Mesenchymal Stem Cell Secretions Improve Donor Heart Function 1 Following Ex-vivo Cold Storage

Objectives Heart transplantation is the gold standard of treatments for end-stage heart failure, but its use is limited by extreme shortage of donor organs. The time “window” between procurement and transplantation sets the stage for myocardial ischemia/reperfusion injury, which constrains the maximal storage time and lowers use of donor organs. Given mesenchymal stem cell (MSC)-derived paracrine protection, we aimed to evaluate the efficacy of MSC-conditioned medium (CM) and extracellular vesicles (EVs) when added to ex vivo preservation solution on ameliorating ischemia/reperfusion–induced myocardial damage in donor hearts. Methods Mouse donor hearts were stored at 0°C-4°C of <1-hour cold ischemia (<1hr-I), 6hr-I + vehicle, 6hr-I + MSC-CM, 6hr-I + MSC-EVs, and 6hr-I + MSC-CM from MSCs treated with exosome release inhibitor. The hearts were then heterotopically implanted into recipient mice. At 24 hours postsurgery, myocardial function was evaluated. Heart tissue was collected for analysis of histology, apoptotic cell death, microRNA (miR)-199a-3p expression, and myocardial cytokine production. Results Six-hour cold ischemia significantly impaired myocardial function, increased cell death, and reduced miR-199a-3p in implanted hearts versus <1hr-I. MSC-CM or MSC-EVs in preservation solution reversed the detrimental effects of prolong cold ischemia on donor hearts. Exosome-depleted MSC-CM partially abolished MSC secretome-mediated cardioprotection in implanted hearts. MiR-199a-3p was highly enriched in MSC-EVs. MSC-CM and MSC-EVs increased cold ischemia–downregulated miR-199a-3p in donor hearts, whereas exosome-depletion neutralized this effect. Conclusions MSC-CM and MSC-EVs confer improved myocardial preservation in donor hearts during prolonged cold static storage and MSC-EVs can be used for intercellular transport of miRNAs in heart transplantation

Screening and characterization of the scFv for chimeric antigen receptor T cells targeting CEA-positive carcinoma

IntroductionChimeric antigen receptor T (CAR-T) cell therapy presents a promising treatment option for various cancers, including solid tumors. Carcinoembryonic antigen (CEA) is an attractive target due to its high expression in many tumors, particularly gastrointestinal cancers, while limited expression in normal adult tissues. In our previous clinical study, we reported a 70% disease control rate with no severe side effects using a humanized CEA-targeting CAR-T cell. However, the selection of the appropriate single-chain variable fragment (scFv) significantly affects the therapeutic efficacy of CAR-T cells by defining their specific behavior towards the target antigen. Therefore, this study aimed to identify the optimal scFv and investigate its biological functions to further optimize the therapeutic potential of CAR-T cells targeting CEA-positive carcinoma.MethodsWe screened four reported humanized or fully human anti-CEA antibodies (M5A, hMN-14, BW431/26, and C2-45), and inserted them into a 3rd-generation CAR structure. We purified the scFvs and measured the affinity. We monitored CAR-T cell phenotype and scFv binding stability to CEA antigen through flow cytometry. We performed repeated CEA antigen stimulation assays to compare the proliferation potential and response of the four CAR-T cells, then further evaluated the anti-tumor efficacy of CAR-T cells ex vivo and in vivo.ResultsM5A and hMN-14 CARs displayed higher affinity and more stable CEA binding ability than BW431/26 and C2-45 CARs. During CAR-T cell production culture, hMN-14 CAR-T cells exhibit a larger proportion of memory-like T cells, while M5A CAR-T cells showed a more differentiated phenotype, suggesting a greater tonic signal of M5A scFv. M5A, hMN-14, and BW431/26 CAR-T cells exhibited effective tumor cell lysis and IFN-γ release when cocultured with CEA-positive tumor cells in vitro, correlating with the abundance of CEA expression in target cells. While C2-45 resulted in almost no tumor lysis or IFN-γ release. In a repeat CEA antigen stimulation assay, M5A showed the best cell proliferation and cytokine secretion levels. In a mouse xenograft model, M5A CAR-T cells displayed better antitumor efficacy without preconditioning.DiscussionOur findings suggest that scFvs derived from different antibodies have distinctive characteristics, and stable expression and appropriate affinity are critical for robust antitumor efficacy. This study highlights the importance of selecting an optimal scFv in CAR-T cell design for effective CEA-targeted therapy. The identified optimal scFv, M5A, could be potentially applied in future clinical trials of CAR-T cell therapy targeting CEA-positive carcinoma

Clipping Noise Compensation for Overlapped Time Domain Multiplexing toward Low Peak-to-Average Power Ratio

Overlapped Time Domain Multiplexing (OvTDM) is a high-rate transmission technology that employs the idea of superposition coded modulation (SCM) scheme for signal generation, aiming to achieve maximum channel capacity sharing. Meanwhile, it is also widely considered as a promising technique toward physical layer security. As a main drawback of such system, a high peak-to-average power ratio (PAPR) issue in this system, arising from multi-layer superposition, can be addressed through intentional clipping. However, the detection at the receiver side is vulnerable to nonlinear distortion caused by clipping, which can degrade the performance. To mitigate this distortion, this paper proposed an iterative scheme for estimating and partially canceling clipping distortion at the receiver. We managed to mitigate the impact of clipping noise as much as possible and minimize the cost of optimizing PAPR, thereby improving the transmission performance of OvTDM in the context of amplitude clipping

Early outcomes of a triple-branched stent graft implantation in elderly patients with acute type a aortic dissection

Abstract Purpose Older patients with acute type A aortic dissection (ATAAD) have higher risk of mortality than that of younger patients when a total arch reconstruction (TAR) is required. Triple-branched stent graft (TBSG) implantation is a novel technique for TAR. However, early outcomes of a TBSG implantation in older patients have not been reported. This study aimed to evaluate the early outcomes of the TBSG technique in older patients with ATAAD. Methods From February 2015 to December 2020, 640 patients who simultaneously underwent an emergent open aortic surgery and TBSG implantation for ATAAD were enrolled in this study. They were categorized into the younger (age ≤ 70 years old, n = 573) and older groups (age > 70 years, n = 67). Clinical data of all patients were retrospectively reviewed. Result The mean ages of the patients in the younger and older groups were 45.3 ± 9.6 years old and 73.5 ± 3.0 years old, respectively. Preoperative characteristics were similar between the two groups, except for weight and incidence of moderate or greater aortic regurgitation, which were lower in the older group than those in the younger group. Surgical procedure and duration (i.e., duration for cardiopulmonary bypass, aortic cross-clamp, selected cerebral perfusion, and total circulation arrest) were comparable between the two groups (p > 0.05). Patients in the older group had higher incidence of dialysis for acute kidney injury and longer ICU stay compared with those in the younger group. However, the incidences of 30-day mortality (5.1% in younger group vs. 7.5% in older group, p = 0.407) and other major complications (i.e., neurological adverse events) were similar between the two groups. Conclusion TBSG implantation for ATAAD resulted in an acceptable mortality rate in patients above 70 years old, thus, it could be a feasible surgical procedure to perform in older patients with ATAAD when a TAR is required

Experimental investigation of wave-driven pore-water pressure and wave attenuation in a sandy seabed

Wave–seabed interaction has become a big concern of coastal researchers and engineers in the past decades as it may largely contribute to the seabed instability and failure of marine foundations. A series of laboratory experiments are carried out in a wave flume to study the wave-driven pore-water pressure in a sandy seabed and the attenuation of wave height. Waves propagating over a sandy seabed lead to oscillatory excess pore-water pressures within the porous seabed. Amplitude of pore-water pressure within the seabed decreases toward the bottom. A phase lag of pore-water pressure is clearly observed, and it contributes to net upward pressure related to seabed instability. Height of the incident wave is reduced as part of wave energy is dissipated by bottom friction, and a maximum attenuation of the incident wave height is up to 7.23% in the experiments. The influences of wave period and height of the incident wave on pore-water pressure and wave attenuation are also analyzed and discussed

Metabolic syndrome increases operative mortality in patients with impaired left ventricular systolic function who undergo coronary artery bypass grafting: a retrospective observational study

Abstract Background Metabolic syndrome (MetS) is a prevalent risk factor for coronary artery disease progression. Past studies have shown that MetS and its components tends to increase mortality after coronary artery bypass grafting (CABG), but data on the impact of MetS on postoperative outcome in patients with a left ventricular (LV) ejection fraction (EF) < 50% are still lacking. Methods Out of 2300 patients who underwent CABG between 2008 and 2018 in our center, 190 patients were identified as having impaired LV systolic function (EF < 50%). The patients were divided into two groups: those with MetS (n = 87, 45.8%) and those without MetS (n = 103, 54.2%). The influence of MetS on postoperative mortality and major complications was investigated. Results Postoperative mortality occurred in 12.6% of patients with MetS and in 3.9% of patients without MetS (p < 0.05). Multivariate analysis showed that patients with MetS had a significantly greater risk of mortality compared with patients without MetS (relative risk 7.23, p < 0.05). After adjustment for other risk factors, the risk of mortality was increased 6.47-fold [95% confidence interval (CI):1.25–33.6; p < 0.05] in patients with MetS and diabetes and 5.4-fold (95% CI: 1.12–29.7; p < 0.05) in patients with MetS and without diabetes, whereas it was not significantly increased in patients with diabetes and without MetS. Conclusions MetS is an important predictor of increased mortality in patients with LVEF<50% who undergo CABG. The components of MetS have synergistic effect in postoperative mortality. Multifactorial intervention in MetS is required to improve surgical efficacy in these patients