Prevalence and clinical implication of adverse childhood experiences and their association with substance use disorder among patients with schizophrenia

Background Adverse childhood experiences (ACEs) and substance use disorder (SUD) are well-known risk factors for psychosis and dramatically affect schizophrenia. In this research, we aimed to measure the prevalence of adverse childhood experiences and substance use disorder in patients with schizophrenia and assess the effect of ACEs on the clinical presentation and overall functioning and the association between them and SUD in patients with schizophrenia. A cross-sectional study included a random sample of 165 schizophrenic patients who were examined by doing drug screen in urine, structured questionnaire to collect Socioeconomic characteristics, history of schizophrenia, structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders-fifth edition, Positive and Negative Syndrome Scale (PANSS), Adverse Childhood Experiences International Questionnaire (ACE-IQ), World Health Organization Disability Assessment Schedule 2.0, compliance rating scale, addiction severity index fifth edition (ASI) for individuals with positive urine drug screen. Results Only 14.4% of the studied patients had no adverse childhood experiences. The prevalence of positive substance abuse screening was 18.2%. There were statistically significant negative correlations between total ACE score and educational level, socioeconomic level, and the onset of schizophrenia. On the other hand, statistically significant positive correlations were found between the total ACE score and PANSS score and ASI score. The first most frequent ACE was significantly associated with female gender, lower education levels, low and middle socioeconomic classes, lifetime substance use, smokers, and positive drug screening. Emotional neglect and contact sexual abuse were significantly associated with positive drug screening. At the same time, Physical abuse was significantly associated with both lifetime substance use and positive drug screening. Conclusion The current study’s findings indicate that childhood adverse experiences and substance abuse are prevalent problems in patients with schizophrenia. Given that there is an association between both issues, they may affect the symptomatology of the disorder, the prognosis, and the therapeutic plan. It is advised that a greater emphasis on and identification of childhood trauma and drug use disorder may be a necessary step in assessing patients with schizophrenia.

Efficacy and Synergy of Small Molecule Inhibitors Targeting FLT3-ITD+ Acute Myeloid Leukemia

Constitutive activation of FLT3 by ITD mutations is one of the most common genetic aberrations in AML, present in ~1/3 of cases. Patients harboring FLT3-ITD display worse clinical outcomes. The integration and advancement of FLT3 TKI in AML treatment provided significant therapeutic improvement. However, due to the emergence of resistance mechanisms, FLT3-ITD+ AML remains a clinical challenge. We performed an unbiased drug screen to identify 18 compounds as particularly efficacious against FLT3-ITD+ AML. Among these, we characterized two investigational compounds, WS6 and ispinesib, and two approved drugs, ponatinib and cabozantinib, in depth. We found that WS6, although not yet investigated in oncology, shows a similar mechanism and potency as ponatinib and cabozantinib. Interestingly, ispinesib and cabozantinib prevent activation of AXL, a key driver and mechanism of drug resistance in FLT3-ITD+ AML patients. We further investigated synergies between the selected compounds and found that combination treatment with ispinesib and cabozantinib or ponatinib shows high synergy in FLT3-ITD+ AML cell lines and patient samples. Together, we suggest WS6, ispinesib, ponatinib and cabozantinib as novel options for targeting FLT3-ITD+ AML. Whether combinatorial tyrosine kinase and kinesin spindle blockade is effective in eradicating neoplastic (stem) cells in FLT3-ITD+ AML remains to be determined in clinical trials.

Mexiletine and False Positive Urine Drug Screen for Amphetamine: A Case Review

Advanced heart failure patients commonly suffer from ventricular arrhythmias which can be managed by antiarrhythmic drugs like mexiletine. These ventricular arrhythmias can be complicated by illicit drug use which alter outcomes and can potentially impact the patient-physician relationship through countertransference. However, mexiletine can lead to false positive urine drug screen testing for amphetamine, and these false-positive urine drug screen test results can affect the decision-making process. Health care providers should be aware of this fact and should either use confirmatory testing or look for confounding compounds in patients who deny using illicit substances and have a positive urine drug screen. Our patient is 64 years old who arrived at the emergency department after experiencing a shock by his intracardiac defibrillator. The patient tested positive for amphetamine on his urine drug screen and was later ruled out by confirmatory quantitative testing.

Waiting for PARIS—A Biological Target in Search of a Drug

A recent breakthrough paper published in Science Translational Medicine has provided compelling evidence that inhibition of Parkin Interacting Substrate (PARIS) may offer clinical researchers an important new therapeutic approach since it shows considerable promise as an important biological target potentially capable of pharmaceutical intervention to slow long term neurodegeneration in patients with Parkinson’s disease (PD). We present several PD-relevant perspectives on this paper that were not discussed in that otherwise entirely scientific narrative. We also outline the some of the work leading up to it, including the massive drug screen that proved necessary to discover a clinically suitable inhibitor of PARIS (Farnesol), as well as relevant PD research within the wider drug class, issues surrounding its future formulation, and next steps in translating this new knowledge into the clinic to evaluate possible long-term PD patient benefits.

DDRE-43. SCREENING OF FDA-APPROVED COMPOUNDS FOR THE TREATMENT OF CHORDOMA, WITH IN VIVO VALIDATION USING THREE DIFFERENT XENOGRAFT MODELS, IDENTIFIES BRIGATINIB AS A POTENTIAL TREATMENT

BACKGROUND Chordoma is a rare malignant tumor with poor surgical control and no existing pharmacotherapies. Therefore, these tumors require additional research into novel therapeutics for their treatment. METHODS In this study we created a high-throughput drug screen and culture system to evaluate the efficacy of existing FDA-approved compounds in 10 chordoma cell lines and primary tumors. The cell lines were graciously donated by the Chordoma Foundation. Primary tumors were collected from our operating room. In vivo validation using three separate chordoma xenograft models was also performed through the Chordoma Foundation. One model was a primary clival pediatric tumor, the second was a metastatic sacral tumor, and the third model was a recurrent skull base tumor. RESULTS Using a 127 FDA-approved compound library, we screened 6 donated chordoma cell lines and 4 tumors resected from our institution. 5 of the chordomas were primary, 3 were recurrent, and 2 were metastatic. 6 chordoma were located in the sacrum, three were located in the mobile spine, and one was located in the clivus. Five tumors came from female patients and five came from male patients. After a single 72-hour 1um dose of brigatinib, the average tumor viability in our drug screen was reduced to 81.5% +/-9.5SD (p=1.61x10-13). In the in vivo studies, brigatinib achieved a full response in the metastatic sacral chordoma xenograft model (TGI=100%, p< 0.0001), a partial response in the recurrent skull base xenograft model (TGI=54%, p=0.3048), and no response in the primary clival pediatric xenograft model (TGI = 0%, p >0.9). CONCLUSIONS Brigatinib may be a viable treatment option for recurrent and metastatic chordomas.

Activators of alpha synuclein expression identified by reporter cell line-based high throughput drug screen

Multiplications, mutations and dysregulation of the alpha synuclein gene (SNCA) are associated with the demise of dopaminergic neurons and are considered to play important roles in the pathogenesis of familial and sporadic forms of Parkinson’s disease. Regulation of SNCA expression might thus be an appropriate target for treatment. We aimed to identify specific modulators of SNCA transcription, generated CRISPR/Cas9 modified SNCA-GFP-luciferase (LUC) genomic fusion- and control cell lines and screened a library of 1649 bioactive compounds, including the FDA approved drugs. We found no inhibitors but three selective activators which increased SNCA mRNA and protein levels.