Depomed (United States)

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by impairments in social communication, reciprocity, and adaptive behavior. Converging neurobiological evidence suggests that these clinical features arise from aberrant connectivity and dysregulated neuronal oscillations across distributed brain networks. In particular, dysfunction within the mirror neuron regions, concentrated in the inferior frontal gyrus (IFG) and inferior parietal lobule (IPL), has been implicated in deficits of imitation, empathy, and social cognition in ASD. Non-invasive neuromodulation using repetitive transcranial magnetic stimulation (rTMS) has shown modest behavioral benefits in ASD. However, most studies apply the conventional protocols targeting the dorsolateral prefrontal cortex. The effects of intermittent theta-burst stimulation (iTBS), a potent excitatory rTMS protocol targeting the mirror neuron regions, on the oscillatory dynamics in ASD remain largely unexplored. To investigate whether iTBS targeting the bilateral IFG and IPL modulates EEG-derived oscillatory activity in adolescents with ASD and to explore the relationship between oscillatory changes and social reciprocity. Six adolescents with Level I or II ASD (ages 13-18) underwent bilateral iTBS targeting the IFG and IPL using a figure-of-eight coil and standardized theta-burst parameters. Participants were randomized to receive either 18 active iTBS sessions or a waitlist-controlled crossover design (9 sham followed by 9 active sessions). Standard 21-channel EEG recordings were obtained during the first (EEG-1) and final (EEG-2) active stimulation sessions, including pre- and post-stimulation epochs. Power spectral analyses were conducted across frequency bands (delta through gamma). Behavioral outcomes were assessed using the Childhood Autism Rating Scale, Second Edition (CARS2), administered pre- and post-intervention. All participants tolerated the intervention without adverse effects. Behavioral analysis demonstrated a significant reduction in CARS2 scores following iTBS and is reported in detail in our prior clinical outcomes manuscript, consistent with improved social reciprocity (p < 0.001). EEG analysis revealed an immediate post-stimulation increase in gamma-band power during EEG-1 in five of six participants, whereas lower-frequency bands exhibited variable responses. In contrast, EEG-2 showed no consistent post-stimulation gamma enhancement. Net comparisons between EEG-1 and EEG-2 demonstrated attenuation of the initial gamma response in the same five participants. At the group level, gamma percent change did not reach statistical significance at EEG-1 (p = 0.12) or EEG-2 (p = 0.66), and exploratory comparisons between the 9-active versus 18-active arms did not reach statistical significance. While ipsi-directional changes in gamma power and CARS2 scores were observed in four participants, correlation was not identified in this pilot sample. Bilateral iTBS targeting the IFG and IPL induces a transient enhancement of gamma oscillations in adolescents with ASD that attenuates with repeated stimulation. This pattern is consistent with adaptive homeostatic plasticity (metaplasticity) within excitatory-inhibitory circuits, potentially mediated by GABAergic interneurons. These findings support the feasibility of EEG as an objective biomarker of neuromodulatory engagement in ASD and highlight the importance of network-level and oscillatory mechanisms in interpreting therapeutic responses. Larger, sham-controlled studies incorporating multimodal biomarkers are warranted to clarify clinical relevance and optimize personalized neuromodulation strategies.

A modelagem tridimensional (3D) assistida por inteligência artificial (IA) ampliou o papel da imagem médica no planejamento cirúrgico; no entanto, seu valor clínico frequentemente é confundido com visualização avançada, em vez de verdadeiro suporte à tomada de decisão. Esta mini-revisão examina criticamente a modelagem 3D orientada por IA como uma ferramenta de precisão para o planejamento cirúrgico, enfatizando a distinção entre reconstruções anatômicas estáticas e sistemas dinâmicos, orientados por inteligência, capazes de se adaptar às condições intraoperatórias. Além das redes neurais convolucionais clássicas, arquiteturas contemporâneas como Vision Transformers e modelos baseados em difusão são discutidas, destacando suas implicações para generalização, estimativa de incerteza e robustez. Também se dá atenção à padronização das imagens, à responsabilidade algorítmica, aos limites econômicos para adoção e à lacuna persistente entre visualização e benefício cirúrgico quantificável.

Introduction: The interest in using Polygenic Risk Scores (PRSs) for CAD risk assessment is growing, but variability in individual risk estimates between different PRS models is a significant concern for their use in primary prevention treatment guidance. This study examines the impact of integrating PRSs with an established clinical model in reducing variability and stabilizing the classification of high-risk individuals. Methods: Using a cohort of 195,688 participants (6,751 incident cases) from the UK Biobank, who were CAD-free at baseline, we compared the stability of PRS-only models with those integrated with the Pooled Cohort Equations (PCE) for 10-year atherosclerotic cardiovascular disease (ASCVD) risk assessment. We analyzed 14 CAD PRSs from the PGS catalog, developed independently of UK Biobank, and ensemble PRS models combining multiple scores. We used the coefficient of variation (CV) as a scale-independent metric to compare individual-level prediction variability between PRS percentiles and absolute risk estimates from integrated PRS models. To evaluate agreement in classifying high-risk participants, we used the Jaccard index. Results: The variability in individual-level risk estimates from models integrating PRS with ASCVD-PCE was lower than predictions based solely on PRS. The CV of individual-level predictions across the top 5 PRSs was 0.392, compared to 0.215 for the corresponding integrated models. Combining PRSs into ensembles further stabilised predictions, with a median CV of 0.044 and 0.029 across the top 5 PRS ensembles and their integrated models, respectively. Consistency in classifying high-risk individuals also improved upon integrating PRS with ASCVD-PCE. The median Jaccard index for single PRS-based classifications (top 5%) was 0.113, compared to 0.497 for the integrated PRS (≥7.5% absolute risk). Similarly, the median Jaccard index was 0.262 for ensemble PRSs and 0.59 for their integrated PRS. Notably, classification concordance improved with successive PRS ensemble iterations (incorporating newly released PRSs), with the Jaccard index ranging from 0.86 to 0.97 between the 5 latest integrated PRS ensembles. Conclusions: Integrating PRSs with clinical risk factors enhances the accuracy and stability of CAD risk predictions, making it superior in comparison to classification based solely on PRS percentiles. Ensemble PRS models present a promising method for incorporating newly developed PRSs, further boosting performance and stability.

The ability to predict breast cancer (BC) risk has seen promising advances through the use of polygenic risk scores (PRS), which calculate an individual's genetic predisposition by analyzing multiple genetic variants. However, a critical limitation of current PRS models is their lack of adjustments for individuals from diverse ancestral backgrounds, which can reduce their predictive accuracy for populations outside of those of primarily European descent. In this study, we aimed to improve the accuracy of BC risk prediction for women of Ashkenazi Jewish (AJ) heritage by examining the performance of three PRS models.

COPD is a disease influenced by environmental factors and the resulting epigenetic modifications. The underlying cause may involve significant dysfunction in epithelial repair. Our aim is to improve airway epithelial repair in COPD by transplanting pre-differentiated induced pluripotent stem cells (iPSC) from the same patient. Epithelial cells from bronchial biopsies were cultured in ALI (air-liquid interface). Native bronchial epithelia were mechanically damaged. iPSC-derived epithelial cells from patient blood (E. Ahmed et al., Stem Cell Res, 2021) were engineered to express or not GFP. Reprogrammed iPSC were differentiated to the early vAFE (ventral foregut endodermis) stage and added to damaged native epithelium. GFP expression was monitored by fluorescence microscopy from the day of transplantation and for 42 days to monitor lesion repair and to assess differentiation of transplanted cells. The formalin-fixed culture wells were then subjected to immunofluorescence labelling (GFP, eCAD, p63). GFP cells derived from vAFE-stage iPSC were successfully transplanted to the site of the ALI epithelial lesion. This was confirmed by observation of GFP under a fluorescence microscope. The detection of fluorescence on day 3, which intensified until day 7, was still present on day 42, underlining the long-lasting viability and stability of the transplanted cultures. Immunofluorescence staining at day 7 also demonstrated that GFP+ cells formed intercellular junctions (eCAD) with GFP- cells. Some GFP+ cells were also found to be p63+. It's possible to repair the pathological epithelium of a COPD patient using iPSC-derived epithelium. The repair mechanisms could provide clues to therapeutic avenues, targeting epigenetics and cell therapy?

Abstract Introduction: Despite the success of anti-PD1/PDL1 therapies, only a small fraction of patients benefit from these checkpoint inhibitors (CPIs). Novel approaches to improve outcomes for patients who are resistant to current CPIs are needed. PVRIG is expressed on CD4+ and CD8+ T cells, NKT and NK cells. PVRIG binds with high affinity with its ligand PVRL2, which is expressed on tumor cells and some myeloid cells. The PVRIG-PVRL2 axis exerts an inhibitory effect on the cytotoxic activity of lymphocytes. Bispecific antibodies that exhibit dual blockade of PD1 and PVRIG provide a promising strategy to enhance anti-tumor immune response. Methods: An anti-PD1 mAb was identified from PD1 KO mice immunized with PD1-ECD-Fc and screened by our proprietary H3 (High-throughput, High-content and High-efficiency) platform. An anti-PVRIG mAb was identified from rats immunized with recombinant PVRIG-ECD-Fc and screened by the H3 platform. Both anti-PD1 and anti-PVRIG antibodies were humanized, and the anti-PD1 scFv was fused to the N-terminus of the heavy chain of the anti-PD1 antibody via a flexible linker. The binding activities and affinities were evaluated by ELISA, FACS and SPR, and the ligand blocking activities were measured by ELISA and FACS. Cell-based reporter assays were used to evaluate the functions of the anti-PD1 and anti-PVRIG mAbs alone and the bispecific antibody. In addition, the activity of the bispecific antibody to reverse PD1 and PVRIG mediated suppression of CMV pp65495-503 antigen specific CD8+ T-cell cytotoxicity was evaluated. Results: BSI-507, an anti-PD1xanti-PVRIG bispecific antibody demonstrated comparable activity to the parental anti-PD1 antibody regarding PD1 binding and PD1/PDL1 blocking. It also exhibited comparable activity to the parental anti-PVRIG antibody in PVRIG binding and PVRIG/PVRL2 blocking. Based on cell-based reporter assays, BSI-507 was able to reverse either PD1 or PVRIG mediated T-cell suppression and exhibited comparable potency to the parental antibodies. BSI-507 was also able to show enhanced reversal of both PD1 and PVRIG mediated T-cell suppression, much better than anti-PD1 or anti-PVRIG alone. In addition, BSI-507 showed the ability to reverse PD1 and PVRIG mediated suppression of CMV pp65495-503 antigen specific CD8+ T-cell cytotoxicity, stronger than either the anti-PD1 or anti-PVRIG monoclonal antibody. Summary: BSI-507 is a first-in-class anti-PD1xanti-PVRIG bispecific antibody for dual blockade of PD-1 and PVRIG pathways to enhance reversal of T cell inhibition. BSI-507 demonstrates favorable biophysical and functional characteristics, supporting the initiation of development activities including manufacturing and IND-enabling studies. Citation Format: Zeyu Peng, Xiaodong F. Liu, Hongyan Li, Wenwen Dai, Jinyu Liu, Xiaoyao Hao, Shukai Xia, Qun Lv, Hugh M. Davis, Mingjiu Chen, Mark Z. Ma. BSI-507, a first-in-class bispecific antibody targeting PD1 and PVRIG for cancer immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6367.

Rapid decision-making is essential in precision medicine for initiating molecular targeted therapy for patients with cancer. This study aimed to extract pathomorphologic features that enable the accurate prediction of genetic abnormalities in cancer from hematoxylin and eosin images using deep learning (DL). A total of 1,657 images (one representative image per patient) of thin formalin-fixed, paraffin-embedded tissue sections from either primary or metastatic tumors with next-generation sequencing-confirmed genetic abnormalities-including BRAFV600E and KRAS mutations, and microsatellite instability high (MSI-H)-that are directly relevant to therapeutic strategies for advanced colorectal cancer were obtained from the nationwide SCRUM-Japan GI-SCREEN project. The images were divided into three groups of 986, 248, and 423 images to create one training and two validation cohorts, respectively. Pathomorphologic feature-prediction DL models were first developed on the basis of pathomorphologic features. Subsequently, gene-prediction DL models were constructed for all possible combinations of pathomorphologic features that enabled the prediction of gene abnormalities based on images filtered by the combination of pathomorphologic feature-prediction models. High accuracies were achieved, with AUCs > 0.90 and 0.80 for 12 and 27, respectively, of 33 analyzed pathomorphologic features, with high AUCs being yielded for both BRAFV600E (0.851 and 0.859) and MSI-H (0.923 and 0.862). These findings show that novel next-generation pathology methods can predict genetic abnormalities without the need for standard-of-care gene tests, and this novel next-generation pathology method can be applied for colorectal cancer treatment planning in the near future.

Background: RT234 (vardenafil inhalation powder) is being developed for pulmonary administration “as needed”, to acutely improve exercise tolerance and symptoms in patients with pulmonary arterial hypertension (PAH).Methods: This single-center, open-label, randomized study in 32 healthy adult subjects evaluated single and multiple inhalation doses of RT234, for safety, tolerability, and pharmacokinetics (PKs).Results: RT234 was generally safe and well tolerated at single doses of 0.2–2.4 mg and after repeated dose administration of up to 2.4 mg q4h for four doses daily for 9 days. The most common treatment-emergent adverse events were mild-to-moderate headaches. There was no evidence of pulmonary irritation or inflammation. Vardenafil was absorbed very rapidly after inhalation as RT234, independent of dose level and number of doses administered. The tmax occurred at the time that the first blood sample following completion of dosing. After Cmax was achieved, plasma vardenafil concentrations declined rapidly in an exponential fashion that appeared to be parallel among dose levels. Vardenafil plasma concentrations and PK parameters increased in a dose-proportional manner. Vardenafil systemic exposure was notably greater after oral administration of 20 mg vardenafil tablets (Levitra®) than after administration of any dose level of RT234. During repeated dose administration of RT234, Cmax was attained rapidly following each dose and in a pattern similar to that observed after single-dose administration. Minor accumulation, characterized by very low mean morning predose vardenafil concentrations (<0.5 ng/mL), occurred after q4h dosing of up to four doses per day for 9 days. Taken together, these findings show that no clinically important vardenafil accumulation is likely after repeated-dose administration of RT234. Mean vardenafil t1/2 values were comparable after single- and repeated-dose administration.Conclusions: Comparative plasma vardenafil bioavailability data from this study provide scientific justification for reliance on Food and Drug Administration findings for Levitra tablets. These findings support further evaluation of RT234 for as-needed treatment of patients with PAH. The Clinical Trials Registration number is ACTRN12618001077257.

Gallbladder cancer (GBC) is an aggressive gastrointestinal malignancy with no approved targeted therapy. Here, we analyze exomes (n = 160), transcriptomes (n = 115), and low pass whole genomes (n = 146) from 167 gallbladder cancers (GBCs) from patients in Korea, India and Chile. In addition, we also sequence samples from 39 GBC high-risk patients and detect evidence of early cancer-related genomic lesions. Among the several significantly mutated genes not previously linked to GBC are ETS domain genes ELF3 and EHF, CTNNB1, APC, NSD1, KAT8, STK11 and NFE2L2. A majority of ELF3 alterations are frame-shift mutations that result in several cancer-specific neoantigens that activate T-cells indicating that they are cancer vaccine candidates. In addition, we identify recurrent alterations in KEAP1/NFE2L2 and WNT pathway in GBC. Taken together, these define multiple targetable therapeutic interventions opportunities for GBC treatment and management.