Citations

ABSTRACT The standard treatment for Haemophilia B (HB) involves frequent intravenous (IV) infusions of recombinant factor IX (FIX), which imposes a significant financial burden on patients. FIX delivery as messenger RNA using lipid nanoparticles (LNPs) presents a promising alternative, but achieving prolonged and effective protein expression remains challenging. To this end, we developed Galactosylated Lipid Nucleic Acid complex (GaLiNAx) to enhance the delivery of chemically modified FIX mRNAs. The nanocarrier encompasses an ionizable galactosylated lipid to enable receptor‐mediated endocytosis and a transfection‐competent cationic lipid for optimal mRNA complexation. We incorporated truncated albumin UTRs and base modifications in functional FIX mRNA to enhance hepatic translation. In an HB mouse model, GaLiNAx demonstrated therapeutically relevant FIX protein expression for about one month after single dose offering a cost‐effective option. Safety assessments indicated that multiple doses of GaLiNAx could be administered without toxicity to any major organs. These results highlight the potential of long‐lasting mRNA therapy as an effective protein replacement strategy for HB, paving the way for future mRNA therapeutics targeting other monogenic liver disorders.

Optineurin (OPTN) is a multifunctional adaptor protein that regulates diverse cellular processes, including inflammatory signaling, autophagy, vesicular trafficking, and immune responses. This multifaceted role of OPTN is made possible by the presence of a complex structure comprising multiple domains that interact with different proteins to exert various functions important for modulating key signaling processes. Mutations in OPTN are linked with several human pathologies including glaucoma, Paget’s disease of bone, Crohn’s disease, and neurodegenerative diseases such as amyotrophic lateral sclerosis, and dementia. Emerging evidence suggests that OPTN has a complex and context-dependent role in cancer biology as well. It is upregulated in pancreatic ductal adenocarcinoma and hepatocellular carcinoma but downregulated in lung and colorectal cancers, indicating its dual role as a potential oncogene or tumor suppressor depending on the cellular environment. Additionally, OPTN plays a critical role in preventing immune evasion in colorectal cancer by maintaining interferon-gamma receptor 1 (IFNGR1) expression and supporting dendritic cell-mediated T-cell priming, thereby enhancing antitumor immune responses. Despite its significance in oncogenic pathways and immune regulation, the therapeutic potential of targeting OPTN in cancer remains largely unexplored. This review aims to provide a comprehensive understanding of OPTN’s pleiotropic functions, highlighting its role in autophagy, inflammation, immune surveillance, and cancer progression. By elucidating its diverse regulatory mechanisms, we seek to encourage further research into the therapeutic implications of OPTN in cancer treatment and immunotherapy.

Background: Stroke is a devastating complication of transcatheter aortic valve replacement (TAVR). Cerebral embolic protection devices (CEPD) have been introduced to reduce TAVR-related stroke by capturing or deflecting debris during the procedure. While these devices can capture embolic material, their clinical benefit in preventing stroke remains uncertain. We aimed to determine whether the use of CEPD during TAVR reduces the incidence of periprocedural stroke. Methods: We performed a systematic review and meta-analysis of studies comparing TAVR with versus without CEPD. We searched PubMed, Embase, and ClinicalTrials.gov for RCTs (randomized controlled trials) comparing CEPDs to no protection in TAVR patients from 2011 to May 2025. Nine RCTs involving a total of 11,608 patients (CEPD group n=5,953; control n=5,655) were included. Stroke outcomes were defined according to Valve Academic Research Consortium-2 (VARC-2) criteria and categorized as- all stroke, disabling stroke, or non-disabling stroke. Risk ratios (RR) with 95% confidence intervals (CI) were calculated using a fixed-effects model. Heterogeneity also was measured. Results: Stroke rates were low and did not differ significantly between the CEPD (n=343) and control (n=319) groups. The incidence of all strokes was 1.96% with CEPD vs 1.88% without CEPD (RR 0.97, 95% CI 0.75–1.15; p=0.50). Disabling stroke occurred in 0.79% of CEPD patients vs 0.95% of controls (RR 0.79, 95% CI 0.57-1.10; p=0.16). Non-disabling stroke occurred in 1.26% of patients in both groups (RR 1.06, 95% CI 0.8 -1.40; p=0.64). There was no significant heterogeneity across trials is (0) for all endpoints. Notably, the largest trial in the analysis (BHF PROTECT-TAVI, n=7,635) showed no difference in stroke rates with CEPD, aligning with the overall results. Subgroup analyses revealed a trend toward fewer disabling strokes with CEPD use, but this trend was not statistically significant. Conclusion: We found no significant stroke risk reduction with the use of CEPDs during TAVR. While a trend toward fewer disabling strokes was observed, it was not statistically significant. Routine use of CEPDs is not supported, and selective use in high-risk patients warrants further large RCTs.

Background: In patients with paradoxical low-gradient severe aortic stenosis (AS) based on aortic valve area (AVA) at rest (<1cm2) and normal left ventricular ejection fraction (LVEF >50%), the role of dobutamine stress echocardiography (DSE) is unclear. While current guidelines recommend assessing aortic valve calcium score in this context, DSE may still offer clinical value. Methods: We conducted a retrospective study on patients with paradoxical low gradient AS (LVEF >50% AVA <1cm 2 , MG < 40 mmHg) at rest who underwent DSE after Institutional Review Board approval. Data was extracted using an internal database. Patients > 18 yrs old with LVEF >50%, mean gradient (MG) < 40 mmHg, and valve area < 1 cm 2 at rest were included. Kruskal-Wallis test was used to identify which resting variables were associated with severe AS (MG >40 mm Hg and Valve area <1 cm 2 ) with DSE. Results: A total of 42 patients were included in the study and variables were reported as means (±SD). The mean age of patients was 78 years (±10) and 60% were female. The mean resting LVEF was 60% (±5%), MG at rest was 28 mmHg (±7) while it was 40 mmHg (±14) with DSE, and mean aortic valve area at rest was 0.9 cm 2 (±0.09) while it was 1.1 cm 2 (±0.23) with DSE. Of the 42 patients, 11 (26%) were found to have severe AS during DSE, defined by a MG >40 mmHg and AVA <1.0 cm 2 . Baseline AVA and MG at rest were significantly associated with severe AS on DSE (p=0.008 and p=0.024, respectively), while age, stroke volume index, and baseline LVEF were not. Univariate regression analysis showed that the area under the curve (AUC) for predicting severe AS was 0.73 for resting MG and 0.77 for resting AVA. A resting AVA cutoff of 0.78 cm 2 provided optimal sensitivity (0.63) and specificity (0.90). For resting MG, a cutoff of 29 mmHg gave a sensitivity of 0.91 and specificity of 0.68 for identifying patients with severe AS. Conclusion: Our study indicated that DSE remains useful in identifying severe AS in substantial number of patients (26%) who exhibit paradoxical low gradient severe AS. Additionally, AVA at rest and baseline mean gradient were statistically the reliable parameters to determine those who may benefit significantly from undergoing DSE. This is one of the first studies to our knowledge in the literature suggesting that DSE may still be useful in identifying severe AS patients despite “paradoxical low gradient severe AS” at rest. Further research is warranted to validate our findings.

Background: Patients with low gradient non-severe aortic stenosis (AS) at rest, in the context of reduced left ventricular ejection fraction (LVEF) (less than 50%), occasionally undergo dobutamine stress echocardiogram (DSE). However, limited data is available in the literature regarding the utility of DSE in this context. Methods: We conducted a retrospective study on patients with non-severe AS and LVEF less than 50% at rest who underwent DSE after Institutional Review Board approval. Retrospective data was extracted including rest and DSE parameters using an internal database. Only patients greater than 18 years old, who had an LVEF less than 50%, mean gradient (MG) less than 40 mmHg, and valve area greater than or equal to 1 cm 2 at rest were included in the study. Univariate and multivariate regression methods were used to identify which resting variables were associated with severe AS (MG greater than 40 mm Hg and valve area less than 1 cm 2 ) with DSE. Results: A total of 124 patients were included in the study. The mean age of patients was 78 years (±9) and 84% were male. The mean resting LVEF was 34% (±8%) while it was 40% (±12%) with DSE, mean stroke volume index at rest was 39 mL/m2 (±9) while it was 45 mL/m2 (±10) with DSE, MG at rest was 20 mmHg (±7) while it was 31 mmHg (±10) with DSE, and mean aortic valve area at rest was 1.27 cm 2 (±0.27) while it was 1.24 cm 2 (±0.29) with DSE. Of the 124 patients with non-severe AS at rest, 13 (10.5%) patients had severe AS with DSE. MG at rest was associated with severe AS (OR 1.3; 95% Cl: 1.1 - 1.5; p < 0.001) in a multivariate logistic regression model after adjusting for age, sex, LVEF at rest, SV index at rest. Resting aortic valve mean gradient also showed the highest AUC in relation to likelihood of having severe AS (0.87) (figure 1). Conclusion: Our study indicated that DSE remains useful in identifying severe AS in certain patients (up to 10%) who exhibit non-severe AS at rest in the setting of reduced LVEF. Additionally, MG at rest is the most reliable parameter to determine those who may benefit from undergoing DSE. This is one of the first studies to our knowledge in the literature suggesting that DSE may still be useful in identifying severe AS patients despite non-severe AS (i.e., valve area greater than or equal to 1 cm 2 ) at rest with reduced LVEF. Further research is warranted to validate our findings.

Problem Statement: The prognostic value of troponin elevation in septic ICU patients without known history of cardiac disease remains unclear, particularly after accounting for overall illness severity. Background: Minor troponin rises are frequent during sepsis, yet clinicians still lack a clear cut-point that signals danger once cardiac disease is ruled out. We asked whether a modest increase in troponin-T predicts in-hospital death beyond global illness severity. Methods: We studied 1 221 adult first ICU stays labelled “sepsis” in the eICU Collaborative Research Database and removed any case with a cardiac admission diagnosis. Implausible or missing laboratory values were imputed by multiple imputation. Hospital mortality was modelled with logistic regression that included troponin (a continuous and a binary model with threshold > 0.04 ng/mL) together with age, sex, lactate, albumin, BUN, creatinine, intubation status, vasopressor use, dialysis requirement and APACHE-IV predicted mortality. A natural-spline model explored non-linear behavior. Findings were checked in a 1:1 propensity-matched cohort. Results: Overall mortality was 11.7%. Troponin exceeded 0.04 ng/mL in 38% of patients. After adjustment for APACHE-IV probability and other covariates, a troponin level > 0.04 ng/mL was associated with almost twice the odds of death (OR ≈ 1.9), whereas the continuous model suggested only a modest trend (OR ≈ 1.1 per ng/mL). The spline curve rose steeply between 0 and 0.10 ng/mL and flattened thereafter, pinpointing an inflection near 0.05 ng/mL. Matching on all measured confounders confirmed that high-troponin patients had about three-fold greater mortality (OR ≈ 2.8, 1.55-5.05; p<0.001), highlighting that even modest troponin elevation is an independent risk marker for death in septic ICU patients. A bedside heat-map combining troponin, albumin and need for intubation illustrated a simple gradient: risk climbs from 2 % in low-troponin, well-albuminised, non-intubated patients to nearly 7 % when troponin exceeds 0.10 ng/mL in intubated, hypo-albuminemic patients. Conclusions: Even modest troponin elevations (> 0.04 ng/mL) independently predict mortality in sepsis after rigorous adjustment and matching on APACHE-IV physiology, lactate, and organ-support variables. This biologic threshold supports incorporating troponin into bedside triage and future septic cardiomyopathy trials.

Abstract Background Glioblastoma (GBM) is the most common high-grade primary malignant brain tumor, characterized by a notably poor prognosis. Current treatments for GBM have shown limited effectiveness in improving patient survival, highlighting the urgent need for novel therapeutic strategies. Combination therapy offers significant potential in overcoming resistance by targeting multiple signaling pathways; however, it often comes with increased toxicity compared to monotherapy. Co-encapsulating multiple therapeutic agents into a tumor-targeted drug delivery platform holds promise for overcoming these limitations and improving treatment outcomes. Methods We developed a tumor-targeted liposomal nanoformulation (TTL) using phospholipids, cholesterol, DSPE-(PEG)2000-OMe, and a proprietary tumor-targeting peptide (TTP). The TTL was loaded with everolimus (TTL-E), vinorelbine (TTL-V), rapamycin (TTL-R), a combination (TTL-EV), or (TTL-RV). These formulations were tested in vivo on orthotopic GBM mice, combined with temozolomide and radiation. RNA sequencing was performed to identify molecular and transcriptome changes post-treatment. Results TTL demonstrated tumor-specific uptake, effectively delivering drugs to GBM tumors. TTL-EV and TTL-RV outperformed single-drug formulations. Radiation combined with TTL-EV/RV improved tumor growth inhibition and survival, while temozolomide provided minimal benefit. Transcriptome analysis revealed differentially expressed genes (DEGs) linked to DNA damage repair, cell cycle, metabolism, and extracellular matrix pathways. Conclusion TTL crossed the blood-brain barrier, targeting tumors effectively. Radiation plus TTL-EV/RV enhanced tumor suppression and survival in GBM models. Gene expression analysis identified DEGs related to DNA damage and cell death. Mechanistic studies suggest TTL-EV plus radiation inhibits mTOR/MAPK pathways and sensitizes tumors to radiation. These findings offer a potential approach for improving GBM treatment.

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by aggressive tumor biology, poor vascularization, dense stromal barriers, and profound resistance to chemotherapy. GAIP-interacting protein C-terminus 1 (GIPC1), a PDZ-domain-containing adaptor protein, is highly overexpressed in PDAC and plays a critical role in tumor progression and chemoresistance. This study aimed to develop and evaluate a novel tumor-targeted liposomal siRNA delivery system (LGIPCsi) to silence GIPC1 and enhance the therapeutic efficacy of gemcitabine (GEM) in PDAC; Methods: LGIPCsi nanoparticles were synthesized and optimized for physicochemical stability, siRNA complexation efficiency, and tumor-targeting capability. Their therapeutic efficacy was assessed using in vitro pancreatic cancer cell models and in vivo orthotopic and patient-derived xenograft (PDX) models of PDAC. Biodistribution, tumor uptake, and antitumor efficacy were evaluated following systemic administration. Combination studies were performed to assess the synergistic effects of LGIPCsi and GEM; Results: GIPC1 silencing significantly sensitized pancreatic cancer cells to GEM, resulting in enhanced inhibition of tumor cell proliferation in vitro. In vivo, systemic administration of LGIPCsi achieved efficient intratumoral delivery of siGIPC1, leading to marked tumor growth suppression. Combination therapy with GEM and LGIPCsi produced synergistic antitumor effects, with substantial tumor regression compared to monotherapy groups. Importantly, no significant systemic toxicity was observed in treated animals; Conclusions: This study identifies GIPC1 as a promising therapeutic target in PDAC and demonstrates that tumor-targeted siRNA nanomedicine can effectively overcome chemoresistance when combined with standard chemotherapy. The LGIPCsi platform offers a rational and translational strategy to enhance treatment efficacy in PDAC through targeted RNAi-based combination therapy.

Objective: In order to streamline patient care and optimize outcomes, we have undertaken a protocol for patients with cranial/intracranial tumors whereby coordinated resection and reconstruction are performed in a single stage procedure using a virtually planned craniotomy, guides, and implants. This represents an advanced interdisciplinary approach offering operative efficiency while avoiding many clinical and technical challenges. We present our experience and a 9-patient series using this method. Methods: Patients with cranial/intracranial tumors which would create a defect from extirpation or with inadequate bone following repeated craniotomies were evaluated by neurosurgery and craniofacial surgery teams. A virtual surgical planning (VSP) webinar was attended by both services, where extirpation and reconstruction were simultaneously planned. For resection cases, cranial CT images were superimposed with MRI to register precise tumor location in relation to bone anatomy. The virtually planned craniotomy position was transferred to the operating room with a custom cutting guide registered to the patient’s cranial contours. Finally, immediate reconstruction was performed using a custom 3D polyether ether ketone (PEEK) implant designed to extend precisely to the edges of the guided craniotomy. Results: Nine patients age 29 to 79 years old (mean = 55) underwent coordinated tumor extirpation and cranial reconstruction via our workflow. They were followed for 28 to 65 months (mean = 42.2). There were no intraoperative complications. One patient developed transient blurry vision which resolved. One patient with history of repeated meningioma removal developed recurrence. All patients have healed without long-term complications, and there have been no explants from these procedures. Conclusion: Our single-stage protocol for cranial tumor extirpation and cranial reconstruction, which includes collaborative preoperative consultation and VSP, is versatile and effective. The use of computer-generated cutting guides and custom implants obviates intraoperative improvisation and minimizes reoperation. Ultimately, this interdisciplinary approach improves the esthetic and functional results for patients, representing an advancement in cranial defect reconstruction.