Transformable Magnetic Liquid-Metal Nanoplatform for Intracellular Drug Delivery and MR Imaging-Guided Microwave Thermochemotherapy.

Improved techniques for the administration of chemotherapeutic drugs are required to enhance tumor therapy efficacy and reduce the side effects of chemotherapy due to insufficient targeting and limited intratumoral drug release. Controlled drug delivery systems combined with thermotherapy are expected to play an important role in personalized tumor therapy. Herein, a novel microwave-responsive transformable magnetic liquid-metal (MLM) nanoplatform is designed for effective endosomal escape that facilitates intracellular drug delivery and enhanced anticancer therapy. The MLM nanoplatform exhibits a sensitive magnetic resonance imaging function for imaging-guided therapy and brilliant synergistic effects of chemotherapy with microwave thermal therapy to kill tumor cells. Once endocytosed by targeted tumor cells, the deep penetration of microwave energy can be absorbed by the MLM nanoplatform to convert heat and reactive oxygen species, which induces the shape transformation from nanospheres to large rods, resulting in the physical disruption of the endosomal membrane for intracellular drug release. Furthermore, the MLM nanoplatform synergistic therapy could activate immunomodulatory effects by M1 macrophage polarization and T cell infiltration, thus inhibiting tumor growth and lung metastasis. This work based on microwave-driven transformable magnetic liquid-metal nanoplatform provides novel ways to precisely control drug delivery and high-efficiency cancer therapy.

From Conversion to Resection for Unresectable Hepatocellular Carcinoma: A Review of the Latest Strategies.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China, accounting for the majority of primary liver cancer cases. Liver resection is the preferred curative method for early-stage HCC. However, up to 80-85% of patients have already missed the opportunity of radical surgery due to tumor advances at the time of consultation. Conversion therapies are a series of medications and treatments for initially inoperable patients. For early-stage unresectable HCC (uHCC) patients, conversion therapies are designed to meet surgical requirements by increasing the volume of the residual liver. Meanwhile, for advanced cases, conversion therapies strive for tumor shrinkage and down-staging, creating the opportunity for liver resection or liver transplantation. This review summarizes the latest advances in conversion therapies and highlights their potential for improving the survival benefit of patients with uHCC.

Layer-by-Layer Microneedle-Mediated rhEGF Transdermal Delivery for Enhanced Wound Epidermal Regeneration and Angiogenesis.

Appropriate treatments for acute traumas tend to avoid hemorrhages, vascular damage, and infections. However, in the homeostasis-imbalanced wound microenvironment, currently developed therapies could not precisely and controllably deliver biomacromolecular drugs, which are confronted with challenges due to large molecular weight, poor biomembrane permeability, low dosage, rapid degradation, and bioactivity loss. To conquer this, we construct a simple and effective layer-by-layer (LBL) self-assembly transdermal delivery patch, bearing microneedles (MN) coated with recombinant human epidermal growth factor (LBL MN-rhEGF) for a sustained release to wound bed driven by typical electrostatic force. Pyramidal LBL MN-rhEGF patches hold so enough mechanical strength to penetrate the stratum corneum, and generated microchannels allow rhEGF direct delivery in situ. The administrable delivery of biomacromolecular rhEGF through hierarchically coated MN arrays follows the diffusion mechanism of Fick's second law. Numerous efforts further have illustrated that finger-pressing LBL MN-rhEGF patches could not only promote cell proliferation of normal human dermal fibroblasts (NHDF) and human umbilical vein endothelial cells (HUVEC) in vitro but also take significant effects (regenerative epidermis: ∼144 µm; pro-angiogenesis: higher CD31 expression) in accelerating wound healing of mechanically injured rats, compared to the traditional dressing, which relies on passive diffusion. Our proof-of-concept features novel LBL biomacromolecular drug-delivery systems and self-administrated precision medicine modes at the point of care.

Efficacy and safety of early drain removal following pancreatic resections: a meta-analysis.

BACKGROUND: No consensus was reached with regard to the effect of EDR on postoperative outcomes after pancreatic surgery. The meta-analysis was designed to explore the efficacy and safety of early drain removal (EDR). METHODS: Systematic literature search was performed. Data extraction and correction were performed by three researchers. For dichotomous and continuous outcomes, we calculated the pooled risk difference and mean difference with 95% confidence intervals, respectively. The heterogeneity of included studies was evaluated using Cochran's Q and I2 test. The stratified analyses of pancreaticoduodenectomy (PD) and distal pancreatectomy (DP) were performed. RESULTS: A total of 10 studies including 3 RCTs and 7 non RCTs were included for meta-analysis, among which 1780 patients with EDR and 5613 patients with late drain removal (LDR) were enrolled. The meta-analysis of both all the available studies and studies only with selected low risk patients indicated that EDR group had significantly lower incidences of Grade B/C postoperative pancreatic fistula (POPF) and total complications for both PD and DP. However, no advantages of EDR were observed in the meta-analysis of the 3 RCTs. In addition, EDR was associated with a lower incidence of intra-abdominal infection after PD. While for DP, EDR group had decreased risk of delayed gastric emptying and re-operation, and shorter postoperative in-hospital stay. CONCLUSIONS: The meta-analysis demonstrates that EDR is effective and safe for both PD and DP considering POPF and total complications, especially for patients with low concentration of postoperative drain fluid amylase.

Immunotherapy combination with regorafenib for refractory hepatocellular carcinoma: A real-world study.

PURPOSE: To compare the efficacy and safety of immunotherapy plus regorafenib versus regorafenib only in patients with pretreated hepatocellular carcinoma (HCC). METHODS: Immunotherapy plus regorafenib or regorafenib alone was analyzed in patients with advanced HCC with documented tumor progression on front-line therapy. Progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and treatment-related adverse events (TRAEs) were assessed. RESULTS: Of the 125 patients enrolled in this study, 50 patients received combination (pCOM) treatment as front-line treatment, and 60 patients received monotherapy (pMONO) as front-line treatment. In the pCOM cohort, median OS was significantly longer with for patients regorafenib plus immunotherapy than regorafenib alone treatment (15.0 vs. 2.0 months; P = 0.035). The DCR numerically increased in the regorafenib plus immunotherapy treatment in both cohorts (40.6 % vs. 22.2 %, 72.7 % vs. 54.7 %, respectively). There were no differences in PFS with regorafenib according to whether or not regorafenib was combined with immunotherapy in the pCOM and pMONO cohorts (PFS, P = 0.17, P = 0.91, respectively). Regarding the number of TRAEs occurred, regorafenib plus immunotherapy group was comparable to regorafenib group in the pCOM cohort (65.6 % vs. 72.2 %). In the pMONO cohort, TRAEs occurred in fewer patients receiving regorafenib than regorafenib plus immunotherapy (69.8 % vs. 95.5 %). CONCLUSIONS: Immunotherapy plus regorafenib may significantly improve clinical outcomes and have a manageable safety profile compared with regorafenib monotherapy in advanced HCC after front-line therapy failure. The efficacy of combination therapy needs to be validated in prospective studies with large samples.

Safety evaluation of early drain removal following pancreaticoduodenectomy: A single-center retrospective cohort study.

Objectives: The effects of early drain removal (EDR) on postoperative complications after pancreaticoduodenectomy (PD) remains to be investigated. This single-center retrospective cohort study was designed to explore the safety of EDR after PD. Methods: A total of 112 patients undergoing PD with drain fluid amylase (DFA) on postoperative day (POD) 1 and 3 <= 5000 were divided into EDR and late drain removal (LDR). Propensity Score Matching (PSM) was used. We compared postoperative outcomes between two groups and explore the risk factors of total complications using univariate and multiple logistic regression analyses. Results: No statistical differences were found in primary outcomes, including Grade B/C postoperative pancreatic fistula (POPF) (Original cohort: 5.71% vs. 3.90%; P = 1.000; PSM cohort: 3.33% vs. 6.67%; P = 1.000), and total complications (Original cohort: 17.14% vs. 32.47%; P = 0.093; PSM cohort: 13.33% vs. 33.33%; P = 0.067). The EDR was associated with shorter in-hospital stay (Original cohort: 11 days vs. 15 days; P < 0.0001; PSM cohort: 11 days vs. 15 days; P < 0.0001). Conclusions: EDR on POD 3 is safe for patients undergoing PD with low risk of POPF.

Long-term effects of total vs. partial pancreatectomy among patients with pancreatic cancer: a population-based study.

Background: Total pancreatectomy (TP) for pancreatic cancer (PC) has been limited historically for fear of elevated perioperative morbidity and mortality. With advances in perioperative care, TP may be an alternative option to partial pancreatectomy (PP). Limited evidence clarified the indication for these two procedures in PC patients, especially in patients with different tumor staging and location. Thus, this study aims to compare the outcomes after TP and PP for PCs of different T stages and locations. Methods: The study identified 14,456 PC patients with potentially curable primary tumor (T1-3) who received TP or PP from the Surveillance, Epidemiology, and End Results (SEER) database during 2000 to 2016. Detailed clinical and tumor covariates were all collected. Overall survival (OS) and cancer-specific survival (CSS) were the primary endpoints of interest in this study. OS and CSS were compared between patients after TP and PP using log-rank analysis. Results: For all patients, except for tumor location, TP group was comparable to the PP group. OS and CSS of the TP group were worse than of the PP group (median OS: 19 vs. 20 months, P=0.0058; median CSS: 24 vs. 26 months, P=0.00098, respectively). In stratifying analyses, TP was significantly related to worse OS and CSS than PP in pancreatic head and neck cancer patients with T2-stage tumors (median OS: 18 vs. 19 months, P=0.0016; median CSS: 22 vs. 24 months, P=0.00055, respectively), whereas for patients with T1- or T3-stage pancreatic head and neck cancer as well as T1- to T3-stage pancreatic body and tail cancer or overlapping location cancer, OS and CSS of the two groups were similar (all P>0.05). Conclusions: Compared with PP, TP offered worse prognosis in pancreatic head and neck cancer patients with T2-stage tumors, furthermore, TP and PP achieved comparable prognosis in patients with T1- or T3-stage pancreatic head and neck cancer as well as T1- to T3-stage pancreatic body and tail cancer or overlapping location cancer.

A novel prognostic nomogram for hepatocellular carcinoma after thermal ablation.

It remains impossible to accurately assess the prognosis after thermal ablation in patients with hepatocellular carcinoma (HCC). Our aim was to build a nomogram to predict the survival rate of HCC patients after thermal ablation. We developed and validated a nomogram using data of 959 HCC patients after thermal ablation from two centers. Harrell's concordance index (C-index), calibration plot and Decision curve analysis (DCA) were used to measure the performance of the nomogram, and we compared it with the Barcelona Clinic Liver Cancer (BCLC) staging system and a previous nomogram. Six variables including age, serum albumin, operation method, risk area, tumor number and early recurrence were selected to construct the nomogram. In the training cohort, internal validation cohort, and external validation cohort, the nomogram all had a higher C-index to predict survival rate than both the BCLC staging system and the previous nomogram (0.736, 0.558 and 0.698, respectively; 0.763, 0.621 and 0.740, respectively; and 0.825, 0.551 and 0.737, respectively). Calibration plots showed a high degree of consistency between prediction and actual observation. Decision curve analysis (DCA) presented that compared with BCLC system and the previous nomogram, our nomogram had the highest net benefit. In all three cohorts, the nomogram could accurately divide patients into three subgroups according to predicted survival risk. A nomogram was developed and validated to predict survival of HCC patients who underwent thermal ablation, which is helpful for prognostic prediction and individual surveillance in clinical practice.

The efficient enrichment of marine peptides from the protein hydrolysate of the marine worm Urechis unicinctus by using mesoporous materials MCM-41, SBA-15 and CMK-3.

Peptides found in marine life have various specific activities due to their special growth environment, and there is increasing interest in the isolation and concentration of these biofunctional compounds. In this study, the protein hydrolysate of the marine worm Urechis unicinctus was prepared by enzymolysis and enriched by using mesoporous materials of silica MCM-41 and SBA-15 and carbon CMK-3. The differences in pore structures and elemental composition of these materials lead to differences in surface area and hydrophobicity. The adsorption capacities of peptides were 459.5 mg g-1, 431.3 mg g-1, and 626.3 mg g-1 for MCM-41, SBA-15 and CMK-3, respectively. Adsorption kinetics studies showed that the pseudo-second-order model fit the adsorption process better, where both external mass transfer and intraparticle diffusion affected the adsorption, while the Langmuir model better fit the adsorption of peptides on MCM-41 and SBA-15 and the Freundlich model was more suitable for CMK-3. Aqueous acetonitrile (ACN, 50/50, v/v) yielded the most extracted peptides. MALDI-TOF mass spectrometry of the extracted peptides showed that the three mesoporous materials, especially the CMK-3, gave good enrichment results. This study demonstrates the great potential of mesoporous materials in the enrichment of marine biofunctional peptides.

The roles of the cell division cycle-associated gene family in hepatocellular carcinoma.

BACKGROUND: The members of the cell division cycle-associated (CDCA) gene family are significant regulators of cell proliferation known to play key roles in various cancers. However, the function of CDCA genes in hepatocellular carcinoma (HCC) is unclear. The aim of this research was to clarify the roles of CDCA family members in HCC using bioinformatics analysis tools. METHODS: We studied data on the mRNA and protein expression of CDCA genes and survival in patients with HCC using the Oncomine, UALCAN, HPA, CCLE, LinkedOmics, cBioPortal, and Metascape databases. RESULTS: Significant overexpression of all CDCA members was found in HCC tissues. The expression levels of CDCAs were related to the tumor stage, and high expression levels were correlated with a low survival rate in patients with HCC. Also, we observed a high mutation rate (45%) of CDCAs in the HCC samples, which manifested as deep deletion, amplification, or increased mRNA expression. In the correlation analysis, we found that any 2 CDCA members were significantly positively correlated with each other. Cycle-related genes including AHCTF1, AKT1, BIRC5, CENPF, CENPL, and CENPQ were closely associated with CDCA gene alterations. CONCLUSIONS: The findings of this study indicate that CDCAs may be potential therapeutic targets and prognostic indicators for patients with HCC.

Application of iron/barium ferrite/carbon-coated iron nanocrystal composites in transcatheter arterial chemoembolization of hepatocellular carcinoma.

Transcatheter arterial chemoembolization (TACE) has been widely used in clinical practice as a first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the current therapeuticeffect of TACE is far from satisfactory and thus requires further improvement. TACE combined with multifunctional magnetic particles may be a promising approach for the treatment of HCC. In this study, we designed a new magnetic drug carrier system consisting of micron-sized iron powder, barium ferrite (BaFe12O19), and carbon-coated iron nanocrystals (CCINs). CCINs possess properties, such as high drug loading and sustained release. BaFe12O19 could attract both CCINs and iron powder to form larger clusters after magnetization. Altogether, the triple therapeutic effects of chemotherapeutic enhancement, embolization, and thermal ablation could be realized herein. Further experiments indicate that the system has a high drug-loading capacity, good controlled-release effect, and no significant cytotoxicity. Under the action of a medium-frequency magnetic induction device, the magnetic induction temperature could reach 43 °C in one min while the maximum temperature of 70.8 °C could be reached in 2.5 h. Overall, this new carrier system displayed excellent antitumor effects in a mouse model. Our findings demonstrate the great application prospects of this system in TACE for HCC.

Physiochemical, rheological, microstructural, and antioxidant properties of yogurt using monk fruit extract as a sweetener.

A yogurt using monk fruit extract (MFE) as a sweetener was developed. The aim of the study was to investigate the viability of using MFE to develop sweetened yogurts without the calories of added sugar. The physiochemical, rheological, microstructural, and antioxidant properties of yogurt were studied. Rheological results showed that MFE affected the yogurt fermentation process and its rheological properties. Yogurt sweetened with MFE had similar microstructural properties to yogurt sweetened with sucrose. Yogurt with MFE showed higher levels of gly-pro-p-nitroanilide and dipeptidyl peptidase IV inhibitory activities, 1,1-diphenyl-2-picrylhydrazyl radical scavenging capacity, α-glucosidase inhibitory activities, and superoxide anion radical scavenging ability compared with other yogurt samples. Results indicated that MFE could be a novel sweetener and a food antioxidant for functional yogurt and related products.

Comprehensive analysis of variation of cadmium accumulation in rice and detection of a new weak allele of OsHMA3.

Excessive cadmium (Cd) accumulation in rice poses a potential threat to human health. Rice varieties vary in their Cd content, which depends mainly on root-to-shoot translocation of Cd. However, cultivars accumulating high Cd in the natural population have not been completely investigated. In this study, we analyzed the variation in Cd accumulation in a diverse panel of 529 rice cultivars. Only a small proportion (11 of 529) showed extremely high root-to-shoot Cd transfer rates, and in seven of these cultivars this was caused by two known OsHMA3 alleles. Using quantitative trait loci mapping, we identified a new OsHMA3 allele that was associated with high Cd accumulation in three of the remaining cultivars. Using heterologous expression in yeast and comparative analysis among different rice cultivars, we observed that this new allele was weak at both the transcriptional and protein levels compared with the functional OsHMA3 genotypes. The weak Cd transport activity was further demonstrated to be caused by a Gly to Arg substitution at position 512. Our study comprehensively analyzed the variation in root-to-shoot Cd translocation rates in cultivated rice and identified a new OsHMA3 allele that caused high Cd accumulation in a few rice cultivars.

Gas-solid reaction based over one-micrometer thick stable perovskite films for efficient solar cells and modules.

Besides high efficiency, the stability and reproducibility of perovskite solar cells (PSCs) are also key for their commercialization. Herein, we report a simple perovskite formation method to fabricate perovskite films with thickness over 1 µm in ambient condition on the basis of the fast gas-solid reaction of chlorine-incorporated hydrogen lead triiodide and methylamine gas. The resultant thick and smooth chlorine-incorporated perovskite films exhibit full coverage, improved crystallinity, low surface roughness and low thickness variation. The resultant PSCs achieve an average power conversion efficiency of 19.1 ± 0.4% with good reproducibility. Meanwhile, this method enables an active area efficiency of 15.3% for 5 cm × 5 cm solar modules. The un-encapsulated PSCs exhibit an excellent T80 lifetime exceeding 1600 h under continuous operation conditions in dry nitrogen environment.