Mindfulness-based real-time fMRI neurofeedback: a randomized controlled trial to optimize dosing for depressed adolescents.

BACKGROUND: Adolescence is characterized by a heightened vulnerability for Major Depressive Disorder (MDD) onset, and currently, treatments are only effective for roughly half of adolescents with MDD. Accordingly, novel interventions are urgently needed. This study aims to establish mindfulness-based real-time fMRI neurofeedback (mbNF) as a non-invasive approach to downregulate the default mode network (DMN) in order to decrease ruminatory processes and depressive symptoms. METHODS: Adolescents (N = 90) with a current diagnosis of MDD ages 13-18-years-old will be randomized in a parallel group, two-arm, superiority trial to receive either 15 or 30 min of mbNF with a 1:1 allocation ratio. Real-time neurofeedback based on activation of the frontoparietal network (FPN) relative to the DMN will be displayed to participants via the movement of a ball on a computer screen while participants practice mindfulness in the scanner. We hypothesize that within-DMN (medial prefrontal cortex [mPFC] with posterior cingulate cortex [PCC]) functional connectivity will be reduced following mbNF (Aim 1: Target Engagement). Additionally, we hypothesize that participants in the 30-min mbNF condition will show greater reductions in within-DMN functional connectivity (Aim 2: Dosing Impact on Target Engagement). Aim 1 will analyze data from all participants as a single-group, and Aim 2 will leverage the randomized assignment to analyze data as a parallel-group trial. Secondary analyses will probe changes in depressive symptoms and rumination. DISCUSSION: Results of this study will determine whether mbNF reduces functional connectivity within the DMN among adolescents with MDD, and critically, will identify the optimal dosing with respect to DMN modulation as well as reduction in depressive symptoms and rumination. TRIAL REGISTRATION: This study has been registered with clinicaltrials.gov, most recently updated on July 6, 2023 (trial identifier: NCT05617495).

Phase Ib study of codrituzumab in combination with sorafenib in patients with non-curable advanced hepatocellular carcinoma (HCC).

PURPOSE: Codrituzumab, a humanized antibody against glypican-3, is highly expressed in HCC. A phase I study evaluated the combination with sorafenib in HCC. PATIENTS AND METHODS: In a 3 + 3 design, codrituzumab was given intravenously in various doses with sorafenib 400 mg twice daily to patients with advanced HCC, age ≥18, ECOG 0-1, Child-Pugh A and B7, adequate organ functions, and no prior systemic therapy, with tumor assessment by RECIST 1.0 and safety by CTCAE 3.0. PK and pre, during, and post-therapy 124I radiolabeled codrituzumab PET scan imaging were performed. RESULTS: 41 patients were enrolled: 2.5 mg/kg weekly (qw) (12), 5 mg/kg qw (12), 10 mg/kg qw (3), 1600 mg every 2 weeks (q2w) (6), and 1600 mg qw (7). Two drug limiting toxicities occurred: grade 3 hyponatremia at 5 mg/kg and grade 3 hyponatremia and hyperglycemia at 1600 mg q2w. Adverse events occurred in 80% of patients, including at least one ≥grade 3: ten (25%) increased AST, three (7.5%) increased ALT, and ten (25%) increased lipase. There were no responses and nine (25.7%) had stable disease. PK C max and AUCt of codrituzumab and sorafenib were comparable to single-agent data. Thirteen out of 14 patients showed 124I radiolabeled codrituzumab uptake in tumor. In all three patients who underwent a post-progression PET, glypican-3 remained expressed. CONCLUSION: Codrituzumab plus sorafenib were tolerated at 1600 mg q2w and 400 mg bid, respectively, with no responses. Codrituzumab exerts selective distribution to HCC cells, and GPC3 does not show any down-regulation post-progression (NCT00976170).

Closed-loop training of attention with real-time brain imaging.

Lapses of attention can have negative consequences, including accidents and lost productivity. Here we used closed-loop neurofeedback to improve sustained attention abilities and reduce the frequency of lapses. During a sustained attention task, the focus of attention was monitored in real time with multivariate pattern analysis of whole-brain neuroimaging data. When indicators of an attentional lapse were detected in the brain, we gave human participants feedback by making the task more difficult. Behavioral performance improved after one training session, relative to control participants who received feedback from other participants' brains. This improvement was largest when feedback carried information from a frontoparietal attention network. A neural consequence of training was that the basal ganglia and ventral temporal cortex came to represent attentional states more distinctively. These findings suggest that attentional failures do not reflect an upper limit on cognitive potential and that attention can be trained with appropriate feedback about neural signals.

Hydropathic analysis and biological evaluation of stilbene derivatives as colchicine site microtubule inhibitors with anti-leukemic activity.

The crucial role of the microtubule in cell division has identified tubulin as a target for the development of therapeutics for cancer; in particular, tubulin is a target for antineoplastic agents that act by interfering with the dynamic stability of microtubules. A molecular modeling study was carried out to accurately represent the complex structure and the binding mode of a new class of stilbene-based tubulin inhibitors that bind at the alphabeta-tubulin colchicine site. Computational docking along with HINT (Hydropathic INTeractions) score analysis fitted these inhibitors into the colchicine site and revealed detailed structure-activity information useful for inhibitor design. Quantitative analysis of the results was in good agreement with the in vitro antiproliferative activity of these derivatives (ranging from 3 nM to 100 muM) such that calculated and measured free energies of binding correlate with an r(2) of 0.89 (standard error +/- 0.85 kcal mol(-1)). This correlation suggests that the activity of unknown compounds may be predicted.

Nitric oxide's pulsatile release in lobster heart and its regulation by opiate signaling: pesticide interference.

BACKGROUND: Data is emerging in the human and invertebrate literature demonstrating that mu opiate receptors and morphine are present in cardiovascular tissues in diverse animals, including human tissues, where they may be exerting a cardioregulatory role via stimulation of constitutive nitric oxide (NO) production. MATERIAL/METHODS: NO release from lobster heart was evaluated without stimulation and after morphine exposure using a real-time NO-specific amperometric probe. In addition, real time NO release was evaluated after treatment with low doses of widely used pesticides (e.g., pyrethroids). Real time RT-PCR was used to investigate the presence of mu opiate receptor subtypes in lobster heart. RESULTS: Basal NO release occurs in lobster heart at the nanomolar level. Morphine enhanced this level of release; naloxone (an opiate antagonist) blocked it, as did exposure to the NO synthase inhibitor L-NAME. In addition, treatment with the pyrethroids, permethrin and resmethrin, abrogated constitutive NO release from lobster heart. Finally, by way of real time RT-PCR we were able to demonstrate the presence of the micro(3) opiate receptor subtype in lobster heart. CONCLUSIONS: Rhythmic NO bursts appear to be involved in normal cardiac muscle activity in Homarus americanus. Lobster heart contains morphinergic signaling components capable of slowing down its beating rate via NO production. In addition, compounds such as pyrethroid pesticides may alter normal cardiac activity by interfering with constitutive NO production and thus, depressing basal NO levels. This may ultimately make these animals more susceptible to environmental assaults/toxins.

Poor correlation of supratherapeutic international normalised ratio and vitamin K-dependent procoagulant factor levels during warfarin therapy.

Patients with a supratherapeutic international normalised ratio (ST-INR) are at risk for bleeding. ST-INR is corrected by withholding warfarin therapy and often by supplementing vitamin K or providing vitamin K-dependent factors; the exact therapeutic decision is based on the extent of the prolonged INR. Currently, ST-INRs are frequently observed in clinical practice due to the use of sensitive recombinant tissue thromboplastin reagents and automation. However, there are scant data correlating an ST-INR with various vitamin K-dependent factors. This prospective cohort study, set in a large tertiary care teaching hospital for the University of Texas Southwestern Medical Center at Dallas, defined the relationship between ST-INR (>5.0) and measured vitamin K-dependent procoagulant factors. Prothrombin time, INR and vitamin K-dependent factors II, VII, IX and X were measured in 78 patients with an INR > 5.0 (ST-INR) who were on warfarin therapy for more than 2 months. There was no significant relationship between the ST-INR and levels of important vitamin K-dependent factors II and X. These data support the recent guidelines that the management of an INR > 5.0 should be driven by the clinical determinants rather than specific INR values per se.

The HPV16 E6/E7 oncogene sensitizes human ovarian surface epithelial cells to low-dose but not high-dose 5-FU and 5-FUdR.

To evaluate the effect of HPV16 E6/E7 on drug sensitivity, primary human OSE cells were infected with HPV16 E6/E7 expressing retrovirus and then exposed to chemotherapeutic agents. Apoptosis induced by mitomycin C was dose-dependent in both primary OSE and E6E7/OSE cells. E6E7/OSE cells were more sensitive to mitomycin C than parental OSE cells. HPV16 E6/E7 also sensitized OSE cells to 5-FU and its derivative 5-FUdR, but only at low doses. This phenomenon was also observed in cervical cancer cells and was independent of thymidylate synthase, a target of thymine and thymidine analogues. We conclude that HPV16 E6/E7 specifically modulates the activity of 5-FU and 5-FUdR, and confers OSE cells hypersensitivity to low-dose but not high-dose 5-FU and 5-FUdR. Molecular analysis indicates that induction of p53 and p21, and suppression of pRB are associated with apoptosis induced by 5-FUdR and may partly explain the hypersensitivity of E6E7/OSE cells to low-dose 5-FUdR.