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Natural products are useful tools for biological mechanism research and drug discovery. Due to the excellent tumor cell growth inhibitory profile and sub-nanomolar potency, Coibamide A (CA), an N-methyl-stabilized depsipeptide isolated from marine cyanobacterium, has been considered as a promising lead compound for cancer treatment. However, the molecular anti-cancer mechanism of the action of CA remains unclear. Here, we showed that CA treatment induced caspase-independent cell death in breast cancer cells. CA treatment also led to severe lysosome defects, which was ascribed to the impaired glycosylation of lysosome membrane protein LAMP1 and LAMP2. As a consequence, the autophagosome-lysosome fusion was blocked upon CA treatment. In addition, we presented evidence that this autophagy defect partially contributed to the CA treatment-induced tumor cell death. Together, our work uncovers a novel mechanism underlying the anti-cancer action of CA, which will promote its further application for cancer therapy.

Background Spontaneous isolated superior mesenteric artery dissection (SISMAD) is a rare vascular disorder, and the treatment strategies remain controversial. This study aimed to compare outcomes of conservative and endovascular treatments in symptomatic patients with SISMAD. Methods Forty-two consecutive SISMAD patients who were admitted to a single center between October 2009 and May 2018 were enrolled in this study. Based on their symptoms, 15 had conservative treatment, and 27 had endovascular treatment. The baseline characteristics, treatments, and follow-up results of the conservative group and endovascular group were analysed. Results The rates of symptom relief were 93.3% in the conservative group and 96.3% in the endovascular group. The procedure-related complications in the endovascular group included one case of pseudoaneurysm formation in the left brachial artery. During the follow-up period (median 28.5 months), a higher proportion of patients in the conservative group had symptom recurrence (42.9% in the conservative group versus 4.8% in the endovascular group, p p = 0.014) and a higher rate of superior mesenteric artery (SMA) remodeling (p Conclusions For symptomatic SISMAD, endovascularly treated patients had a lower rate of symptom recurrence and a higher rate of SMA remodeling in the long term. Prospective, multi-center studies are needed to confirm the long-term outcomes of both treatments.

There is no consensus for determining which vessel should be revascularized in patients with multiple diseased infrapopliteal arteries. The angiosome concept may guide a more efficient targeted direct revascularization. Therefore, we conducted a study to assess whether the regional evaluation of foot blood volume may guide direct revascularization (DR) and if it will lead to better perfusion improvement than indirect revascularization (IR). We performed a prospective single-center observational cohort study in patients treated in the Department of Vascular Surgery of Peking Union Medical College Hospital from November 2016 to April 2019. Twenty-seven patients treated with endovascular intervention were included. The intraoperative parenchymal blood volume of different foot regions was obtained for each patient using C-arm CT before and after intervention. The intervention procedure significantly increased the overall blood volume (48.95 versus 81.97 ml/1000 ml, p = 0.002). Patients with direct revascularization had a 197% blood volume increase while patients with indirect revascularization had a 39% increase (p = 0.028). The preoperative blood volume was higher in patients with mild symptoms than in patients with severe symptoms (58.20 versus 30.45 ml/1000 ml, p = 0.039). However, in regard to postoperative blood volume, no significant difference was discovered between these two groups (75.05 versus 95.01 ml/1000 ml, p = 0.275). Based on quantitative measurements, we conclude that overall blood volume can rise significantly after the intervention. Revascularizing the supplying vessel of the ischemic area directly will result in better perfusion improvement than restoring blood supply through the collateral circulation. Preoperative blood volume is associated with preoperative symptoms. • Flat panel detector CT can obtain intraoperative perfusion status and guide treatment in endovascular intervention. • Revascularizing the supplying vessel of the ischemic area directly will result in better perfusion improvement than restoring the blood supply through the collateral circulation. • Patients with severer clinical manifestations have lower blood volumes.

Objective The safety and effectiveness of using the hybrid approach to treat tandem carotid lesions is controversial, and the clinical significance of the technical variants on the perioperative outcomes has not been evaluated. The present meta-analysis was performed to evaluate the technique, safety, effectiveness, and long-term outcomes of the hybrid approach. Methods The PubMed, Embase, and Cochrane Library databases were searched to identify studies from January 1, 1996 to January 11, 2020. The baseline patient characteristics, comorbidities, procedural details, and perioperative and long-term outcomes were collected and analyzed. A pooled overall survival curve was drawn. Univariate analysis was performed to compare the perioperative stroke risk between subgroups. Results Overall, 275 patients (mean age, 66.94 years) from 15 studies were included. All the patients had presented with tandem stenosis of ≥50%, and 67.2% were symptomatic. The overall technical success rate was 99.8% (95% confidence interval [CI], 98.0%-100.0%). The pooled perioperative complications rates were as follows: death, 1.5% (95% CI, 0.0%-2.9%); stroke, 2.6% (95% CI, 0.7%-4.4%); combined stroke/death, 3.3% (95% CI, 1.2%-5.4%); and myocardial infarction, 3.2% (95% CI, 0.7%-9.1%). The overall primary patency rates were 99.2% (95% CI, 96.0%-100.0%) and 88.2% (95% CI, 78.8%-95.4%) at 1 and 2 years, respectively. Reintervention was performed in 6.6% of the patients (95% CI, 3.0%-11.2%). The pooled overall survival rates were 89.9% (95% CI, 83.7%-96.7%), 83.7% (95% CI, 75.9%-92.2%), and 75.9% (95% CI, 66.5%-86.7%) at 1, 3, and 5 years, respectively. Operations in which carotid endarterectomy was performed first carried a significantly greater risk of perioperative stroke compared with those in which proximal intervention had been performed first (5.7% vs 0.0%; P = .01). No difference was found in perioperative stroke risk between the subgroups of baseline symptomatic status (asymptomatic, 5.1%; symptomatic, 1.9%; P = .32), preoperative antiplatelet therapy (dual, 3.6%; single, 5.8%; P = .79), and carotid clamping during intervention (clamping, 2.8%; unclamping, 6.3%; P = .40). Conclusions For patients with a presumed high risk of neurologic events because of carotid tandem lesions, the hybrid approach could be considered a reasonable option with high technical success and acceptable perioperative and long-term results. Performing carotid artery stenting before carotid endarterectomy and administering perioperative dual antiplatelet therapy should be considered to promote technical success and better outcomes. Prospective and randomized controlled studies are needed to confirm the results and provide recommendations on patient selection for the hybrid approach.

The serine/threonine kinase Polo-like kinase 1 (Plk1) plays a pivotal role in cell proliferation and has been validated as a promising anticancer drug target. However, very limited success has been achieved in clinical applications using existing Plk1 inhibitors, due to lack of sufficient specificity toward Plk1. To develop a novel Plk1 inhibitor with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide–Hoechst conjugate, PIP3, targeted to specific DNA sequence in the PLK1 promoter. PIP3 could specifically inhibit the cell cycle–regulated Plk1 expression and consequently retard tumor cell growth. Cancer cells treated with PIP3 exhibited severe mitotic defects and increased apoptosis, whereas normal cells were not affected by PIP3 treatment. Furthermore, subcutaneous injection of PIP3 into mice bearing human cancer xenografts induced significant tumor growth suppression with low host toxicity. Therefore, PIP3 exhibits the potential as an effective agent for targeted cancer therapy. Mol Cancer Ther; 17(5); 988–1002. ©2018 AACR.

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Background The performance of drug-coated balloons (DCBs) in femoropopliteal interventions has been proven through randomized trials in short lesions and lesions with relatively low proportion of occlusions. There is limited evidence of DCBs in long or occlusive lesions. This study is to investigate the efficacy of the paclitaxel-coated balloon for treatment of long and occlusive femoropopliteal arterial lesions. Methods A single-arm trial including 44 femoropopliteal lesions (chronic total occlusion (CTO) plus > 10 cm) treated with DCBs was performed to collect data of average 1-year follow-up. Endpoints contain primary patency, target lesion revascularization (TLR), amelioration of the Rutherford classification, change of ankle brachial index (ABI) and major adverse events. Results Technical success is 97.7% while device success is 100%. Mean lesion length was 186 ± 86.3 cm. Stent implantation was performed in 13.6%. Cumulative probability of primary patency was 78.8% ± 6.8% at 1 year while that of freedom from TLR was 91.4% ± 4.9%. Rutherford classification improved from average 3.3 ± 1.0 to 2.1 ± 1.4 (p p = 0.002). No major adverse event was observed. Conclusion These results suggest that it is safe and effective to treat long and totally occlusive femoropopliteal artery disease with DCBs. Further studies are demanded to confirm these results.

// Jianchao Zhang 1 , Ximing Shao 1 , Haiyan Sun 1 , Ke Liu 1 , Zhihao Ding 1 , Juntao Chen 1 , Lijing Fang 1 , Wu Su 1 , Yang Hong 4 , Huashun Li 2, 3 , Hongchang Li 1 1 Shenzhen Key Laboratory for Molecular Biology of Neural Development, Guangdong Key Laboratory of Nanomedicine, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China 2 SARITEX Center for Stem Cell Engineering Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine and Advanced Institute of Translational Medicine, Shanghai 200123, China 3 ATCG Corporation, BioBay, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China 4 Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA Correspondence to: Hongchang Li, email: hc.li@siat.ac.cn Huashun Li, email: huashunli@tongji.edu.cn Keywords: NUMB, EMT, TNBC, Notch, metastasis Received: March 26, 2016 Accepted: July 19, 2016 Published: August 05, 2016 ABSTRACT Triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer with higher rates of early relapse and metastasis, is frequently associated with aberrant activation of epithelial-mesenchymal transition (EMT). Nonetheless, how EMT is initiated and regulated during TNBC progression is not well understood. Here, we report that NUMB is a negative regulator of EMT in both human mammary epithelial cells and breast cancer cells. Reduced NUMB expression was significantly associated with elevated EMT in TNBC. Conversely, overexpression of NUMB strongly attenuated the EMT program and metastasis of TNBC cell lines. Interestingly, we showed that NUMB employs different molecular mechanisms to regulate EMT. In normal mammary epithelial cells and breast cancer cells expressing wild-type p53, NUMB suppressed EMT by stabilizing p53. However, in TNBC cells, loss of NUMB facilitated the EMT program by activating Notch signaling. Consistent with these findings, low NUMB expression and high Notch activity were significantly correlated with the TNBC subtype in patients. Collectively, these findings reveal novel molecular mechanisms of NUMB in the regulation of breast tumor EMT, especially in TNBC.

Background This study aimed to synthesize data from recently published literature to evaluate the safety and efficacy of endovascular treatment (EVT) for infrarenal aortic occlusion (IAO). Methods The PubMed and Embase were searched to identify all studies reporting EVT for IAO from January 1st, 2000 to December 31st, 2017. Information about patients' characteristics, comorbidities, technical success, mortality, complications, and patency was collected and analyzed. Results 9 articles consisting of 220 patients were included in this meta-analysis. Patients often had severe symptoms and many comorbidities. The overall technical success and periprocedural mortality was 95.64% (95% confidence interval [CI], 88.60%–99.42%) and 0.35% (95% CI, 0.00% to 2.33%). In successful cases, ankle-brachial index was raised from 0.42 to 0.91. The complication described in one article is of the whole samples and that of the technical success cases was not represented separately. We made the meta-analysis on the other 8 articles. Periprocedural complications included vascular complications (11.35% [95% CI: 3.50%–19.20%]) mainly pseudoaneurysm, thromboses, hematoma, and dissections; limb complications 8.28% (95% CI: 4.86%–13.77%); and renal complications 1.25% (95% CI: 0.00%–3.65%). In an article, vascular complications of whole samples were 12.24%, limb complication 6.12%, and renal complication 10.20%. Overall primary patency was 93.53% (95% CI: 89.37%–97.68%) at 1 year, 78.96% (95% CI: 72.26%–84.96%) at 3 years, and 75.31% (95% CI: 66.42%–84.20%) at 5 years. Overall secondary patency was 98.25% (95% CI: 95.50%–99.73%) at 1 year, 95.92% (95% CI: 89.25%–99.47%) at 3 years, and 94.02% (95% CI: 88.10%–98.00%) at 5 years. Conclusions EVT for IAO is acceptable with relatively high technical success rate, low mortality, and satisfying short-term patency. Although primary patency was lower than after surgery, secondary patency was roughly similar to that of surgical repair. However, this conclusion is based on retrospective observational studies, and the results could be imprecise due to the limited sample sizes, especially in midterm and long-term patency. More studies with longer follow-up and bigger sample size are needed to further elucidate this.

Natural albumin ligand (fatty acids)-conjugated peptides can rapidly bind to circulating albumin and form complexes to control the release of peptides. The purpose of this study was to prolong the half-life and immune-modulating effects of thymopentin (TP5) by using the albumin binding strategy. We synthesized myristic acid-modified TP5 (TP5-MA) by conjugating a myristic acid-acylated lysine to a permissive site of TP5, which improved the albumin binding affinity of TP5-MA and dramatically enhanced its stability in human plasma. We observed well-preserved bioactivities of TP5-MA in RAW264.7 macrophages using a tumor necrosis factor (TNF)-α stimulation assay. Moreover, the prolonged immune-modulating effect of TP5-MA was confirmed by the normalized CD4+/CD8+ ratio in immune-depressed rat models, which resulted in a reduced administration frequency (twice per week). In general, the enhanced pharmacokinetic and pharmacodynamic properties of TP5-MA make it a promising product for the treatment of immunodeficiency diseases.