Senotherapy targeting for senescent cells is designed to attenuate age-related dysfunction. Senescent T cells, defined as CD4 + CD44 high CD62L low PD-1 + CD153 + cells, accumulate in visceral adipose tissues (VAT) in obese individuals. Here, we show the long-lasting effect of using CD153 vaccination to remove senescent T cells from high-fat diet (HFD)-induced obese C57BL/6J mice. We administered a CD153 peptide-KLH (keyhole limpet hemocyanin) conjugate vaccine with Alhydrogel (CD153-Alum) or CpG oligodeoxynucleotide (ODN) 1585 (CD153-CpG) and confirmed an increase in anti-CD153 antibody levels that was sustained for several months. After being fed a HFD for 10-11 weeks, adipose senescent T cell accumulation was significantly reduced in the VAT of CD153-CpG-vaccinated mice, accompanied by glucose tolerance and insulin resistance. A complement-dependent cytotoxicity (CDC) assay indicated that the mouse IgG2 antibody produced in the CD153-CpG-vaccinated mice successfully reduced the number of senescent T cells. The CD153-CpG vaccine is an optional tool for senolytic therapy.

Objectives Administrative data have been used to compare carotid endarterectomy (CEA) and carotid artery stenting (CAS). However, there are limitations in defining symptom status, CMS high-risk status, as well as complications. Therefore, we did a direct comparison between administrative data and physician chart review as well as between data collected for the National Surgical Quality Improvement Program (NSQIP) and physician chart review for CEA and CAS. Methods We performed an outcomes analysis on all CEA and CAS procedures from 2005–2011. We obtained ICD-9 diagnosis codes from hospital discharge records regarding symptom status, high-risk status, and perioperative stroke. We also obtained data on all CEA patients submitted to NSQIP over the same time period. A physician then performed a chart review of the same patients to determine symptom status, high-risk status, and perioperative strokes and the results were compared. Results We identified 1342 patients who underwent CEA or CAS between 2005–2011 and 392 patients who underwent CEA that were submitted to NSQIP. Administrative data identified fewer symptomatic patients (17.0% vs. 34.0%), fewer physiologic high-risk patients (9.3% vs. 23.0%), fewer anatomic high-risk patients (0% vs. 15.2%), and a similar proportion of perioperative strokes (1.9% vs. 2.0%). However, administrative data identified 8 false positive and 9 false negative perioperative strokes. NSQIP data identified more symptomatic patients compared to chart review (44.1% vs. 30.3%), fewer physiologic high-risk patients (13.0% vs. 18.6%), fewer anatomic high-risk patients (0% vs. 6.6%), and a similar proportion of perioperative strokes (1.5% vs. 1.8%, only 1 false negative stroke and no false positives). Conclusions Administrative data are unreliable for determining symptom status, high-risk status, and perioperative stroke and should not be used to analyze CEA and CAS. NSQIP data do not adequately identify high-risk patients, but do accurately identify perioperative strokes and to a lesser degree, symptom status.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates expression of low-density lipoprotein (LDL) receptors via receptor internalization and subsequent lysosomal degradation. Thus, an anti-PCSK9 antibody is well known as an anti-hyperlipidemia drug. Here, we aimed to develop vaccine for a long-term treatment of dyslipidemia targeted to PCSK9. In This study, we designed a peptide vaccine for mouse PCSK-9, which consisted of short peptides conjugated to keyhole limpet hemocyanin (KLH) as a carrier protein. Vaccines were administered to male apolipoprotein E (ApoE) deficient mice with adjuvants and significantly elicited an antibody response against PCSK9. The PCSK9 vaccines were administered to mice three times in 2-week intervals, and antibody titers and lipoprotein levels were evaluated up to 24 weeks after the first immunization to determine the therapeutic effect. Anti-PCSK9 antibody titers reached peak levels 6 weeks after the first immunization, and theses titers were maintained for up to 24 weeks. Decreased plasma levels of total cholesterol, very low-density lipoprotein (VLDL), and chylomicron (CM) were maintained for up to 24 weeks. Immunized mice exhibited a significant increase in cell-surface LDL receptor expression. Stimulation with KLH, but not PCSK9, induced the production of INF-gamma and interleukin-4 (IL-4), as determined with ELISPOT assays, thus indicating that PCSK9 vaccine did not elicit T-cell activation in our vaccine system. The present anti-PCSK9 vaccine induced long-lasting anti-PCSK9 antibody production and improved lipoprotein profiles. Thus, anti-PCSK9 vaccine could become a new option for the treatment of dyslipidemia as a long-acting therapy in future.

The aim of this study is to understand adaptive immunity to SARS-CoV-2 through the analysis of B cell epitope and neutralizing activity in coronavirus disease 2019 (COVID-19) patients. We obtained serum from forty-three COVID-19 patients from patients in the intensive care unit of Osaka University Hospital (n = 12) and in Osaka City Juso Hospital (n = 31). Most individuals revealed neutralizing activity against SARS-CoV-2 assessed by a pseudotype virus-neutralizing assay. The antibody production against the spike glycoprotein (S protein) or receptor-binding domain (RBD) of SARS-CoV-2 was elevated, with large individual differences, as assessed by ELISA. We observed the correlation between neutralizing antibody titer and IgG, but not IgM, antibody titer of COVID-19 patients. In the analysis of the predicted the linear B cell epitopes, hot spots in the N-terminal domain of the S protein were observed in the serum from patients in the intensive care unit of Osaka University Hospital. Overall, the analysis of antibody production and B cell epitopes of the S protein from patient serum may provide a novel target for the vaccine development against SARS-CoV-2.

To determine whether or not the methylation status of blood leukocyte DNA can be used as a surrogate marker of the risk for cancer, we quantitatively determined the methylation levels of insulin-like growth factor 2 (IGF2) and TUSC3 in 299 gastric cancer cases, and 299 age-and gender-matched controls. The IGF2 methylation levels in blood leukocyte DNA of the cases were lower than those of the healthy controls and there was a significant trend of increasing gastric cancer risk with decreasing methylation level of IGF2. Patients with hypermethylated IGF2 in blood leukocyte DNA showed a significantly better survival rate than those with hypomethylated IGF2, indicating that the IGF2 methylation level in blood leukocyte DNA can be a possible marker not only of the risk for but also of the prognosis of gastric cancer. In contrast, the TUSC3 methylation level in blood leukocyte DNA was higher in the cases than in the healthy controls, but the difference was not significant. The past lifestyle and clinicopathological characteristics of the participants were analyzed for any relationship with the methylation level. With aging and smoking, methylation of IGF2 and TUSC3 decreased and increased in blood leukocyte DNA, respectively. These results indicate that the methylation level of IGF2 in blood leukocyte DNA may be used as an important surrogate marker of the risk for gastric cancer.

Although the regulation of post-ischemic inflammation is an important strategy to treat ischemic stroke, all clinical trials have failed to show its efficacy. To solve the problem, we previously developed a novel partial peptide of RANKL, microglial healing peptide 1 (MHP1), which could reduce ischemic injury by inhibiting Toll-like receptor (TLR) induced inflammation. However, optimization of the peptide was necessary to increase the stability and efficacies for clinical use. According to information gathered through HPLC/MS in serum, we have newly designed a series of modified MHP1 peptides and have found that N-terminal acetylation and C-terminal amidation in MHP1 (MHP1-AcN), can strengthen its anti-inflammatory effects and increase its stability with anti-osteoclastogenic effects. Anti-TLR activity was reported to be reduced in MHP1 when incubated at 37 °C for 24 hrs, but MHP1-AcN could keep the activity under the same condition. The therapeutic effect of MHP1-AcN was observed in transient ischemic stroke model at lower dose than MHP1. Importantly, MHP1-AcN did not affect thrombolytic effects of tissue plasminogen activator (tPA) and inhibited tPA-induced hemorrhagic transformation. These findings indicated that MHP1-AcN was stable and effective anti-TLR signal peptide and could be a promising agent for treating stroke patients receiving tPA and endovascular therapy.

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Background There is a growing trend across health care to perform increasingly complex procedures in less acute settings. This shift has been fueled, in part, by enhanced recovery protocols, which have shortened hospital stays after major surgeries. We set out to determine the timing of microvascular complications after deep inferior epigastric artery perforator (DIEP) free flap breast reconstruction in a high-volume practice using continuous flap monitoring technologies. Methods The medical charts of all patients who underwent breast reconstruction with DIEP flaps over 24 consecutive months were reviewed. Postoperatively, all flaps were monitored according to a protocol that included continuous tissue oximetry with near-infrared spectroscopy. The primary end points evaluated included any unplanned return to the operating room, time to takeback, and flap loss rate. Results A total of 196 patients underwent breast reconstruction with a total of 301 DIEP flaps. Five of the flaps (1.7%) were taken back to the operating room for microvascular issues, and nine (3.0%) were taken back for nonvascular issues. Of patients who were brought back for microvascular issues, all five (100.0%) were initially identified by continuous noninvasive monitoring and taken back to the operating room within the first 14 hours (range: 1.2–13.6 hours). In the series, the flap failure rate was 0.66% (n = 2). Conclusion All of the microvascular issues were detected in the initial 23 hours after surgery, leading to prompt flap salvage. The results of this study bring into question the need for lengthy flap monitoring protocols and suggest that shorter inpatient, or even observation admissions, may be reasonable, particularly when flap monitoring protocols incorporating continuous noninvasive flap monitoring are used.