Healthcare resource utilisation and suicidal ideation amongst adolescents in the US with posttraumatic stress disorder, major depressive disorder, and substance use disorders using electronic health records.

BACKGROUND: While PTSD is commonly associated with multiple comorbidities, studies have yet to quantify the impact of these comorbidities on key clinical outcomes and HCRU. This study explored risks of emergency room (ER) visits, inpatient admissions (IA), suicidal ideation (SI), and treatment follow-up duration (FU), amongst PTSD patients with comorbid MDD and/or SUD. METHODS: Using real-world data (RWD) generated by electronic health records accessed from the NeuroBlu database, a cohort of adolescent patients (12-17 yrs) was examined over a one-year study period following PTSD diagnosis. RESULTS: 5794 patients were included in the cohort. Compared to patients with only PTSD (n = 3061), those with comorbid MDD (n = 1820) had greater odds of ER (4.5 times), IA (1.6 times), and FU (4.3 times). Those with comorbid SUD (n = 653) had greater odds of IA (4.5 times), shorter FU (34 days), and lower odds of ER (0.5 times). Both comorbidities (n = 260) had greater odds of ER (3.8 times), IA (2.6 times), SI (3.6 times), and shorter FU (12 days). LIMITATIONS: These RWD had a high proportion of missingness. Health records of patients who changed service providers could not be accounted for in this study. CONCLUSIONS: Both MDD and SUD substantially elevated the risk of HCRU and suicidal ideation for PTSD patients.

The influence of socio-economic status on child temperament and psychological symptom profiles.

The influence of socio-economic status (SES) on child temperament and psychological symptoms was examined using a nationally representative sample in Singapore. Data were available for 2169 children from 1987 families. Caregivers' reports were obtained on children aged 4-6. SES was operationalized as an aggregation of household income per capita, parental education level and housing type. Compared to their counterparts from higher SES families, children from low-SES families tended to exhibit (a) higher negative affectivity but lower effortful control, and (b) higher internalizing and externalizing symptoms. In addition, children with a 'resilient' temperamental profile (i.e. low negative affectivity and high effortful control) were more likely to come from families with much higher SES, relative to children with other profiles. Children with high internalizing symptoms tended to come from low-SES backgrounds, regardless of their externalizing symptoms. Among children with low internalizing symptoms, those with high externalizing symptoms came from lower SES backgrounds compared to those with low externalizing symptoms. Parental warmth and distress mediated the association between SES and child temperament and symptom profiles, with the exception of distress in the SES-temperament link. These findings supported the family stress model and highlighted the novel perspective of SES's influence on configurations of child temperament and symptom characteristics.

Long-term Efficacy and Safety Following Switch Between Upadacitinib and Adalimumab in Patients with Rheumatoid Arthritis: 5-Year Data from SELECT-COMPARE.

INTRODUCTION: This study aimed to describe the long-term efficacy and safety of upadacitinib and adalimumab through 228 weeks following immediate switch to the alternate therapy with a different mechanism of action (MoA) in patients with rheumatoid arthritis (RA) not achieving treatment goals with their initial randomized therapy in the ongoing phase 3 SELECT-COMPARE study. METHODS: Patients with non-response or incomplete response to initially prescribed upadacitinib 15 mg once daily or adalimumab 40 mg every other week were switched to the alternate therapy by week 26. Efficacy was evaluated through 228 weeks post-switch using validated outcome measures, including Clinical Disease Activity Index (CDAI) low disease activity (LDA; ≤ 10)/remission (≤ 2.8); 28-joint Disease Activity Score based on C-reactive protein ≤ 3.2/< 2.6; ≥ 20%/50%/70% improvement in American College of Rheumatology (ACR) response criteria; and change from baseline in ACR core components. Data are reported as observed. Safety was assessed by treatment-emergent adverse events (TEAEs) through week 264. RESULTS: Of patients initially randomized to upadacitinib and adalimumab, 38.7% and 48.6%, respectively, switched to the alternate therapy by week 26. Clinically relevant improvements in all efficacy measures were observed through 228 weeks post-switch and were generally similar between groups, with small numeric differences mostly in favor of switching to upadacitinib. CDAI remission was achieved by 32.7% and 28.6% of initial non-responders, and 27.5% and 27.3% of incomplete responders, while CDAI LDA was achieved by 76.9% and 72.9% of non-responders, and 72.5% and 72.7% of incomplete responders switching to upadacitinib and to adalimumab, respectively. TEAE rates were similar between groups, although herpes zoster infection, lymphopenia, and creatine phosphokinase elevation were more frequent when switching to upadacitinib. No new safety signals were identified. CONCLUSION: Switching to a different MoA may provide long-term benefit to patients with RA not achieving treatment goals with their initial therapy, with acceptable safety profiles. TRIAL REGISTRATION: NCT02629159.

Here Puppy, Chew on This: Short-Term Provision of Toys Does Not Improve Welfare in Companion Dogs.

Retail dog toys are often provided to companion animals to provide cognitive and physical stimu- lation and improve the animals' quality of life. These toys, sometimes known as "enrichment toys", have been shown to play a role in increasing appetite and activity levels and decreasing undesirable behaviors (e.g., barking, self-isolating behaviors) in some domestic dog (Canis familiaris) populations. In this study, we evaluate the effect of toys on appetite, activity levels, and positive affective states as measures of well- being in companion dogs. Behaviors were compared before and after regular interactions with different types of toys over twelve days. We found that provisioning companion dogs with toys did not significantly alter their activity level, rate of food consumption, or cognitive bias. While dogs who received more complex toys showed a slightly improved cognitive bias, there were no significant differences in behaviors be- tween the subjects who received "less complex" toys (e.g., a bone, ball) and "more complex" toys (e.g., puzzle toys). We conclude with reflections on the relevance of our subject population to the result seen, and on the different forms of the cognitive bias test.

Associations of comorbid substance use disorders with clinical outcomes in schizophrenia using electronic health record data.

BACKGROUND AND HYPOTHESIS: Schizophrenia and comorbid substance use disorders (SUDs) are associated with poor treatment outcomes but differences between the associations of different SUDs with clinical outcomes are poorly characterized. This study examines the associations of comorbid SUDs with clinical outcomes in schizophrenia using a largescale electronic health record (EHR) database. DESIGN: Real-world data (RWD) analysis using the NeuroBlu database; de-identified EHR data were analysed. Multivariable logistic regression, Poisson and CoxPH models were used to compare the associations of specific comorbid SUDs with outcome variables. RESULTS: Comorbid SUD was significantly different on all outcome measures compared to no SUD (U = 1.44e7-1.81e7, all ps < .001), except number of unique antipsychotics (U = 1.61e7, p = .43). Cannabis (OR = 1.58, p < .001) and polysubstance (OR = 1.22, p = .007) use disorders were associated with greater CGI-S. Cannabis (IRR = 1.13, p = .003) and polysubstance (IRR = 1.08, p = .003) use disorders were associated with greater number of unique antipsychotics prescribed, while cocaine (HR = 1.87, p < .001), stimulants (HR = 1.64, p = .024), and polysubstance (HR = 1.46, p < .001) use disorders were associated with a shorter time to antipsychotic discontinuation. Conversely, alcohol use (IRR = 0.83, p < .001), cocaine use (IRR = 0.61, p < .001), opioid use (IRR = 0.61, p < .001), stimulant use (IRR = 0.57, p < .001) and polysubstance use (IRR = 0.87, p < .001) disorders were associated fewer inpatient days. CONCLUSION: Comorbid SUDs were generally associated with greater CGI-S and poorer clinical outcomes in patients with schizophrenia. Treatment strategies should target not only schizophrenia symptoms but also comorbid SUD to improve management of both conditions.

Honest, Open, Proud (HOP) for people with mental illness in Hong Kong: a randomized controlled trial.

BACKGROUND: Self-stigma among people with mental illness is negatively associated with personal and clinical recovery. Due to the concealable nature of mental illness, people with mental illness experience constant struggles between concealment and disclosure. Disclosure of mental health challenges can potentially minimize negative impacts of self-stigma and enhance self-esteem and sense of empowerment. Honest, Open, Proud (HOP) is a peer-led intervention that promotes autonomous and dignified decisions about disclosure. PURPOSE: This study examined the effectiveness of HOP on concealment motivation, empowerment, self-stigma, stigma stress, and recovery among people with lived experience of mental illness in Hong Kong. METHODOLOGY: A total of 162 participants with a mean age of 45.38 were recruited and randomized into intervention group and waitlist control group. Participants in the intervention group were invited to attend a 6-session HOP group intervention. RESULTS: Significant improvement in optimism score from the empowerment scale was found in the intervention group compared to the waitlist control group and the effect was sustained at 1-month follow-up. However, significant changes were not found in other outcome variables. CONCLUSION: Only improvement in optimism was observed in the current study. Future study needs to examine the effects of HOP with further modification to maximize the benefit for people with lived experience of mental illness in the local context.

Emotion dysregulation and symptoms of anxiety and depression in early adolescence: Bidirectional longitudinal associations and the antecedent role of parent-child attachment.

Difficulties in emotion regulation have been consistently associated with various psychological difficulties, including anxiety and depression; however, less is known about the directionality of this relationship, particularly in adolescents. In addition, early parent-child attachment quality has been closely linked to the development of emotion regulation. Previous studies have proposed an overarching model in attempt to describe the developmental trajectory of anxiety and depression from early attachment, albeit with several limitations that are discussed in this paper. This study adds to this field of research by investigating the longitudinal associations between emotion dysregulation (ED) and symptoms of anxiety and depression among 534 early adolescents in Singapore over three timepoints in a school year, and the antecedent role of attachment quality on individual differences on these variables. Bidirectional influences were found between ED and anxiety and depression symptoms, respectively, between T1 and T2, but not T2 and T3, at the between- and within-individual levels of analysis. Additionally, attachment anxiety and avoidance were both significantly predictive of individual differences in ED and for both psychological symptoms. The current findings provide preliminary evidence of a mutually reinforcing relationship between ED and symptoms of anxiety and depression in early adolescence, where attachment quality serves as a developmental antecedent that sets these longitudinal associations in motion.

Associations between public and self-stigma of help-seeking with help-seeking attitudes and intention: A meta-analytic structural equation modeling approach.

The present study examined the association between help-seeking public stigma and help-seeking self-stigma (i.e., internalization of stigma) and the relative association of both types of stigma with help-seeking attitude and intention using a full-information meta-analytic structural equation modeling approach. We also investigated the moderating effect of gender, age, collectivism, and social group in the internalization process. Results from 115 independent samples containing data from 54,793 individuals showed that public stigma of help-seeking was strongly and positively associated with self-stigma of help-seeking. Moreover, after controlling for the effect of each other, self-stigma, but not public stigma, remained significantly associated with help-seeking attitude and help-seeking intention. Gender, age, collectivism, and social group did not significantly moderate the association between public and self-stigma. The findings highlight that people who perceive more stigma of help-seeking from others tend to have higher levels of self-stigma. Compared with help-seeking public stigma, help-seeking self-stigma might have a larger impact on one's help-seeking attitude and intention. Help-seeking promotion campaigns should be devised to tackle both types of stigma to foster positive help-seeking attitude and intention. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Effects of financial toxicity on prescription drug use and mental well-being in cancer patients.

Background: In the US, medical costs for cancer patients have grown from $27 billion in 1990 to $174 billion in 2020. The increased financial strain that cancer patients and survivors endure is referred to as financial toxicity. Objective: To quantify the relationship between indicators of financial toxicity and health utilization and quality of life in patients ever diagnosed with cancer. Methods: Adult cancer patients and survivors in 2017 were identified using the Medical Expenditure Panel Survey. Multiple logistic regression models were used to quantify the relationship between three financial toxicity exposures (concern for keeping an income, paying large medical bills, and going into debt or borrowing money) and two discrete outcomes of being able to purchase prescriptions and often worrying that cancer would worsen or come back. Results: This study assessed 609 respondents. After survey weighting was applied, that represented 16,215,673 individuals. Patients who reported concern for keeping an income were at 2.91 (95% Confidence Interval [CI], 1.16 to 7.31) and 2.97 (95% CI, 2.01 to 2.67) times increased odds to report avoiding purchase of prescriptions and worry of cancer status, respectively, versus those who did not. Patients who reported worry about paying large medical bills were at 4.46 (95% CI, 2.15 to 9.24) and 2.80 (95% CI, 1.98 to 3.96) times increased odds to report avoiding purchase of prescriptions and worry of cancer status, respectively, versus those who did not. Patients who reported borrowing money or going into debt were at 3.04 (95% CI, 1.19 to 7.76) and 2.42 (95% CI, 1.54 to 3.18) times increased odds to report avoiding purchase of prescriptions and worry of cancer status, respectively, versus those who did not. Conclusions: Financial toxicity is associated with decreased prescription utilization and quality of life in the form of excessive worry among cancer patients including cancer survivors.

Safety of apixaban for venous thromboembolic primary prophylaxis in patients with newly diagnosed malignant glioma.

The cumulative incidence of symptomatic venous thromboembolism (VTE) among patients with malignant gliomas (MG) is estimated to be as high as 36% during the course of therapy. Development of VTE is associated with an increased risk of hospitalization, delays in cancer treatment, and an increased risk of complications including intracranial hemorrhage as well as VTE specific symptoms. Despite the high risk of VTE and associated morbidity, there is no standard recommendations regarding long term outpatient VTE prophylaxis in patients with MG due to the lack of clinical trial evidence in this patient population. In this study, we treated ten patients with newly diagnosed MG with apixaban, 2.5 mg twice daily beginning 2-21 days after craniotomy and continuing for up to 6 months. Unacceptable toxicity was defined by ≥ grade 2 CNS or non-CNS hemorrhage, a thromboembolic event (i.e. stroke) or cardiovascular event requiring anticoagulation or anti-platelet therapy. There were no unacceptable toxicities to report and no treatment-related adverse events. None of the patients on the study were diagnosed with a VTE while receiving apixaban. We conclude that apixaban can be given safely to patients with primary MG shortly after craniotomy and should be considered for VTE prevention in these high-risk patients.

Internalization process of stigma of people with mental illness across cultures: A meta-analytic structural equation modeling approach.

This meta-analytic study synthesized findings from 108 independent data sets across 22 cultures to investigate whether the stigma internalization model (the internalization of experienced stigma and perceived stigma to self-stigma) is associated with well-being and recovery of people with mental illness. We also examined the moderating role of collectivism in the internalization process. Results of the meta-analytic structural equation modeling suggested that self-stigma is a significant mediator in the relationships between experienced stigma and perceived stigma with well-being and recovery variables (indirect effects = 0.02 to -0.16). Experienced and perceived stigma had significant direct effects on well-being and recovery variables (Bs = 0.07 to -0.21, p < 0.05), suggesting that both external (e.g., public stigma) and internal (i.e., self-stigma) influences of stigma work concurrently to affect recovery and well-being of people with mental illness. The results of the mixed effect three-level meta-analytic models showed that collectivism significantly moderated the relationship between experienced and perceived stigma with self-stigma (Bs = 0.06 to 0.11, p < 0.05). This implied that the more collectivistic a culture is, the stronger the correlation between experienced and perceived stigma with self-stigma. Implications to stigma reduction approaches were discussed.

Transthyretin Amyloid Cardiomyopathy-Current and Future Therapies.

OBJECTIVE: To describe the clinical presentation of transthyretin amyloid cardiomyopathy (ATTR-CM) and discuss current treatments and investigational products and their effect on patient outcomes. DATA SOURCES: A literature search was performed in PubMed (September 2018 to December 2020) using the following keywords: transthyretin amyloidosis, cardiomyopathy, polyneuropathy and transthyretin amyloid cardiomyopathy, monoclonal light-chain, tafamidis, cardiac amyloidosis, ATTR cardiomyopathy, green tea and inhibition of cardiac amyloidosis, AG10, tolcapone, tolcapone and leptomeningeal ATTR, PRX004, NI006, patisiran, inotersen, vutrisiran, AKCEA-TTR-LRx, and NTLA-2001. STUDY SELECTION AND DATA EXTRACTION: Clinical trials were evaluated for evidence supporting pharmacology, safety, efficacy, and measured outcomes. DATA SYNTHESIS: Until 2019, there were no approved treatments for ATTR-CM. Treatment consisted of symptom management and organ transplant. Nonpharmacological and pharmacological treatments focused on the symptoms of heart failure (HF) associated with ATTR-CM. However, there are several emerging therapies recently approved or in development to address the underlying pathophysiology. Treatment classes for ATTR-CM include transthyretin stabilizers, human monoclonal antibodies, gene silencers, and CRISPR/Cas9 gene editing. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: ATTR-CM is a complex disease in which amyloidosis causes cardiomyopathy. Underdiagnosis is attributed to the clinical presentation being heterogeneous, indistinguishable from HF caused by other etiologies, and the need for invasive testing modalities, including endomyocardial biopsy. Improved diagnostic approaches along with targeted therapies can slow disease progression and enhance patient quality of life. CONCLUSION: Diagnostic modalities along with biomarker and genetic testing could detect disease earlier and target therapy more accurately. Novel therapies demonstrate potential treatment benefits and can help shape the standard of care for these patients.

PROLACTIN LEVELS DO NOT RISE AMONG TRANSGENDER WOMEN TREATED WITH ESTRADIOL AND SPIRONOLACTONE.

OBJECTIVE: Existing transgender treatment guidelines suggest that there is a need to monitor prolactin levels in patients receiving transfeminine hormone treatment. Also, recent studies suggest that use of cyproterone acetate as an adjunctive anti-androgen during transgender hormone treatment may elevate serum prolactin. We sought to determine whether the reported relationship between transfeminine estradiol treatment and hyperprolactinemia would be evident when the regimen used spironolactone as the adjunctive anti-androgen. METHODS: Estradiol levels, testosterone levels, prolactin levels, body mass index (BMI), and prescribed spironolactone dosage were extracted from the electronic medical records of 98 de-identified transgender women treated with estrogen therapy at the Endocrinology Clinic at Boston Medical Center (BMC). Up to 6 years of data were available for some patients. RESULTS: We found no statistically significant relationship between prolactin and any of the other measures. No estrogen dose-associated elevations in prolactin were found. None of the patients were diagnosed with prolactinoma. CONCLUSION: Our data suggest that there may be no significant rise in prolactin when transgender women are treated with estrogen along with spironolactone as the adjunct anti-androgen. It may be unnecessary to monitor prolactin in patients on this treatment combination. ABBREVIATIONS: BMI = body mass index; BMC = Boston Medical Center; HT = hormone therapy.

EXOGENOUS TESTOSTERONE DOES NOT INDUCE OR EXACERBATE THE METABOLIC FEATURES ASSOCIATED WITH PCOS AMONG TRANSGENDER MEN.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a complex condition which can include menstrual irregularity, metabolic derangement, and increased androgen levels. The mechanism of PCOS is unknown. Some suggest that excess production of androgens by the ovaries may cause or exacerbate the metabolic findings. The purpose of this study was to assess the role of increased testosterone on metabolic parameters for individuals presumed to be chromosomally female by examination of these parameters in hormone-treated transgender men. METHODS: In 2015 and 2016, we asked all transgender men who visited the Endocrinology Clinic at Boston Medical Center treated with testosterone for consent for a retrospective anonymous chart review. Of the 36 men, 34 agreed (94%). Serum metabolic factors and body mass index (BMI) levels for each patient were graphed over time, from initiation of therapy through 6 years of treatment. Bivariate analyses were conducted to analyze the impact of added testosterone. RESULTS: Regressions measuring the impact of testosterone demonstrated no significant changes in levels of glycated hemoglobin (HbA1c), triglycerides, or low-density-lipoprotein cholesterol. There was a statistically significant decrease in BMI with increasing testosterone. There was also a statistically significant decrease in high-density lipoprotein levels upon initiation of testosterone therapy. CONCLUSION: Testosterone therapy in transgender men across a wide range of doses and over many years did not result in the dyslipidemia or abnormalities in HbA1c seen with PCOS. Instead, treatment of transgender men with testosterone resulted only in a shift of metabolic biomarkers toward the average physiologic male body. ABBREVIATIONS: BMI = body mass index; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; LDL = low-density lipoprotein; PCOS = polycystic ovary syndrome.

ESTROGEN LEVELS DO NOT RISE WITH TESTOSTERONE TREATMENT FOR TRANSGENDER MEN.

OBJECTIVE: Existing transgender treatment guidelines suggest that for transmasculine treatment, there is a possible need for estrogen-lowering strategies adjunct to testosterone therapy. Further, guidelines advocate consideration of prophylactic female reproductive tissue surgeries for transgender men to avoid the possibility of estrogen-related health risks. Despite the paucity of objective data, some transgender men seek conversion inhibitors. We sought to determine estradiol levels in transgender men treated with testosterone therapy and the change in those levels with treatment, if any. METHODS: Estradiol levels were extracted from the electronic medical records of 34 anonymized transgender men treated with testosterone therapy at the Endocrinology Clinic at Boston Medical Center. Data were sufficient to observe 6 years of follow-up. RESULTS: With increased testosterone levels in trans-gender men, a significant decrease in estradiol levels was noted. There was a significant negative correlation between testosterone levels and body mass index, which may serve to explain part of the mechanism for the fall in estradiol levels. Even though the fall in estradiol levels was significant statistically, the actual levels remained within the normal male range, even with 6 years of follow-up. CONCLUSION: These data suggest that when exogenous testosterone is used to achieve normal serum male testosterone levels for transgender men, it is converted to normal male levels of estradiol, with some decline in those estradiol levels that might be attributable to a fall in fat mass. There appears to be no role for aromatase conversion inhibitors or other estrogen-reducing strategies in trans-gender men. Abbreviation: BMI = body mass index.

Assessing speech, language and communication difficulties in children referred for ADHD: A qualitative evaluation of a UK child and adolescent mental health service.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is one of the most common childhood neuropsychiatric disorders and is highly comorbid with speech, language and communication difficulties (SLCDs). However, it is unclear how often SLCDs are identified in ADHD referrals in routine practice and whether there are unidentified SLCDs within this population. METHOD: A thematic analysis was conducted on a random sample of case notes from 18 referrals for ADHD made to a child and adolescent mental health service (CAMHS) in London, United Kingdom. Analyses aimed to identify (a) the types of SLCDs detected during assessment, (b) at which point of the episode of care these SLCDs were suspected and (c) whether a referral or consultation was made to a speech and language therapist (SLT) for further evaluation. RESULTS: Out of 18 cases investigated, 15 were found to have possible SLCDs based on case notes and reports provided by external agencies. However, only four were referred by CAMHS for further assessment. It is unclear what, if any, steps other external agencies took. Themes describing types of SLCDs, comorbidities and the process of identification are discussed. CONCLUSION: The analysis of this service's case notes revealed a range of different routes to the identification of SLCDs, and it was unclear what steps were taken as a result of assessment. A limitation is that this is just one service and the results may not generalise. However, given the similarity in practitioner training received across the country and that practitioners move from service to service, there are grounds for repeating the study in other services. We recommend a more structured approach to identifying SLCDs and recording assessment and treatment decisions made.

TESTOSTERONE LEVELS ACHIEVED BY MEDICALLY TREATED TRANSGENDER WOMEN IN A UNITED STATES ENDOCRINOLOGY CLINIC COHORT.

OBJECTIVE: Most transgender women depend on medical treatment alone to lower testosterone levels in order to align physical appearance with gender identity. The medical regimen in the United States typically includes spironolactone and estrogens. The purpose of this cross-sectional study was to assess the testosterone suppression achieved among transgender women treated with spironolactone and estrogens. METHODS: Testosterone and estradiol levels were extracted from the electronic medical records of 98 anonymized transgender women treated with oral spironolactone and oral estrogen therapy at the Endocrinology Clinic at Boston Medical Center. RESULTS: Patients starting therapy required about 9 months to reach a steady-state testosterone, with significant heterogeneity of levels achieved among patients. Patients with normal body mass index (BMI) had higher testosterone levels, whereas patients with obese BMI had lower testosterone levels throughout treatment. Stratification of patients by age or spironolactone dosage revealed no significant difference in testosterone levels achieved. At steady state, patients in the highest suppressing quartile were able to achieve testosterone levels of 27 ng/dL, with a standard deviation of 21 ng/dL. Measured serum estradiol levels did not change over time and did not correlate with dosage of estradiol administered. CONCLUSION: Among a cohort of transgender women treated with spironolactone and estrogen, the highest suppressing quartile could reliably achieve testosterone levels in the female range at virtually all times. The second highest suppressing quartile could not achieve female levels but remained below the male range virtually all of the time. One quartile was unable to achieve any significant suppression. ABBREVIATIONS: BMC = Boston Medical Center BMI = body mass index CPY = cyproterone acetate LC-MS/MS = liquid chromatography-tandem mass spectrometry Q = quartile.

Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic.

Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.

Matrix metalloproteinase 1 is necessary for the migration of human bone marrow-derived mesenchymal stem cells toward human glioma.

Human mesenchymal stem cells (MSCs) have increasingly been used as cellular vectors for the delivery of therapeutic genes to tumors. However, the precise mechanism of mobilization remains poorly defined. In this study, MSCs that expressed similar cell surface markers and exhibited multilineage differentiation potentials were isolated from various donors. Interestingly, different MSC isolates displayed differential migration ability toward human glioma cells. We hypothesized that distinct molecular signals may be involved in the varied tumor tropisms exhibited by different MSC isolates. To test this hypothesis, gene expression profiles of tumor-trophic MSCs were compared with those of non-tumor-trophic MSCs. Among the various differentially regulated genes, matrix metalloproteinase one (MMP1) gene expression and its protein activities were enhanced by 27-fold and 21-fold, respectively, in highly migrating MSCs compared with poorly migrating MSCs. By contrast, there was no change in the transcriptional levels of other MMPs. Functional inactivation of MMP1 abrogated the migratory potential of MSCs toward glioma-conditioned medium. Conversely, the nonmigratory phenotype of poorly migrating MSC could be rescued in the presence of either recombinant MMP1 or conditioned medium from the highly migrating MSCs. Ectopic expression of MMP1 in these poorly migrating cells also rendered the cells responsive to the signaling cues from the glioma cells in vivo. However, blocking the interaction of MMP1 and its cognate receptor PAR1 effectively diminished the migratory ability of MSCs. Taken together, this study provides, for the first time, supporting evidence that MMP1 is critically involved in the migration capacity of MSCs, acting through the MMP1/PAR1 axis.