The majority of patients with Major Depressive Disorder (MDD) suffer from significant executive dysfunctions. To investigate the time course of executive functions during antidepressant treatment, repeated measures of executive functions are necessary. In order to avoid practice effects, the assessment of alternate forms is suggested. The aim of this study was to compare the processing times of four alternate versions of the Trail Making Test (TMT) A and B in patients with MDD. Fifty-five subjects with DSM-IV MDD were included in the study. We analyzed mean processing times and retest reliability of the four versions of TMT A and B. Mean processing times did not differ between the four tested versions of TMT A and B. Retest reliability of TMT A and B was between 0.76 and 0.89 and between 0.86 and 0.94, respectively. Because of their identical difficulty and high reliability, the herein described versions of the TMT A and B are suitable for sequential testing of executive functioning.
Abstract Shasqi is advancing the Click Activated Protodrugs Against Cancer (CAPAC®) platform based on click chemistry, a Nobel Prize winning technology. The platform is modular and comprises 1) an activator that target specific antigens, and 2) inert cancer drugs, protodrugs, which are selectively activated at tumors via click chemistry. The CAPAC technology separates the tumor targeting function from the payload and re-unites them at the tumor creating the flexibility to optimize activity while limiting toxicity during preclinical and clinical development. The modularity of the platform enables the rapid development of new therapies as well as unlocking unique treatment benefits such as tunable combinations and payload cycling. We envision that CAPAC will expand the scope of potential targets, widen the therapeutic window, and enhance the safety of locally activated cancer therapeutics. Here, we demonstrate the efficacy and safety of our exatecan protodrug (SQP07) used with intratumorally injected activators. The activators, tetrazine-modified sodium hyaluronate biopolymer(s), are injected at the tumor site and followed by a systemic dose of SQP07, a trans-cyclooctene (TCO)-modified protodrug of exatecan (Exa). An efficient covalent reaction between tetrazine and TCO moieties releases active Exa at the tumor. In vitro cytotoxicity studies showed that SQP07 activated with tetrazine was effective against mouse and human tumor cell lines (MC38, CT26, EMT6 and NCI-N87); SQP07 without activator had potency attenuated by 60-133 fold. In vivo tumor distribution and activity of SQP07 with the intratumoral biopolymer activators was evaluated in an NCI-N87 gastric cancer xenograft model. Female C.B-17 SCID mice received a single intravenous dose of vehicle (10% HPCD), Exa (50 mg/kg) or biopolymer (40 or 100 μL intratumorally) followed by SQP07 or SQP07 alone (50 mg/kg Exa mol equivalent). 1 hour after biopolymer + SQP07 treatment, activated Exa was highly concentrated in the tumor and stroma. This led to tumor regression in animals up to 40 days, performing significantly better than the free drug cytotoxic, Exa alone. Similarly, median survival with biopolymer + SQP07 was higher (>81 days) compared to Exa (68.5 days). Toxicity, measured as body weight loss, was comparable (~5%) and transient between Exa and biopolymer + SQP07. SQP07 alone treatment without the biopolymer was not differentiated from the vehicle control. These data show that the CAPAC platform, which separates the targeting agent from the payload, is an effective way to administer cytotoxic therapies systemically. Additional work with other tumor models, different biopolymers and the SQP07 protodrug is ongoing. Citation Format: Sangeetha Srinivasan, Stefanie Wagner, George Coricor, Tri-Hung Nguyen, Jesse M. McFarland, José M. Mejía Oneto. Tumor targeted activation of an attenuated exatecan protodrug through Click Chemistry demonstrates efficacy in murine tumor studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7213.
Abstract Background Risk communication is a core aspect of a physician’s work and a fundamental prerequisite for successful shared decision-making. However, many physicians are not able to adequately communicate risks to patients due to a lack of understanding of statistics as well as inadequate management of conflicts of interest (COI). Objective To evaluate the effects of an integrated curriculum encompassing COI and shared decision-making on the participants’ risk communication competence, that is, their competence to advise patients on the benefits and harms of diagnostic or therapeutic interventions. Design A rater-blind randomized controlled trial with a 30 (± 1)-week follow-up conducted from October 2016 to June 2017 at two German academic medical centers. Participants Sixty-three medical students in their fourth or fifth year. Interventions Participants received either a newly developed 15-h curriculum or a course manual adapted from teaching as usual. Main Measures Primary outcome: change in risk communication performance in a video-observed structured clinical examination (VOSCE). Key Results Participants were 25.7 years old on average (SD 3.6); 73% (46/63) were female. Increase in risk communication performance was significantly higher in the intervention group with post-intervention Cohen’s d of 2.35 (95% confidence interval (CI) 1.62 to 3.01, p < 0.01) and of 1.83 (CI 1.13 to 2.47, p < 0.01) 30 (± 1) weeks later. Secondary outcomes with the exception of frequency of interactions with the pharmaceutical industry also showed relevant improvements in the intervention as compared with the control group ( d between 0.91 and 2.04 ( p < 0.001)). Conclusions Our results show that an integrated curriculum encompassing COI and risk communication leads to a large and sustainable increase in risk communication performance. We interpret the large effect sizes to be a result of the integration of topics that are usually taught separately, leading to a more effective organization of knowledge. Trial Registration: The trial is registered in the International Clinical Trials Registry with the trial number DRKS00010890.
