In situ Reprogramming as a Pro-Angiogenic Inducer to Rescue Ischemic Tissues.

Background: Enhanced regenerative therapeutic strategies are required to treat intractable ischemic heart disease. Summary: Since the discovery of putative endothelial progenitor cells (EPCs) in 1997, many studies have focused on their extraction, ex vivo processing, and autotransplantation under ischemic conditions. Nonetheless, numerous randomized clinical trials involving thousands of patients have yielded only marginal treatment effects, highlighting the need for advances regarding insufficient dosage and complex ex vivo processing. The prevailing paradigm of cellular differentiation highlights the potential of direct cellular reprogramming, which paves the way for in situ reprogramming. In situ reprogramming holds the promise of significantly enhancing current therapeutic strategies, yet its success hinges on the precise targeting of candidate cells for reprogramming. In this context, the spleen emerges as a pivotal "in situ reprogramming hub," owing to its dual function as both a principal site for nanoparticle distribution and a significant reservoir of putative EPCs. The in situ reprogramming of splenic EPCs offers a potential solution to overcome critical challenges, including the aforementioned insufficient dosage and complex ex vivo processing. Key Messages: This review explores the latest advancements in EPC therapy and in situ reprogramming, spotlighting a pioneering study that integrates those two strategies with a specific focus on the spleen. Such an innovative approach will potentially herald a new era of regenerative therapy for ischemic heart disease.

Chip collection of hepatocellular carcinoma based on O2 heterogeneity from patient tissue.

Hepatocellular carcinoma frequently recurs after surgery, necessitating personalized clinical approaches based on tumor avatar models. However, location-dependent oxygen concentrations resulting from the dual hepatic vascular supply drive the inherent heterogeneity of the tumor microenvironment, which presents challenges in developing an avatar model. In this study, tissue samples from 12 patients with hepatocellular carcinoma are cultured directly on a chip and separated based on preference of oxygen concentration. Establishing a dual gradient system with drug perfusion perpendicular to the oxygen gradient enables the simultaneous separation of cells and evaluation of drug responsiveness. The results are further cross-validated by implanting the chips into mice at various oxygen levels using a patient-derived xenograft model. Hepatocellular carcinoma cells exposed to hypoxia exhibit invasive and recurrent characteristics that mirror clinical outcomes. This chip provides valuable insights into treatment prognosis by identifying the dominant hepatocellular carcinoma type in each patient, potentially guiding personalized therapeutic interventions.

Effect of FIXed-dose combination of ARb and statin on adherence and risk factor control: The randomized FIXAR study.

BACKGROUND: The efficacy of fixed-dose combinations (FDCs) in improving adherence and risk factor control for cardiovascular disease has not been reported consistently. Here, we compared adherence and efficacy between an olmesartan/rosuvastatin FDC and the usual regimen. METHODS: In this 6-month, open-label, randomized, active-control study, we screened 154 patients; of these, 150 were randomly assigned to receive either olmesartan/rosuvastatin FDC or the usual regimen with separate angiotensin receptor blockers and statins. In total, 135 patients completed the study (median age: 68 years; male: 68.9%). The primary outcome was patients' adherence; the secondary outcomes were changes in blood pressure (BP) and lipid parameters. RESULTS: During follow-up, adherence in both groups was high and similar between the groups (98.9% and 98.3% in the FDC and usual regimen groups, respectively, p = 0.328). Changes in systolic (-8 and -5 mmHg, respectively, p = 0.084) and diastolic BP (-5 and -2 mmHg, p = 0.092) did not differ significantly, although they were numerically greater in the FDC group. Changes in low-density lipoprotein cholesterol (LDL-C) were greater in the FDC group (-13 and -4 mg/dL, respectively, p = 0.019), whereas changes in other lipid parameters were similar between the groups. The test drugs were well tolerated, showing no difference in safety between the groups. CONCLUSIONS: Patients' adherence was excellent and similar in the groups, whereas the reduction in the LDL-C level was greater in the FDC group. We provide comprehensive information on the adherence and efficacy of an FDC compared to the usual regimen in Korean patients with high cardiovascular risk.

Sprayable nanomicelle hydrogels and inflammatory bowel disease patient cell chips for development of intestinal lesion-specific therapy.

All-in-one treatments represent a paradigm shift in future medicine. For example, inflammatory bowel disease (IBD) is mainly diagnosed by endoscopy, which could be applied for not only on-site monitoring but also the intestinal lesion-targeted spray of injectable hydrogels. Furthermore, molecular conjugation to the hydrogels would program both lesion-specific adhesion and drug-free therapy. This study validated this concept of all-in-one treatment by first utilizing a well-known injectable hydrogel that underwent efficient solution-to-gel transition and nanomicelle formation as a translatable component. These properties enabled spraying of the hydrogel onto the intestinal walls during endoscopy. Next, peptide conjugation to the hydrogel guided endoscopic monitoring of IBD progress upon adhesive gelation with subsequent moisturization of inflammatory lesions, specifically by nanomicelles. The peptide was designed to mimic the major component that mediates intestinal interaction with Bacillus subtilis flagellin during IBD initiation. Hence, the peptide-guided efficient adhesion of the hydrogel nanomicelles onto Toll-like receptor 5 (TLR5) as the main target of flagellin binding and Notch-1. The peptide binding potently suppressed inflammatory signaling without drug loading, where TLR5 and Notch-1 operated collaboratively through downstream actions of tumor necrosis factor-alpha. The results were produced using a human colorectal cell line, clinical IBD patient cells, gut-on-a-chip, a mouse IBD model, and pig experiments to validate the translational utility.

Cell-Membrane-Derived Nanoparticles with Notch-1 Suppressor Delivery Promote Hypoxic Cell-Cell Packing and Inhibit Angiogenesis Acting as a Two-Edged Sword.

Cell-cell interactions regulate intracellular signaling via reciprocal contacts of cell membranes in tissue regeneration and cancer growth, indicating a critical need of membrane-derived tools in studying these processes. Hence, cell-membrane-derived nanoparticles (CMNPs) are produced using tonsil-derived mesenchymal stem cells (TMSCs) from children owing to their short doubling time. As target cell types, laryngeal cancer cells are compared to bone-marrow-derived MSCs (BMSCs) because of their cartilage damaging and chondrogenic characteristics, respectively. Treating spheroids of these cell types with CMNPs exacerbates interspheroid hypoxia with robust maintenance of the cell-cell interaction signature for 7 days. Both cell types prefer a hypoxic environment, as opposed to blood vessel formation that is absent in cartilage but is required for cancer growth. Hence, angiogenesis is inhibited by displaying the Notch-1 aptamer on CMNPs. Consequently, laryngeal cancer growth is suppressed efficiently in contrast to improved chondroprotection observed in a series of cell and animal experiments using a xenograft mouse model of laryngeal cancer. Altogether, CMNPs execute a two-edged sword function of inducing hypoxic cell-cell packing, followed by suppressing angiogenesis to promote laryngeal cancer death and chondrogenesis simultaneously. This study presents a previously unexplored therapeutic strategy for anti-cancer and chondroprotective treatment using CMNPs.

Rare case of isolated true aneurysm in the superficial femoral artery treated with endovascular intervention: a case report.

BACKGROUND: Isolated true aneurysms in the superficial femoral artery (SFA) have rarely been reported. Most cases are undiagnosed until rupture or the occurrence of complications. CASE SUMMARY: A 36-year-old woman presented with a palpable, pulsating mass on her right thigh which had increased in size over 2 months. She also had a swollen right leg and mild claudication (Stage II in Rutherford classification). For 2 months, the patient was treated by manual massage, acupuncture, and extracorporeal shock wave therapy in local clinics. Bed-side ultrasonography identified a 3.4-cm sized true aneurysm of the right SFA. There were no other aneurysms in arteries from head to toe. There was no evidence of atherosclerotic risk factors or connective tissue disease. The patient was successfully treated by a covered stent graft implantation without any complications. DISCUSSION: Isolated true aneurysm in the SFA is rare and tends to go undiagnosed especially in young women. Ultrasonography is an easy and useful diagnostic tool for differential diagnosis of thigh mass. In this case, endovascular treatment was safely applied for a true aneurysm without rupture.

Stroke and Systemic Embolism and Other Adverse Outcomes of Heart Failure With Preserved and Reduced Ejection Fraction in Patients With Atrial Fibrillation (from the COmparison study of Drugs for symptom control and complication prEvention of Atrial Fibrillation [CODE-AF]).

It is unknown whether heart failure (HF) with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) carry a similar risk of stroke or systemic embolism (SE) and other outcomes in patients with nonvalvular atrial fibrillation (AF). A prospective, multicenter outpatient registry with echocardiographic data which enrolled 10,589 patients from June 2016 to May 2019 was analyzed. In this registry, 935 (8.8%) patients had HF, and the proportions of patients with HFpEF and HFrEF were 43.2% and 56.8%, respectively. During follow-up over 1.33 years, 11 (2.07 per 100 person-years [PYR]) and 5 (0.76 per 100 PYR) patients had stroke/SE in the HFpEF and HFrEF groups, respectively, whereas 102 patients (0.84 per 100 PYR) had these sequelae in the no-HF group. The HFpEF group had a significantly higher cumulative incidence of stroke/SE (p = 0.004) and risk of stroke/SE (adjusted hazard ratio [HR] 2.23, 95% confidence interval [CI] 1.19 to 4.18) than the no-HF group. The risk of stroke/SE in the HFpEF group compared with that in the no-HF group was consistently increased even in patients on oral anticoagulation therapy (adjusted HR 2.55, 95% CI 1.31 to 4.96). There was a correlation between larger left atrial size and risk of stroke/SE (adjusted HR 1.53, 95% CI 1.03 to 2.29), but not between reduced left ventricular ejection fraction and this risk. In conclusion, these results suggest that strict oral anticoagulation therapy helps reduce the risk of stroke/SE in patients with nonvalvular AF and HFpEF, especially in those with a larger left atrial size.