Assessment of the Enzymatic Dephosphorylation Kinetics in the Assemblies of a Phosphopentapeptide that Forms Intranuclear Nanoribbons.

Although the formation of peptide assemblies catalyzed by alkaline phosphatase (ALP) has received increasing attention in inhibiting cancer cells, the detailed enzyme kinetics of the dephosphorylation of the corresponding phosphopeptide assemblies have yet to be determined. We recently discovered that assemblies from a phosphopentapeptide can form intracellular nanoribbons that kill induced pluripotent stem cells or osteosarcoma cells, but the kinetics of enzymatic dephosphorylation remain unknown. Thus, we chose to examine the enzyme kinetics of the dephosphorylation of the phosphopentapeptide [NBD-LLLLpY (1)] from concentrations below to above its critical micelle concentration (CMC). Our results show that the phosphopeptide exhibits a CMC of 75 µM in phosphate saline buffer, and the apparent Vmax and Km values of alkaline phosphatase catalyzed dephosphorylation are approximately 0.24 µM/s and 5.67 mM, respectively. Despite dephosphorylation remaining incomplete at 60 min in all the concentrations tested, dephosphorylation of the phosphopeptide at concentrations of 200 µM or above mainly results in nanoribbons, dephosphorylation at concentrations of CMC largely produces nanofibers, and dephosphorylation below the CMC largely generates nanoparticles. Moreover, the formation of nanoribbons correlates with the intranuclear accumulation of the pentapeptide. By providing the first examination of the enzymatic kinetics of phosphopeptide assemblies, this work further supports the notion that the assemblies of phosphopentapeptides can act as a new functional entity for controlling cell fates.

Does the low-carbon pilot policy improve urban economic resilience? Evidence from China.

Identifying the relationship between carbon neutrality initiatives and its economic impact is crucial in evaluating the cost of low-carbon transition for policy makers. In this paper, a theoretical model is built to discuss the effects of the low-carbon pilot policy in China on urban economic resilience and an empirical test is conducted to examine the relationship using the Heckman two stage model and a panel data of 277 cities from 2004 to 2020. The results show that low-carbon pilot policy significantly enhanced urban economic resilience and the stimulating effect is mainly achieved by motivating technology innovations. In addition, further analysis indicates that low-carbon pilot policy has a more pronounced effect on improving urban economic resilience of cities in the central and western regions than eastern regions. The effect is also more prominent in non-first-tier cities than first-tier cities. The results are robust to placebo test, the Propensity Score Matching Difference-in-Difference test and the test for alternative measure of urban economic resilience. The findings show that the low-carbon pilot policy is consistent with the goal of improving urban economic resilience and technology innovation is the essential pillar of sustainable development.

Assessment of Therapeutic Benefit and Option Strategy on Intravesical Instillation for Preventing Bladder Cancer Recurrence after Radical Nephroureterectomy in Patients with Upper Urinary Tract Urothelial Carcinoma.

Objective: Upper urinary tract urothelial carcinoma (UUT-UC) is a very aggressive disease, characterized by 22%-50% of patients suffering from subsequent bladder recurrence after radical nephroureterectomy (RNU). Although the therapy of intravesical instillation is reported to be effective in preventing bladder recurrence, no study had been reported in Northeast China. The findings relating to the clinical effectiveness of intravesical instillation after RNU are somewhat controversial, and the best efficacy and least adverse effects of instillation drugs have not been widely accepted. Here, we aimed at evaluating the efficacy of intravesical instillation for the prevention intravesical recurrence systematically. Methods: In this retrospective cohort study, from October 2006 to September 2017, 158 UUT-UC patients underwent RNU were divided into 4 groups: epirubicin (EPB) instillation group, hydroxycamptothecin (HCPT) instillation group, bacillus Calmette-Guerin (BCG) instillation group, and noninstillation group. Cox univariate and multivariate analyses were employed to identify the risk factors for intravesical recurrence-free survival (IVRFS). The nomogram model was also applied to predict patient outcomes. Subsequently, to evaluate the clinical significance of intravesical instillation comprehensively, several databases including PubMed, Ovid, and Embase were searched and data from published studies with our results were combined by direct meta-analysis. Moreover, a network meta-analysis comparing instillation therapies was conducted to evaluate the clinical efficacy of different instillation drugs. Results: In our retrospective cohort study, the Kaplan-Meier survival curve demonstrated noninstillation groups were associated with worsened IVRFS. Meanwhile, multivariate analysis indicated that intravesical instillation was independent protective factors for IVRFS (hazard ratio [HR] = 0.731). Moreover, calibration plots, receiver operating characteristic (ROC) curves, area under the curve (AUC) values, and the C-index showed the priority of nomogram's predictive accuracy. Next, direct meta-analysis including 19 studies showed that intravesical instillation could prevent the recurrence of bladder cancer with a pooled risk ratio (RR) estimate of 0.53. Subgroup analysis by study type, year of intravesical recurrence, first instillation time, and instillation times also confirmed the robustness of the results. Moreover, intraoperative instillation was associated with a decrease in the risk of bladder recurrence compared with postoperative instillation. Then, a network meta-analysis including 7 studies indicated that pirarubicin (THP) (surface under the cumulative ranking curve [SUCRA] = 89.2%) is the most effective therapy to reduce the risk of bladder recurrence, followed by BCG (SUCRA = 83.5%), mitomycin C (MMC) (SUCRA = 53.6%), EPB (SUCRA = 52.6%), and HCPT (SUCRA = 5.1%) after the analysis of the value ranking. Conclusions: A maintenance schedule of intravesical instillation prevents the recurrence of bladder cancer after RNU in UUT-UC patients effectively. Large, prospective trials are needed to further confirm its value. Compared with other chemotherapy regimens, THP may be a promising drug with favorable efficacy to prevent bladder recurrence. As included studies had moderate risk of bias, the results of network meta-analysis should be applied with caution.

Levels, distribution and risk assessment of hexabromocyclododecane (HBCD) in fish in Xiamen, China.

In this study, hexabromocyclododecane (HBCD) was detected in 114 fish samples collected from 6 administrative regions of Xiamen city, China. HBCD amounts ranged between ND (not detected) and 2.216 ng g-1 ww (mean, 0.127 ± 0.318 ng g-1 ww). Besides, α-HBCD was the main diastereoisomer in these fish specimens, followed by ß-HBCD. Meanwhile, γ-HBCD was not detected in any of the samples. Significant differences were recorded among fish species. The results indicated that the levels and detection rates of HBCD were higher in Trachinotus ovatus compared with other aquatic organisms. Therefore, Trachinotus ovatus could be used as a marine biological indicator of HBCD. Within the regions investigated, Siming was significantly different from Jimei, Haicang, and Xiang'an. The spatial distribution of HBCD concentrations indicated higher mean levels in samples collected from Haicang, Jimei, and Xiang'an, respectively, with the highest detection rates in Jimei and Xiang'an, which might be related to geographical location and intense industrial and urban activities. Estimation of daily HBCD intake was performed according to fish consumption in Xiamen residents. The medium bound HBCD amounts in fish were approximately 0.073 and 0.088 ng kg bw-1d-1 for male and female residents of Xiamen, respectively. Exposure doses of HBCD indicated no health concern for Xiamen residents.

Textbook Outcome as a measure of surgical quality assessment and prognosis in gastric neuroendocrine carcinoma: A large multicenter sample analysis.

OBJECTIVE: Quality assurance is crucial for oncological surgical treatment assessment. For rare diseases, single-quality indicators are not enough. We aim to develop a comprehensive and reproducible measurement, called the "Textbook Outcome" (TO), to assess the quality of surgical treatment and prognosis of gastric neuroendocrine carcinoma (G-NEC) patients. METHODS: Data from patients with primary diagnosed G-NEC included in 24 high-volume Chinese hospitals from October 2005 to September 2018 were analyzed. TO included receiving a curative resection, ≥15 lymph nodes examined, no severe postoperative complications, hospital stay ≤21 d, and no hospital readmission ≤30 d after discharge. Hospital variation in TO was analyzed using a case mix-adjusted funnel plot. Prognostic factors of survival and risk factors for non-Textbook Outcome (non-TO) were analyzed using Cox and logistic models, respectively. RESULTS: TO was achieved in 56.6% of 860 G-NEC patients. TO patients had better overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS) than non-TO patients (P<0.05). Moreover, TO patients accounted for 60.3% of patients without recurrence. Multivariate Cox analysis revealed non-TO as an independent risk factor for OS, DFS, and RFS of G-NEC patients (P<0.05). Increasing TO rates were associated with improved OS for G-NEC patients, but not hospital volume. Multivariate logistic regression revealed that non-lower tumors, open surgery, and >200 mL blood loss were independent risk factors for non-TO patients (P<0.05). CONCLUSIONS: TO is strongly associated with multicenter surgical quality and prognosis for G-NEC patients. Factors predicting non-TO are identified, which may help guide strategies to optimize G-NEC outcomes.

Assessment of the presence and anti-tumor potential of tumor-infiltrating lymphocytes in patients with acute myeloid leukemia.

Purpose: Assessing the possibility of finding tumor-infiltrating lymphocytes (TIL) in bone marrow of acute myeloid leukemia (AML) patients and evaluating the anti-tumor activity of these TIL against autologous AML cells. Patients and methods: TIL were immunomagnetically isolated by using anti-CD3 from bone marrow samples of 20 patients at the presentation of AML or four weeks upon completion of chemotherapy. TIL were ex vivo expanded for two weeks and immunophenotyped. Functionality in terms of cytokine secretion and cytotoxicity was assessed by γ-interferon quantitation and Elispot assay, respectively. Results: TIL were detected in bone marrow samples of 50% (10/20) of the patient cohort. They were noted to highly express CD137 and PD-1 and display a significantly higher anti-tumor reactivity compared to that of autologous peripheral blood lymphocytes. TIL could be expanded in co-cultures with irradiated feeder cells supplemented with interleukin (IL)-7 and IL-15. Conclusion: Data suggested the presence of reactive γ-interferon-secreting TIL in AML patients. They are expandable and possess anti-tumor activity, which might have a great potential in the development of adoptive cellular therapy for AML.