potential role of glutamate neurotransmission in anxiety disorders and highlight specific glutamate receptors that are potential targets for novel anxiety disorder treatments. We also review clinical trials of medications targeting the glutamate system in DSM-5 anxiety disorders. Understanding the role of the glutamate system in the pathophysiology of anxiety disorder may aid in developing novel pharmacological agents that are effective in treating anxiety disorders.

Inter-Institutional Partnerships to Develop Veterinarian-Investigators through the NIH Comparative Biomedical Scientist Training Program Benefit One Health Goals.

Limitations in workforce size and access to resources remain perennial challenges to greater progress in academic veterinary medicine and engagement between human and veterinary medicine (One Health). Ongoing resource constraints occur in part due to limited public understanding of the role veterinarians play in improving human health. One Health interactions, particularly through interdisciplinary collaborations in biomedical research, present constructive opportunities to inform resource policies and advance health care. To this end, inter-institutional partnerships between individual veterinary medical education programs (VMEPs) and several National Institutes of Health (NIH) intramural research programs have created synergies beyond those provided by individual programs. In the NIH Comparative Biomedical Scientist Training Program (CBSTP), interdisciplinary cross-training of veterinarians consisting of specialty veterinary medicine coupled with training in human disease research leading to a PhD, occurs collaboratively on both VMEP and NIH campuses. Pre-doctoral veterinary student research opportunities have also been made available. Through the CBSTP, NIH investigators and national biomedical science policy makers gain access to veterinary perspective and expertise, while veterinarians obtain additional opportunities for NIH-funded research training. CBSTP Fellows serve as de facto ambassadors enhancing visibility for the profession while in residence at NIH, and subsequently through a variety of university, industry, and government research appointments, as graduates. Thus, the CBSTP represents an inter-institutional opportunity that not only addresses critical needs for veterinarian-scientists in the biomedical workforce, but also simultaneously exposes national policy makers to veterinarian-scientists' specialized training, leading to more effective realization of One Health goals to benefit human and animal health.

Efficacy, Tolerability, and Pharmacokinetics of Combined Targeted MEK and Dual mTORC1/2 Inhibition in a Preclinical Model of Mucosal Melanoma.

Melanomas arising in the mucous membranes are a rare and aggressive subtype. New treatment approaches are needed, yet accumulating sufficient evidence to improve patient outcomes is difficult. Clinical and pathological correlates between human and canine mucosal melanomas are substantial, and the relatively greater incidence of spontaneous naturally occurring mucosal melanoma in dogs represents a promising opportunity for predictive modeling. The genomic landscapes of human and canine mucosal melanoma appear highly diverse and generally lack recurring hotspot mutations associated with cutaneous melanomas. Although much remains to be determined, evidence indicates that Ras/MAPK and/or PI3K/AKT/mTOR signaling pathway activations are common in both species and may represent targets for therapeutic intervention. Sapanisertib, an mTORC1/2 inhibitor, was selected from a PI3K/mTOR inhibitor library to collaborate with MEK inhibition; the latter preclinical efficacy was demonstrated previously for canine mucosal melanoma. Combined inhibition of MEK and mTORC1/2, using trametinib and sapanisertib, produced apoptosis and cell-cycle alteration, synergistically reducing cell survival in canine mucosal melanoma cell lines with varying basal signaling activation levels. Compared with individual inhibitors, a staggered sapanisertib dose, coupled with daily trametinib, was optimal for limiting primary mucosal melanoma xenograft growth in mice, and tumor dissemination in a metastasis model, while minimizing hematologic and renal side effects. Inhibitors downmodulated respective signaling targets and the combination additionally suppressed pathway reciprocal crosstalk. The combination did not significantly change plasma sapanisertib pharmacokinetics; however, trametinib area under the curve was increased in the presence of sapanisertib. Targeting Ras/MAPK and PI3K/AKT/mTOR signal transduction pathways appear rational therapies for canine and human mucosal melanoma.

Hormonal Treatments for Major Depressive Disorder: State of the Art.

Major depressive disorder is a common psychiatric disorder associated with marked suffering, morbidity, mortality, and cost. The World Health Organization projects that by 2030, major depression will be the leading cause of disease burden worldwide. While numerous treatments for major depression exist, many patients do not respond adequately to traditional antidepressants. Thus, more effective treatments for major depression are needed, and targeting certain hormonal systems is a conceptually based approach that has shown promise in the treatment of this disorder. A number of hormones and hormone-manipulating compounds have been evaluated as monotherapies or adjunctive treatments for major depression, with therapeutic actions attributable not only to the modulation of endocrine systems in the periphery but also to the CNS effects of hormones on non-endocrine brain circuitry. The authors describe the physiology of the hypothalamic-pituitary-adrenal (HPA), hypothalamic-pituitary thyroid (HPT), and hypothalamic-pituitary-gonadal (HPG) axes and review the evidence for selected hormone-based interventions for the treatment of depression in order to provide an update on the state of this field for clinicians and researchers. The review focuses on the HPA axis-based interventions of corticotropin-releasing factor antagonists and the glucocorticoid receptor antagonist mifepristone, the HPT axis-based treatments of thyroid hormones (T3 and T4), and the HPG axis-based treatments of estrogen replacement therapy, the progesterone derivative allopregnanolone, and testosterone. While some treatments have largely failed to translate from preclinical studies, others have shown promising initial results and represent active fields of study in the search for novel effective treatments for major depression.

Annual Research Review: Defining and treating pediatric treatment-resistant depression.

BACKGROUND: Adolescent major depressive disorder (MDD) is a significant health problem, associated with substantial morbidity, cost, and mortality. Depression is a significant risk factor for suicide, which is now the second leading cause of death in young people. Up to twenty per cent of adolescents will experience MDD before adulthood, and while a substantial proportion will improve with standard-of-care treatments (psychotherapy and medication), roughly one third will not. METHODS: Here, we have reviewed the literature in order to discuss the concept of treatment-resistant depression (TRD) in adolescence, examine risk factors, diagnostic difficulties, and challenges in evaluating symptom improvement, and providing guidance on how to define adequate medication and psychotherapy treatment trials. RESULTS: We propose a staging model for adolescent TRD and review the treatment literature. The evidence base for first- and second-line treatments primarily derives from four large pediatric clinical trials (TADS, TORDIA, ADAPT, and IMPACT). After two medications and a trial of evidence-based psychotherapy have failed to alleviate depressive symptoms, the evidence becomes quite thin for subsequent treatments. Here, we review the evidence for the effectiveness of medication switches, medication augmentation, psychotherapy augmentation, and interventional treatments (i.e., transcranial magnetic stimulation, electroconvulsive therapy, and ketamine) for adolescent TRD. Comparisons are drawn to the adult TRD literature, and areas for future pediatric depression research are highlighted. CONCLUSIONS: As evidence is limited for treatments in this population, a careful consideration of the known risks and side effects of escalated treatments (e.g., mood stabilizers and atypical antipsychotics) is warranted and weighed against potential, but often untested, benefits.