Safety and efficacy of radiotherapy combined with chemotherapy for recurrent metastatic renal pelvic and ureteral carcinoma.

PURPOSE: To retrospectively investigate the safety and efficacy of radiotherapy combined with chemotherapy for recurrent metastatic renal pelvic and ureteral carcinoma. METHODS: 109 patients were enrolled in this study, including 44 patients in the radiochemotherapy group and 65 patients in the chemotherapy group. Propensity score matching (PSM) was used to balance the baseline characteristics of the two groups by 1:1 matching. Kaplan-Meier method was used to calculate PFS and OS. Cox regression model was used for multivariate analysis. The side effects were evaluated by CTCAE v5.0 RESULTS: The median follow-up time was 14.5 months. Multivariate analysis showed that radiotherapy was a good independent prognostic factor for OS (HR: 0.327, 95% CI 0.157-0.680, P = 0.003). After matching, there were 40 patients in both groups, and the median PFS and OS in the radiochemotherapy group were longer than those in the chemotherapy group (PFS: 10.4 vs. 6.7 months, P = 0.035; OS: 43.5 vs. 18.8 months, P < 0.001). In addition, in the radiochemotherapy group, patients treated with radiotherapy before first-line chemotherapy failure had a longer PFS than those treated with radiotherapy after chemotherapy failure (median PFS: 15.7 vs. 6 months, P = 0.003). There was no significant difference in the incidence of grade 3-4 toxicities between the two groups (52.3% vs. 50.8%, P = 0.878). CONCLUSION: For patients with recurrent metastatic renal pelvic and ureteral carcinoma, radiotherapy combined with chemotherapy is well tolerable and expected to bring long-term survival benefits, and the benefits of early interventional radiotherapy may be more obvious.

Biomarkers for Prostate Cancer: From Diagnosis to Treatment.

Prostate cancer (PCa) is a widespread malignancy with global significance, which substantially affects cancer-related mortality. Its spectrum varies widely, from slow-progressing cases to aggressive or even lethal forms. Effective patient stratification into risk groups is crucial to therapeutic decisions and clinical trials. This review examines a wide range of diagnostic and prognostic biomarkers, several of which are integrated into clinical guidelines, such as the PHI, the 4K score, PCA3, Decipher, and Prolaris. It also explores the emergence of novel biomarkers supported by robust preclinical evidence, including urinary miRNAs and isoprostanes. Genetic alterations frequently identified in PCa, including BRCA1/BRCA2, ETS gene fusions, and AR changes, are also discussed, offering insights into risk assessment and precision treatment strategies. By evaluating the latest developments and applications of PCa biomarkers, this review contributes to an enhanced understanding of their role in disease management.

Bile acids and their receptors: Potential therapeutic targets in inflammatory bowel disease.

Chronic and recurrent inflammatory disorders of the gastrointestinal tract caused by a complex interplay between genetics and intestinal dysbiosis are called inflammatory bowel disease. As a result of the interaction between the liver and the gut microbiota, bile acids are an atypical class of steroids produced in mammals and traditionally known for their function in food absorption. With the development of genomics and metabolomics, more and more data suggest that the pathophysiological mechanisms of inflammatory bowel disease are regulated by bile acids and their receptors. Bile acids operate as signalling molecules by activating a variety of bile acid receptors that impact intestinal flora, epithelial barrier function, and intestinal immunology. Inflammatory bowel disease can be treated in new ways by using these potential molecules. This paper mainly discusses the increasing function of bile acids and their receptors in inflammatory bowel disease and their prospective therapeutic applications. In addition, we explore bile acid metabolism and the interaction of bile acids and the gut microbiota.

Uncovering the Secrets of Prostate Cancer's Radiotherapy Resistance: Advances in Mechanism Research.

Prostate cancer (PCa) is a critical global public health issue with its incidence on the rise. Radiation therapy holds a primary role in PCa treatment; however, radiation resistance has become increasingly challenging as we uncover more about PCa's pathogenesis. Our review aims to investigate the multifaceted mechanisms underlying radiation therapy resistance in PCa. Specifically, we will examine how various factors, such as cell cycle regulation, DNA damage repair, hypoxic conditions, oxidative stress, testosterone levels, epithelial-mesenchymal transition, and tumor stem cells, contribute to radiation therapy resistance. By exploring these mechanisms, we hope to offer new insights and directions towards overcoming the challenges of radiation therapy resistance in PCa. This can also provide a theoretical basis for the clinical application of novel ultra-high-dose-rate (FLASH) radiotherapy in the era of PCa.

Biomimetic nanovaccine based on erythrocyte membrane enhances immune response and protection against tilapia lake virus.

An infectious disease emerged in recent years, Tilapia Lake Virus Disease (TiLVD), has severely restricted the development of global tilapia industry. Vaccination has proved potential strategy to prevent its causative agent Tilapia Lake Virus (TiLV) infectious. However, the response intensity of subunit vaccine is limited by its low immunogenicity, thus inclusion of adjuvants is required. Thus, we prepared a biomimetic nano-system (Cs-S2@M-M) with a particle size of ∼100 nm and an encapsulation efficiency of about 79.15% based on erythrocyte membrane. The immune response was detected after intramuscular injection to assess the effectiveness of the vaccine. The biomimetic system significantly up-regulates the expression of immune genes, enhances the activity of non-specific immune-related enzymes (P < 0.05) and improved relative percentage survival by 17.4%-26.1% in TiLV challenge. The biomimetic nano-system based on erythrocyte membrane induced significant immune response in tilapia and enhanced protection against TiLV, promising as a model for fish vaccines.

Outcomes of High-Dose Stereotactic Ablative Radiotherapy to All/Multiple Sites for Oligometastatic Renal Cell Cancer Patients.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is one of the treatment options for oligometastatic renal cell carcinoma (RCC) but is limited by a lack of data to evaluate high-dose SABR to all/multiple sites. OBJECTIVE: This study retrospectively investigated the efficacy and prognostic factors of high-dose SABR for oligometastatic RCC patients. DESIGN, SETTING, AND PARTICIPANTS: Patients with oligometastatic RCC on systemic therapy were retrospectively collected. INTERVENTION(S): All patients were treated with SABR (40-50 Gy/5 fractions) for small tumors or partial-SABR (tumor center boosted with 6-8 Gy/3-5 fractions with 50-60 Gy/20-25 fractions to the whole tumor volume) for bulky tumors or tumors adjacent to critical organs. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Progression-free survival (PFS) and overall survival (OS) were calculated. RESULTS AND LIMITATIONS: In total, 35 patients were enrolled, of which 88.5% had intermediate- or high-risk disease, with 60% on second- to fourth-line systemic therapy. The median follow-up time was 17 months. The median PFS and OS times were 11.3 and 29.7 months, respectively. Univariate analysis showed that an OS benefit was found in patients who received radiation before tyrosine kinase inhibitor (TKI) failure (p = 0.006) and where there was a short time interval (

Radiation therapy for nonmetastatic medically inoperable upper-tract urothelial carcinoma.

BACKGROUND: The standard management for upper urinary tract urothelial carcinoma (UTUC) is radical nephroureterectomy (RNU). However, some patients cannot undergo this procedure for several reasons, such as unresectable disease, old age, and multiple comorbidities. Our study explored the potential safety and effectiveness of radiotherapy as a curative treatment for UTUC patients unfit for surgery. METHODS: The data of patients treated with radiotherapy between December 2017 and November 2019 were retrospectively reviewed. For the literature review, computerized PubMed Medline, Index Medicus, and Web of Science databases and reference lists from the identified publications of interest were used. And "upper-tract urothelial carcinoma" and "radiotherapy" were used as key words in the search. RESULTS: We describe 8 patients with UTUC who were treated with radiotherapy. The median follow-up time was 13.5 months (range, 8.6-30.9 months). Local tumor control was achieved in all patients. However, distant metastases were observed in 2 patients with T3-4/N+ status. One patient had T4 status and the other had N2+ status. The patients died of tumor progression at 15.0 and 17.7 months. In addition, the other 6 patients who were still alive had relatively early-stage tumors without nodal involvement. Regarding acute toxicity, according to the CTCAE v5.0, mild side effects were noted, including grade 1 nausea and diarrhea. Four patients developed mild anemia, generally of grade 1-2. One patient experienced grade 3 anemia, but it was manageable and improved with symptomatic support. In addition, no grade 4 acute or late toxicities were observed. No significant long-term impairment of renal function occurred. CONCLUSIONS: For patients with nonmetastatic UTUC who are not suitable for surgery, radiotherapy is a safe treatment and can achieve good local tumor control.

Assistance by Routine CT Features Combined With 3D Texture Analysis in the Diagnosis of BRCA Gene Mutation Status in Advanced Epithelial Ovarian Cancer.

PURPOSE: To evaluate the predictive value of routine CT features combined with 3D texture analysis for prediction of BRCA gene mutation status in advanced epithelial ovarian cancer. METHOD: Retrospective analysis was performed on patients with masses occupying the pelvic space confirmed by pathology and complete preoperative images in our hospital, including 37 and 58 cases with mutant type and wild type BRCA, respectively (total: 95 cases). The enrolled patients' routine CT features were analyzed by two radiologists. Then, ROIs were jointly determined through negotiation, and the ITK-SNAP software package was used for 3D outlining of the third-stage images of the primary tumor lesions and obtaining texture features. For routine CT features and texture features, Mann-Whitney U tests, single-factor logistic regression analysis, minimum redundancy, and maximum correlation were used for feature screening, and the performance of individual features was evaluated by ROC curves. Multivariate logistic regression analysis was used to further screen features, find independent predictors, and establish the prediction model. The established model's diagnostic efficiency was evaluated by ROC curve analysis, and the histogram was obtained to conduct visual analysis of the prediction model. RESULTS: Among the routine CT features, the type of peritoneal metastasis, mesenteric involvement, and supradiaphragmatic lymph node enlargement were correlated with BRCA gene mutation (P < 0.05), whereas the location of the peritoneal metastasis (in the gastrohepatic ligament) was not significantly correlated with BRCA gene mutation (P > 0.05). Multivariate logistic regression analysis retained six features, including one routine CT feature and five texture features. Among them, the type of peritoneal metastasis was used as an independent predictor (P < 0.05), which had the highest diagnostic efficiency. Its AUC, accuracy, specificity, and sensitivity were 0.74, 0.79, 0.90, and 0.62, respectively. The prediction model based on the combination of routine CT features and texture features had an AUC of 0.86 (95% CI: 0.79-0.94) and accuracy, specificity, and sensitivity of 0.80, 0.76, and 0.81, respectively, indicating a better performance than that of any single feature. CONCLUSIONS: Both routine CT features and texture features had value for predicting the mutation state of the BRCA gene, but their predictive efficiency was low. When the two types of features were combined to establish a predictive model, the model's predictive efficiency was significantly higher than that of independent features.

Expanding Cyclic Topology-Based Biomedical Polymer Panel: Universal Synthesis of Hetero-"8"-Shaped Copolymers and Topological Modulation of Polymer Degradation.

8-Shaped copolymers with two macrocycles connected together represent an interesting cyclic topology-derived polymer species due to the simultaneous incorporation of two cyclic moieties and the reported unique physical and chemical properties. To provide a proof-of-concept for a broad readership on biomedical polymers, a well-defined hetero-8-shaped amphiphilic copolymer, cyclic-poly(oligo(ethylene glycol)monomethyl ether methacrylate)-b-cyclic PCL (cPOEGMA-b-cPCL) is synthesized by an elegant integration of intrachain click cyclization and interchain click coupling. The potential of the self-assembled micelles of cPOEGMA-b-cPCL for controlled drug release is evaluated by in vitro drug loading and drug release, cellular uptake, cytotoxicity, and degradation studies. Most importantly, the micelles based on cPOEGMA-b-cPCL show much slower degradation profiles than the previously reported linear counterpart, POEGMA-b-PCL and tadpole-shaped analog, PEG-b-cPCL because of the presence of cyclic hydrophilic POEGMA segment. Therefore, this study not only develops a robust strategy for a universal precise synthesis of well-defined hetero-8-shaped copolymers based on diverse vinyl and ring-structured monomers, but also reveals the first modulation of polymer degradation property by topological control of the nondegradable moiety in the polymer construct through advanced macromolecular engineering.

Population-Based Comparison of Different Risk Stratification Systems Among Prostate Cancer Patients.

BACKGROUND: It is not known which risk stratification system has the best discrimination ability for predicting prostate cancer death. METHODS: We identified patients with non-metastatic primary prostate adenocarcinoma diagnosis between 2004 and 2015 using the Surveillance, Epidemiology, and End Results database. Patients were categorized in different risk groups using the three frequently used risk stratification systems of the National Comprehensive Cancer Network guideline (NCCN-g), American Urological Association guideline (AUA-g), and European Association of Urology guideline (EAU-g), respectively. Associations between risk classification and prostate cancer-specific mortality (PCSM) were determined using Kaplan-Meier analyses and multivariable regression with Cox proportional hazards model. Area under the receiver operating characteristics curve (AUC) analyses were used to test the discrimination ability of the three risk grouping systems. RESULTS: We analyzed 310,062 patients with a median follow-up of 61 months. A total of 36,368 deaths occurred, including 6,033 prostate cancer deaths. For all the three risk stratification systems, the risk groups were significantly associated with PCSM. The AUC of the model relying on NCCN-g, AUA-g, and EAU-g risk stratification systems for PCSM at specifically 8 years were 0.818, 0.793, and 0.689 in the entire population; 0.819, 0.795, and 0.691 in Whites; 0.802, 0.777, and 0.681 in Blacks; 0.862, 0.818, and 0.714 in Asians; 0.845, 0.806, and 0.728 in Chinese patients. Regardless of the age, marital status, socioeconomic status, and treatment modality, AUC of the model relying on NCCN-g and AUA-g for PCSM was greater than that relying on EAU-g; AUC of the model relying on NCCN-g system was greater than that of the AUA-g system. CONCLUSIONS: The NCCN-g and AUA-g risk stratification systems perform better in discriminating PCSM compared to the EAU-g system. The discrimination ability of the NCCN-g system was better than that of the AUA-g system. It is recommended to use NCCN-g to evaluate risk groups for prostate cancer patients and then provide more appropriate corresponding treatment recommendations.

Emergence of a Complete Heavy-Quark Spin Symmetry Multiplet: Seven Molecular Pentaquarks in Light of the Latest LHCb Analysis.

A recent analysis by the LHCb Collaboration suggests the existence of three narrow pentaquarklike states-the P_{c}(4312), P_{c}(4440), and P_{c}(4457)-instead of just one in the previous analysis [the P_{c}(4450)]. The closeness of the P_{c}(4312) to the D[over ¯]Σ_{c} threshold and the P_{c}(4440) and P_{c}(4457) to the D[over ¯]^{*}Σ_{c} threshold suggests a molecular interpretation of these resonances. We show that these three pentaquarklike resonances can be naturally accommodated in a contact-range effective field theory description that incorporates heavy-quark spin symmetry. This description leads to the prediction of all the seven possible S-wave heavy antimeson-baryon molecules [that is, there should be four additional molecular pentaquarks in addition to the P_{c}(4312), P_{c}(4440), and P_{c}(4457)], providing the first example of a heavy-quark spin symmetry molecular multiplet that is complete. If this is confirmed, it will not only give us an impressive example of the application of heavy-quark symmetries and effective field theories in hadron physics, it will also uncover a clear and powerful ordering principle for the molecular spectrum, reminiscent of the SU(3)-flavor multiplets to which the light hadron spectrum conforms.

Clinical characteristics and prognostic value of pre-retreatment plasma epstein-barr virus DNA in locoregional recurrent nasopharyngeal carcinoma.

PURPOSE: To define the clinical characteristics and prognostic value of pre-retreatment plasma Epstein-Barr virus (EBV) DNA, we investigated EBV status in locoregional recurrent nasopharyngeal carcinoma (lrNPC) patients. METHODS: Between April 2008 and August 2016, the data of patients with nonmetastatic lrNPC were retrospectively reviewed. The survival indexes of patients between different pre-retreatment EBV status groups were compared. RESULTS: A total of 401 patients with nonmetastatic lrNPC were enrolled, and 197 (49.1%) patients had detectable pre-retreatment plasma EBV DNA. Treatment included radiotherapy alone (n = 37 patients), surgery alone (n = 105), radiotherapy (n = 208), surgery combined with radiotherapy (n = 20), chemotherapy and targeted therapy (n = 31). Median follow-up was 32 months. The 3-year locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival (OS) rates for the entire cohort were 64.8%, 89.4%, and 58.8%, respectively. The estimated 3-year LRRFS, DMFS, and OS rates for the pre EBV-positive group vs the pre EBV-negative group were 54.2% vs 75.0% (P < 0.001), 86.6% vs 91.9% (P = 0.05), 51.6% vs 65.9% (P = 0.01), respectively. Among patients in the clinical stage rI/II, there were 17 patients in the radiotherapy alone group and 49 patients in the surgery alone group. And there was no significant difference in overall survival between radiotherapy and surgery, even among the different pre-EBV statuses (P > 0.05). In terms of long-term toxic and side effects, the incidence of radioactive temporal lobe injury in the radiotherapy group was higher than that in the surgery group (35.3% vs 8.2%, P < 0.001), and no statistically significant difference was found in other long-term toxic and side effects. CONCLUSIONS: The positive rate of pre-retreatment plasma EBV DNA in lrNPC is lower than primary NPC. The prognosis of EBV DNA negative group is better than positive group. For locally early-stage lrNPC, regardless of EBV DNA status, radiotherapy and surgery are available options and both can achieve better long-term survival.

Long-term outcome and pattern of failure for patients with nasopharyngeal carcinoma treated with intensity-modulated radiotherapy.

PURPOSE: To analyze the long-term outcome and pattern of failure for patients with nasopharyngeal carcinoma (NPC) after intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: Patients with NPC after IMRT from 2001 to 2008 were recruited (n = 865). Clinical features, laboratory data, and treatments were collected. RESULTS: The 10-year local recurrence-free survival, distant metastasis-free survival, and disease-specific survival (DSS) were 92.0%, 83.4%, and 78.6%, respectively. A total of 209 patients died: 59% of whom died from distant metastasis. The 10-year DSS was higher in patients who received chemoradiotherapy than those who received IMRT alone for patients with high-risk stage III disease, while there was no survival difference for patients with stage II and low-risk stage III disease. CONCLUSIONS: IMRT provides satisfactory long-term survival for patients with NPC. Distant metastasis has been the most common reason for failure. Adding chemotherapy did not improve survival in patients with stage II and low-risk stage III disease.

Fabrication of Reduction-Sensitive Amphiphilic Cyclic Brush Copolymer for Controlled Drug Release.

The cyclic brush polymers, due to the unique topological structure, have shown in the previous studies higher delivery efficacy than the bottlebrush analogues as carriers for drug and gene transfer. However, to the best of knowledge, the preparation of reduction-sensitive cyclic brush polymers for drug delivery applications remains unexplored. For this purpose, a reduction-sensitive amphiphilic cyclic brush copolymer, poly(2-hydroxyethyl methacrylate-g-poly(ε-caprolactone)-disulfide link-poly(oligoethyleneglycol methacrylate)) (P(HEMA-g-PCL-SS-POEGMA)) with reducible block junctions bridging the hydrophobic PCL middle layer and the hydrophilic POEGMA outer corona is designed and synthesized successfully in this study via a "grafting from" approach using sequential ring-opening polymerization (ROP) and atom transfer free radical polymerization (ATRP) from a cyclic multimacroinitiator PHEMA. The resulting self-assembled unimolecular core-shell-corona (CSC) micelles show sufficient salt stability and efficient destabilization in the intracellular reducing environment for a promoted drug release toward a greater therapeutic efficacy relative to the reduction-insensitive analogues. The overall results demonstrate the reducible cyclic brush copolymers developed herein provides an elegant solution to the tradeoff between extracellular stability and intracellular high therapeutic efficacy toward efficient anticancer drug delivery.

Confined Molybdenum Phosphide in P-Doped Porous Carbon as Efficient Electrocatalysts for Hydrogen Evolution.

Highly efficient electrocatalysts for hydrogen evolution reactions (HER) are crucial for electrochemical water splitting, where high-cost and low-abundance Pt-based materials are the benchmark catalysts for HER. Herein, we report the fabrication of MoP nanoparticles confined in P-doped porous carbon (MoP@PC) via a metal-organic framework-assisted route for the first time. Remarkably, due to the synergistic effects of MoP nanocrystals, P dopant, and porous carbon, the resulting MoP@PC composite exhibits superior HER catalytic activity with an onset overpotential of 97 mV, a Tafel slope of 59.3 mV dec-1, and good long-term durability, which compares to those of most reported MoP-based HER catalysts. Most importantly, the work opens a new route in the development of high-performance nonprecious HER electrocatalysts derived from MOFs.

Prospective matched study on comparison of volumetric-modulated arc therapy and intensity-modulated radiotherapy for nasopharyngeal carcinoma: dosimetry, delivery efficiency and outcomes.

Background: The purpose of this study is to assess the feasibility of volumetric-modulated arc therapy (VMAT) for nasopharyngeal carcinoma (NPC) patients by comparing the physical dosimetry, delivery efficiency and clinical outcomes with intensity-modulated radiotherapy (IMRT). Methods: A prospective matched study was performed for patients with newly diagnosed NPC who underwent VMAT or IMRT. The patients in two groups were equally matched in terms of gender, age, tumor stage and chemotherapy. The target coverage, homogeneity index (HI) and conformity index (CI) of the planning target volume (PTV), organs at risk (OARs) sparing, average treatment time and clinical outcomes were analyzed. Results: From June 2013 to August 2015, a total of 80 patients were enrolled in this study, with 40 patients in each group. The coverage of PTV was similar for both groups. D2 was observed slight difference only in early stage disease (T1-2) (VMAT vs. IMRT, 7494±109 cGy vs. 7564±92 cGy; p=0.06). The HI of VMAT group was better than that of IMRT group (p=0.001), whereas CI was slightly worse (p=0.061). The maximum doses received by the brain stem, spinal cord, and optic nerve of VMAT were higher than those of IMRT (p<0.05). But the irradiation volumes in healthy tissue were generally lower for VMAT group, with significant differences in V20, V25 and V45 (p<0.05). With regard to the delivery efficiency compared with IMRT (1160 ± 204s), a 69% reduction in treatment time was achieved by VMAT (363 ± 162s). Both groups had 5 cases of nasopharyngeal residual lesions after radiotherapy. The 2-year estimated local relapse-free survival, regional relapse-free survival and locoregional relapse-free survival, distant metastasis-free survival, disease-free survival and overall survival were similar between two groups, with the corresponding rates of 100%, 97.4%, 97.4%, 90.0%, 90.0% and 92.4% in VMAT group, and 100%, 100%, 100%, 95.0%, 95.0% and 97.5% in IMRT group, respectively. Conclusions: Both VMAT and IMRT can meet the clinical requirements for the treatment of NPC. The short-term tumor regression rates and 2-year survival rates with the two techniques are comparable. The faster treatment time benefits of VMAT will enable more patients to receive precision radiotherapy.

Prognostic Model for Stratification of Radioresistant Nasopharynx Carcinoma to Curative Salvage Radiotherapy.

Purpose To investigate for a prognostic index (PI) to personalize recommendations for salvage intensity-modulated radiotherapy (IMRT) in patients with locally recurrent nasopharyngeal carcinoma (lrNPC). Methods Patients with lrNPC from two academic institutions (Sun Yat-Sen University Cancer Center [SYSUCC-A; n = 251 (training cohort)] and National Cancer Centre Singapore [NCCS; n = 114] and SYSUCC-B [n = 193 (validation cohorts)]) underwent salvage treatment with IMRT from 2001 to 2015. Primary and secondary clinical end points were overall survival (OS) and grade 5 toxicity-free rate (G5-TFR), respectively. Covariate inclusion to the PIs was qualified by a multivariable two-sided P < .05. Discrimination and calibration of the PIs were assessed. Results The primary PI comprised covariates that were adversely associated with OS in the training cohort (gross tumor volumerecurrence hazard ratio [HR], 1.01/mL increase [ P < .001], agerecurrence HR, 1.02/year increase [ P = .008]; repeat IMRT equivalent dose in 2-Gy fractions [EQD2] ≥ 68 Gy HR, 1.42 [ P = .03]; prior radiotherapy-induced grade ≥ 3 toxicities HR, 1.90 [ P = .001]; recurrent tumor [rT]-category 3 to 4 HR, 1.96 [ P = .005]), in ascending order of weight. Discrimination of the PI for OS was comparable between training and both validation cohorts (Harrell's C = 0.71 [SYSUCC-A], 0.72 [NCCS], and 0.69 [SYSUCC-B]); discretization by using a fixed PI score cutoff of 252 determined from the training data set yielded low- and high-risk subgroups with disparate OS in the validation cohorts (NCCS HR, 3.09 [95% CI, 1.95 to 4.89]; SYSUCC-B HR, 3.80 [95% CI, 2.55 to 5.66]). Our five-factor PI predicted OS and G5-TFR (predicted v observed 36-month OS and G5-TFR, 22% v 15% and 38% v 44% for high-risk NCCS and 26% v 31% and 45% v 46% for high-risk SYSUCC-B). Conclusion We present a validated PI for robust clinical stratification of radioresistant NPC. Low-risk patients represent ideal candidates for curative repeat IMRT, whereas novel clinical trials are needed in the unfavorable high-risk subgroup.

Fabrication of Thermosensitive Cyclic Brush Copolymer with Enhanced Therapeutic Efficacy for Anticancer Drug Delivery.

Adaptation of cyclic brush polymer for drug delivery applications remains largely unexplored. Herein, cyclic brush copolymer of poly(2-hydroxyethyl methacrylate-g-poly(N-isopropylacrylamide-st-N-hydroxyethylacrylamide)) (cb-P(HEMA-g-P(NIPAAm-st-HEAAm))), comprising a cyclic core of PHEMA and thermosensitive brushes of statistical copolymer of P(NIPAAm-st-HEAAm), is designed and synthesized successfully via a graft-from approach using atom transfer free radical polymerization from a cyclic multimacroinitiator. The composition of the brush is optimized to endow the resulting cyclic brush copolymer with a lower critical solution temperature (LCST) slightly above the physiological temperature, but lower than the localized temperature of tumor tissue, which is suitable for the hyperthermia-triggered anticancer drug delivery. Critical aggregation concentration determination reveals better stability for the unimolecular nanoparticle formed by the cyclic brush copolymer than that formed by the bottlebrush analogue. The dramatically increased size with elevated temperatures from below to above the LCST confirms hyperthermia-induced aggregation for both formulations. Such structural destabilization promotes significantly the drug release at 40 °C. Most importantly, the drug-loaded cyclic brush copolymer shows enhanced in vitro cytotoxicity against HeLa cells than the bottlebrush counterpart. The better stability and higher therapeutic efficacy demonstrates that the thermosensitive cyclic brush copolymer is a better formulation than bottle brush copolymer for controlled drug release applications.

[Effect of endomorphin-1 postconditioning against myocardial ischemia-reperfusion injury in rats and the role of Erk1/2 signaling pathway].

OBJECTIVE: To investigate the effect of postischemic treatment with endomorphin-1 (EM-1) against myocardial ischemia/reperfusion (IR) injury in rats and on extracellular signal regulated kinase 1/2 (Erk1/2)-dependent signaling pathway. METHODS: Sprague-Dawley rats were randomly divided into 5 groups, namely the sham-operated group, IR group, EM-1 post-treatment group (EM50 group), EM-1 post-treatment group with PD98059 treatment (EM50+PD group), and PD98059 post-treatment group (PD group). The hemodynamic indexes of the rats were recorded. After reperfusion, CK-MB, LDH, CTnI, MDA, IL-6, TNF-α, and SOD activities or contents were measured, the infarct size was determined, and the expression levels of Erk1/2, P-Erk1/2 and cleaved caspase-3 were detected using Western blotting. RESULTS: Compared with the sham group, the IR group showed significantly decreased heart rate and mean arterial pressure (P<0.05), which were increased obviously by EM-1 post-treatment (P<0.05). EM-1 post-treatment also resulted in significantly decreased LDH, CK-MB, CTnI, MDA, IL-6, and TNF-α activities or contents (P<0.05), increased SOD activity (P<0.05), reduced the infarct size (P<0.05), and increased the expression level of P-Erk protein (P<0.05). Compared with EM50 group, EM50+PD group showed significantly decreased heart rate and mean arterial pressure (P<0.05), increased LDH, CK-MB, CTnI, MDA, IL-6, and TNF-α activities or contents (P<0.05), decreased SOD activity, increased infarct size (P<0.05), and lowered expression of P-Erk protein (P<0.05). CONCLUSION: Postischemic treatment with EM-1 protects the heart against IR injury by improving the cardiac function, inhibiting inflammation, and inhibiting oxidative stress and myocardial apoptosis, and Erk1/2 signaling pathway may be involved in this process.