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The discretization approximation method used to simulate the open dynamics of the environment in continuum often suffers from recurrence, which results in inefficiency. To address this issue, this paper proposes a generalization of the discretization approximation method in the complex plane using complex Gauss quadratures. The resulting effective Hamiltonian is non-Hermitian due to the dissipative dynamics of the system. The proposed method is applied to two solvable models, namely the dephasing model and the single-excitation open dynamics in the generalized Aubry-Andr\'{e}-Harper model. The results demonstrate that the occurrence of complex discrete modes in the environment can significantly reduce recurrence, thereby enabling the efficient and accurate simulation of open dynamics in both models., Comment: The statement and expression have been improved. Submitted

Lu Gao, Wei Zhao, Qi Liu, Mingzhao Qin Department of Geriatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Lu Gao Email audreygao@qq.comBackground: Peripheral artery disease (PAD) is a manifestation of atherosclerotic cardiovascular disease (ASCVD) and significantly increases the risk of myocardial infarction and stroke. As most patients with PAD are asymptomatic, this condition is largely neglected in clinical practice. Type 2 diabetes (T2DM) patients have higher prevalence of PAD. Therefore, early detection and intervention of diabetic PAD are very important. Metabolic syndrome (MetS) is a group of interrelated metabolic risk factors, a predictor of poor prognosis in elderly patients with ASCVD. Recently, many of the metabolic risk factors as well as the overall concept of MetS itself have sparked a great deal of debate regarding their precise roles in PAD.Objective: To evaluate the relationship between metabolic syndrome (MetS) and peripheral arterial disease (PAD) in elderly patients with type 2 diabetes (T2DM).Methods: Two hundred and eighty-one elderly T2DM patients admitted to Beijing Tongren Hospital from October 2016 to December 2017 were divided into PAD group (n=136) and non-PAD (NPAD) group (n=145). Their medical records, physical examination parameters and laboratory testing parameters were later recorded and analyzed by multivariate logistic regression analysis.Results: No significant difference was detected in general clinical data and laboratory testing parameters between the two groups (P> 0.05). The incidence of MetS was significantly higher in PAD group than in NPAD group (88.2% vs 70.3%, P=0.001). Multivariate logistic regression analysis showed that the risk of PAD was 1.762-fold higher in MetS patients after adjustment for age, sex, history of smoking and alcohol consumption, WC, SBP, serum TC and HbA1c level, eGFR and duration of DM (95% CI: 1.205– 6.330, P=0.016).Conclusion: MetS closely correlates with PAD in elderly T2DM patients, though no significant difference has been detected in their metabolic indicators.Keywords: elderly, type 2 diabetes, metabolic syndrome, peripheral arterial disease

Yejing Shen,1,2 Xiaowen Xu,2 Siming Meng,2 Meng Qin,2 Hailing Li,2 Dejie Chu,1 Cuixia Zheng2 1Department of Respiratory Medicine, Shanghai Eighth People’s Hospital, Shanghai, 200235, People’s Republic of China; 2Department of Respiratory Medicine, Yangpu Hospital Affiliated to Tongji University, Shanghai, 200090, People’s Republic of ChinaCorrespondence: Dejie ChuDepartment of Respiratory Medicine, Shanghai Eighth People’s Hospital, 8 Caobao Road, Shanghai, 200235, People’s Republic of ChinaEmail chudejie@yandex.comCuixia ZhengDepartment of Respiratory Medicine, Yangpu Hospital Affiliated to Tongji University, 450 Tengyue Road, Shanghai, 200090, People’s Republic of ChinaEmail zhengcuixiash@163.comObjective: To assess the impact of blood glucose levels on the prognosis of patients with community-acquired pneumonia (CAP) who were elderly or middle-aged.Methods: From January 1, 2018, to December 31, 2020, patients with CAP (≥ 45 years) were retrospectively enrolled in this observational study. They were stratified by age (45– 64 or ≥ 65 years) and blood glucose level (≥ 11.1 or < 11.1 mmol/l). The effect of admission blood glucose on 28-day mortality was assessed with the Cox proportional hazards model, adjusted for demographic factors and comorbidity.Results: Among 1656 patients with CAP, increased blood glucose (HR=2.08, 95% CI: 1.38– 3.49; P< 0.01) and advanced age (HR=2.76, 95% CI: 1.65– 3.77; P< 0.01) were significantly associated with a higher risk of 28-day mortality, after controlling for potential confounding factors. The strength of the association of blood glucose level with 28-day mortality decreased with age (P=0.01 for the interaction) as the adjusted HRs for death were 4.48 (95% CI: 1.40– 13.65; P< 0.01) for middle-age patients 45– 64 years and 1.52 (95% CI: 1.09– 2.17; P=0.05) for elderly patients ≥ 65 years.Conclusion: The association of blood glucose level upon admission for CAP with all-cause mortality was stronger at younger ages.Keywords: age, community-acquired pneumonia, hyperglycemia, mortality, prognosis

Wenli Yang,1,* Guanghua Zhu,2,* Maoquan Qin,2 Zhigang Li,3 Bin Wang,2 Jun Yang,2 Tianyou Wang2 1Department of Clinical Nutrition, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of China; 2Department of Hematology and Oncology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, National Key Discipline of Pediatrics, Beijing, People’s Republic of China; 3Hematology and Oncology Laboratory, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, National Key Discipline of Pediatrics, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tianyou WangDepartment of Hematology and Oncology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, National Key Discipline of Pediatrics, Nanlishi Road No. 56, Xicheng District, Beijing 100045, People’s Republic of ChinaTel +86 10 5961 7123Fax +86 10 5971 8700Email wangtiany_wty@163.comObjective: This study aimed to evaluate the effectiveness of Ruxolitinib for acute/chronic graft-versus-host disease in children.Methods: This study was a retrospective trial. We analyzed the clinical characteristics of children who responded poorly to previous treatment for graft-versus-host disease (GVHD) and received ruxolitinib treatment after allogeneic hematopoietic stem cell transplantation (allo-HSCT) as an additional or replacement therapy.Results: A total of 53 patients were analyzed: aGVHD and cGVHD. The overall response rate (ORR) to ruxolitinib was 75.5%. The ORR was 64.7% (11/17) in the aGVHD group including 6, 5, and 6 patients with partial responses (PRs), complete responses (CRs), and treatment failure, respectively. The ORR was 80.6% (29/36) in the cGVHD group including 10 with CRs and 19 with PRs. Five and 2 patients showed no response and treatment failure, respectively. Four and 14 patients were GVHD recurrence in aGVHD and cGVHD respectively. A total of 14 patients (39%) discontinued steroids and 8 patients (22.2%) reduced steroids. The incidence of obvious adverse events was 94.1% (16/17) in the aGVHD group, which was higher than that in the cGVHD group. Meanwhile, the prognosis of children with cGVHD was superior to that of children with aGVHD after treatment with ruxolitinib. During the ruxolitinib treatment, only 1 patient suffered a relapse of the primary tumor. Eleven patients also suffered transplantation-associated thrombotic microangiopathy (TA-TMA) after allo-HSCT.Conclusion: Pediatric patients with GVHD (especially cGVHD) responded well to ruxolitinib treatment. Ruxolitinib can also be used as an alternative treatment for patients with TMA.Keywords: ruxolitinib, graft-versus-host disease, allogeneic hematopoietic stem cell transplantation, Janus kinase1/2 inhibitor, pediatric patients

Ying Zhao, Zhi-jun Xia, Qing Hu, Mei-ying Qin Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of ChinaCorrespondence: Zhi-jun XiaDepartment of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang City, Liaoning Province 110004, People’s Republic of ChinaTel +86-18940251266Fax +86-24-83955092Email xia_pd@163.comPurpose: To investigate the effect of total pelvic floor reconstruction with a six-arm mesh in the treatment of pelvic organ prolapse.Patients and Methods: This is a retrospective observational cohort study. A total of 368 patients with pelvic organ prolapse underwent pelvic floor reconstruction surgery. Patients were categorized by the type of surgical mesh: 176 patients received a six-arm mesh and 192 patients received an anteroposterior approach mesh. The 1-year effect of the two groups was compared. The Pelvic Floor Distress Inventory Questionnaire (PFDI-20), Colorectal-Anal Distress Inventory (CRADI-8) and the Pelvic Organ Prolapse Quantitation (POP-Q) staging were used for evaluation. The incidence of complications was recorded. A cure standard was registered by a POP-Q score of grade I or below. A P value < 0.05 indicates the difference is statistically significant.Results: There was no recurrence documented in the patients; the cure rate was 100% in both groups. After surgery, the length of the vagina in the six-arm mesh group was longer than that of the control group at 6 months and 12 months, respectively (P < 0.05). The six-arm mesh group had lower PFDI-20 and CRADI-8 scores after surgery than those of the control group at 6 and 12 months, respectively (P < 0.05). Pelvic floor and rectal dysfunction symptom improvement were superior in the six-arm mesh group compared with the control group. After surgery, the Female Sexual Function Inventory (FSFI) score of the six-arm mesh group was superior to that of the control group at 6 and 12 months, respectively (P < 0.05). The incidence of complications in the six-arm mesh group was lower than that of the control group (P < 0.05).Conclusion: The total pelvic floor reconstruction using six-arm mesh has the same healing rate as anteroposterior approach mesh surgery, and it is better than traditional surgery in improving subjective symptoms and reducing postoperative complications.Keywords: pelvic floor reconstruction, pelvic organ prolapse, six-arm mesh

Skin diseases such as lupus, cancer, psoriasis, and hyperhidrosis can potentially be treated effectively by suppressing allele-specific genes using small interfering RNA (siRNA). Injections of siRNA into skin, though effective, are painful and cover small surface areas and thus are not suitable as a long-term treatment option. Topical delivery of siRNA is an attractive alternative option to mediate RNA interference (RNAi). However, the barrier function of the epidermis impedes effective permeation of siRNA into the skin. Herein, we describe topical delivery of siRNA using ionic liquids (ILs) capable of complexing with siRNA non-covalently and delivering it effectively. Using complementary and synergistic strategies of ionic liquids, we report delivery of effective doses of siRNA into skin. The first strategy involved the use of hydrophobic cations to robe the siRNA and the second strategy involved the use of choline-geranic acid ionic liquid (CAGE) to enhance its dermal penetration. In vitro studies in porcine skin confirmed the synergistic effect of these strategies in enhancing epidermal and dermal penetration. In vivo application of siRNA formulation to SKH-1E hairless mice significantly suppressed GAPDH expression with no clinical evidence of toxicity. This is a simple, personalized, and scalable platform for effective topical delivery of siRNA for treating genetic skin diseases.

Reactive Oxygen Species (ROS) are generated as by-products of aerobic metabolism. The production of ROS increases during xenobiotic stress and under multiple pathological conditions. Although ROS are considered harmful historically, mounting evidence recently indicates a signaling function of ROS, preceding to and regulating transcriptional or post-transcriptional events, contributing to cell death or cell survival and adaptation. Among the cellular defense mechanisms activated by ROS is formation of stress granules (SGs). The stalled translational apparatus, together with mRNA, aggregates into microscopically detectable and molecularly dynamic granules. We found that with H2O2, the dose most potent for inducing SGs in HeLa cells is 400–600 μM. With 200 μM H2O2, 2 h treatment induced the highest percentage of cells containing SGs. Whether ROS signaling pathways regulate the formation of SGs was tested using pharmacological inhibitors. We probed the potential role of PI3K, MAPKs, PKC or histone deacetylation in SG formation. Using deferoxamine as a positive control, we found a lack of inhibitory effect of wortmannin, LY-294002, JNK-I, SB-202190, PD-98059, or H89 when the percentage of cells containing SGs was counted. About 35% inhibition was observed with HDAC6 inhibitor Tubastatin A, whereas general HDAC inhibitor Trichostatin A provided a complete inhibition of SG formation. Our data point to the need of investigating the role of HDACs in SG formation during oxidative stress.

In patients with trastuzumab-resistant HER2-positive breast cancer, the combination of everolimus (mTORC1 inhibitor) with trastuzumab failed to show a clinically significant benefit. However, the combination of mTOR inhibition and the antibody-drug conjugate (ADC) trastuzumab-emtansine (T-DM1) remains unexplored. We tested T-DM1 plus everolimus in a broad panel of HER2-positive breast cancer cell lines. The combination was superior to T-DM1 alone in four cell lines (HCC1954, SKBR3, EFM192A, and MDA-MB-36) and in two cultures from primary tumor cells derived from HER2-positive patient-derived xenografts (PDX), but not in BT474 cells. In the trastuzumab-resistant HCC1954 cell line, we characterized the effects of the combination using TAK-228 (mTORC1 and 2 inhibitor) and knockdown of the different mTOR complex components. T-DM1 did not affect mTOR downstream signaling nor induct autophagy. Importantly, mTOR inhibition increased intracellular T-DM1 levels, leading to increased lysosomal accumulation of the compound. The increased efficacy of mTOR inhibition plus T-DM1 was abrogated by lysosome inhibitors (chloroquine and bafilomycin A1). Our experiments suggest that BT474 are less sensitive to T-DM1 due to lack of optimal lysosomal processing and intrinsic resistance to the DM1 moiety. Finally, we performed several in vivo experiments that corroborated the superior activity of T-DM1 and everolimus in HCC1954 and PDX-derived mouse models. In summary, everolimus in combination with T-DM1 showed strong antitumor effects in HER2-positive breast cancer, both in vitro and in vivo. This effect might be related, at least partially, to mTOR-dependent lysosomal processing of T-DM1, a finding that might apply to other ADCs that require lysosomal processing. Implications: Inhibition of mTOR increases the anti-tumor activity of T-DM1, supporting that the combination of mTOR inhibitors and antibody-drug conjugates warrants clinical evaluation in patients with HER2-positive breast cancer.

Coronary artery reperfusion is essential for the management of symptoms in the patients with myocardial ischemia. However, the benefit of reperfusion often comes at an expense of paradoxical injury, which contributes to the adverse events, and sometimes heart failure. Reperfusion is known to increase the production of reactive oxygen species (ROS). We address whether N-acetylcysteine (NAC) reduces the ROS and alleviates reperfusion injury by improving the clinical outcomes. A literature search for the randomized controlled trials (RCTs) was carried out in the five biomedical databases for testing the effects of NAC in patients undergoing coronary artery reperfusion by percutaneous coronary intervention, thrombolysis, or coronary artery bypass graft. Of 787 publications reviewed, 28 RCTs were identified, with a summary of 2,174 patients. A meta-analysis using the random effects model indicated that NAC administration during or prior to the reperfusion procedures resulted in a trend toward a reduction in the level of serum cardiac troponin (cTn) [95% CI, standardized mean difference (SMD) −0.80 (−1.75; 0.15), p = 0.088, n = 262 for control, 277 for NAC group], and in the incidence of postoperative atrial fibrillation [95% CI, relative risk (RR) 0.57 (0.30; 1.06), p = 0.071, n = 484 for control, 490 for NAC group]. The left ventricular ejection fraction or the measures of length of stay in intensive care unit (ICU) or in hospital displayed a positive trend that was not statistically significant. Among the nine trials that measured ROS, seven showed a correlation between the reduction of lipid peroxidation and improved clinical outcomes. These lines of evidence support the potential benefit of NAC as an adjuvant therapy for cardiac protection against reperfusion injury.

Myocardial infarction is the most common form of acute coronary syndrome. Blockage of a coronary artery due to blood clotting leads to ischemia and subsequent cell death in the form of necrosis, apoptosis, necroptosis and ferroptosis. Revascularization by coronary artery bypass graft surgery or non-surgical percutaneous coronary intervention combined with pharmacotherapy is effective in relieving symptoms and decreasing mortality. However, reactive oxygen species (ROS) are generated from damaged mitochondria, NADPH oxidases, xanthine oxidase, and inflammation. Impairment of mitochondria is shown as decreased metabolic activity, increased ROS production, membrane permeability transition, and release of mitochondrial proteins into the cytoplasm. Oxidative stress activates Nrf2 transcription factor, which in turn mediates the expression of mitofusin 2 (Mfn 2) and proteasomal genes. Increased expression of Mfn2 and inhibition of mitochondrial fission due to decreased Drp1 protein by proteasomal degradation contribute to mitochondrial hyperfusion. Damaged mitochondria can be removed by mitophagy via Parkin or p62 mediated ubiquitination. Mitochondrial biogenesis compensates for the loss of mitochondria, but requires mitochondrial DNA replication and initiation of transcription or translation of mitochondrial genes. Experimental evidence supports a role of Nrf2 in mitophagy, via up-regulation of PINK1 or p62 gene expression; and in mitochondrial biogenesis, by influencing the expression of PGC-1α, NResF1, NResF2, TFAM and mitochondrial genes. Oxidative stress causes Nrf2 activation via Keap1 dissociation, de novo protein translation, and nuclear translocation related to inactivation of GSK3β. The mechanism of Keap 1 mediated Nrf2 activation has been hijacked for Nrf2 activation by small molecules derived from natural products, some of which have been shown capable of mitochondrial protection. Multiple lines of evidence support the importance of Nrf2 in protecting mitochondria and preserving or renewing energy metabolism following tissue injury.