Bone metastasis of malignant solid tumors has become one of the most serious complications, especially in breast cancer, which was particularly challenging for early detection and treatment in ...clinical practice. In this work, we reported a new fluorescently labeled bisphosphonate for bone metastasis detection of breast cancer. The designed probes were based on Rhodamine B and bisphosphonate as recognition group, which can specifically target hydroxyapatite (HA) existed in bone tissue. After the osteoclasts were adsorbed on the bone surface, the surrounding microenvironment was acidified, causing the HA to locally dissolve. The probe bound to the HA was then released, and realized the fluorescence turn on under acidic conditions. In vitro experiments showed that G0 was more excellent than G2 owing to shorter connecting arm. Subsequently, we proved that G0 could combine with HA rapidly and exhibit excellent response in solid state. More importantly, we established a model of bone metastasis with MDA-MB-231 cells which was similar to the clinical cases and evaluated the theranostics value of G0 prospectively, which provide the potential application prospect in clinical.
The probe G0 bound to the HA and realized the fluorescence turn on under acidic conditions in the model of bone metastasis. Display omitted
•The novel fluorescent probes G0 and G2 were synthesized..•The probe G0 exhibited fast response, the sensitivity to pH and the affinity of bisphosphonate with HA.•G0 was relatively less toxic to normal cells and had certain anticancer activity.•The bone metastasis model was built by injecting MDA-MB-231 cells into the left ventricle of mice.•G0 proved to be the theranostics probe in tumor bone metastasis.
Hepatocellular carcinoma (HCC) has a high mortality rate due to the lack of effective treatments and drugs. Arsenic trioxide (ATO), which has been proved to successfully treat acute promyelocytic ...leukemia (APL), was recently reported to show therapeutic potential in solid tumors including HCC. However, its anticancer mechanisms in HCC still need further investigation. In this study, we demonstrated that ATO inhibits tumorigenesis and distant metastasis in mouse models, corresponding with a prolonged mice survival time. Also, ATO was found to significantly decrease the cancer stem cell (CSC)-associated traits. Minichromosome maintenance protein (MCM) 7 was further identified to be a potential target suppressed dramatically by ATO, of which protein expression is increased in patients and significantly correlated with tumor size, cellular differentiation, portal venous emboli, and poor patient survival. Moreover, MCM7 knockdown recapitulates the effects of ATO on CSCs and metastasis, while ectopic expression of MCM7 abolishes them. Mechanistically, our results suggested that ATO suppresses MCM7 transcription by targeting serum response factor (SRF)/MCM7 complex, which functions as an important transcriptional regulator modulating MCM7 expression. Taken together, our findings highlight the importance of ATO in the treatment of solid tumors. The identification of SRF/MCM7 complex as a target of ATO provides new insights into ATO's mechanism, which may benefit the appropriate use of this agent in the treatment of HCC.
Background and Objective
According to the Barcelona Clinic Liver Cancer (BCLC) algorithm, tumor burden and liver function, but not tumor biology, are the key factors in determining tumor staging and ...treatment modality, and evaluating treatment prognosis. The serum α‐fetoprotein (AFP) level is an important characteristic of hepatocellular carcinoma (HCC) biology, and we aimed to evaluate its prognostic value for patients undergoing liver resection of early-stage HCC.
Methods
Patients who underwent curative liver resection for early-stage HCC were identified from a multi‐institutional database. Patients were divided into three groups according to preoperative AFP levels: low (< 400 ng/mL), high (400–999 ng/mL), and extremely-high (≥ 1000 ng/mL) AFP groups. Overall survival (OS) and recurrence rates were compared among these three groups.
Results
Among 1284 patients, 720 (56.1%), 262 (20.4%), and 302 (23.5%) patients had preoperative low, high, and extremely-high AFP levels, respectively. The cumulative 5-year OS and recurrence rates were 71.3 and 38.9% among patients in the low AFP group, 66.3 and 48.5% in the high AFP group, and 45.7 and 67.2% in the extremely-high AFP group, respectively (both
p
< 0.001). Multivariate Cox regression analysis identified both high and extremely-high AFP levels to be independent risk factors of OS (hazard ratio HR 1.275 and 1.978, 95% confidence interval CI 1.004–1.620 and 1.588–2.464, respectively;
p
= 0.047 and
p
< 0.001, respectively) and recurrence (HR 1.290 and 2.050, 95% CI 1.047–1.588 and 1.692–2.484, respectively;
p
= 0.017 and
p
< 0.001, respectively).
Conclusions
This study demonstrated the important prognostic value of preoperative AFP levels among patients undergoing resection for early-stage HCC. Incorporating AFP to prognostic estimation of the BCLC algorithm can help guide individualized risk stratification and identify neoadjuvant/adjuvant treatment necessity.
As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib has a powerful ability to penetrate the blood-brain barrier and a high potency for ...controlling brain metastases (BMs) from EGFR-mutant non-small cell lung cancer (NSCLC). The clinical value of cranial radiation therapy in osimertinib-treated NSCLC with BMs remains largely unknown.
Patients with NSCLC and BMs and receiving osimertinib treatment as the standard of care were retrospectively enrolled from 2 institutions. Cranial radiation therapy (RT; whole-brain radiation therapy WBRT or/and stereotactic radiosurgery SRS) performed before disease progression (PD) to osimertinib was categorized as upfront cranial radiation therapy (ucRT group), excluding those treatments performed during prior EGFR-TKI treatment. Overall survival (OS), progression-free survival (PFS), and the time to intracranial progression (iTTP) were compared between the 2 groups, with adjustment by covariates in propensity-score matched (PSM) analyses. The state of having 1 to 3 BM lesions, with a maximal size of ≤3 cm, was defined as having oligo-BM; otherwise; the cases were defined as having multiple BMs.
Of the 205 patients enrolled, osimertinib was used as first-line therapy in 74 and second-line therapy in 131. There were 48 patients who received ucRTs, including WBRT in 24 and SRS in 24. All patients with oligo-BM in the ucRT group received SRS alone (n = 17), whereas most (n = 28; 90.3%) patients with multiple BMs received WBRT. Failure pattern analyses indicated that in the non-ucRT group, 40.2% of the initial PD involved the brain and 76.9% of the cranial PD involved the original sites, indicating the potential roles of ucRT. Indeed, the iTTP was significantly prolonged (P = .010) in the ucRT group among the whole population. In the PSM oligo-BM cohort, the ucRT group showed superior PFS (P = .033) and OS (P = .026) compared with the non-ucRT group, and the differences remained after multivariate Cox analyses. No such differences were observed in the subpopulation with multiple BMs.
In osimertinib-treated NSCLC patients with BMs, oligo-BM status could be used as a potential factor to select patients for upfront cranial RT. Further investigation by well-designed clinical trials is warranted.
miR-15b-5p has frequently been reported to function as a biomarker in some malignancies; however, the function of miR-15b-5p in hepatocellular carcinoma (HCC) and its molecular mechanism are still ...not well understood. The present study was designed to confirm the clinical value of miR-15b-5p and further explore its underlying molecular mechanism. A comprehensive investigation of the clinical value of miR-15b-5p in HCC was investigated by data mining The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets as well as literature. In addition, intersected target genes of miR-15b-5p were predicted using the miRWalk database and differentially expressed genes of HCC from TCGA. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out. Then, a protein-protein interaction network (PPI) was constructed to reveal the interactions between some hub target genes of miR-15b-5p. The miR-15b-5p expression level in HCC was predominantly overexpressed compared with non-HCC tissues samples (SMD=0.618, 95% CI: 0.207, 1.029; P<0.0001) based on 991 HCC and 456 adjacent non-HCC tissue samples. The pooled summary receiver operator characteristic (SROC) of miR-15b-5p was 0.81 (Q*=0.74), and the pooled sensitivity and specificity of miR-15b-5p in HCC were 72% (95% CI: 69-75%) and 68% (95% CI: 65-72%), respectively. Bioinformatically, 225 overlapping genes were selected as prospective target genes of miR-15b-5p in HCC, and profoundly enriched GO terms and KEGG pathway investigation in silico demonstrated that the target genes were associated with prostate cancer, proximal tubule bicarbonate reclamation, heart trabecula formation, extracellular space, and interleukin-1 receptor activity. Five genes (ACACB, RIPK4, MAP2K1, TLR4 and IGF1) were defined as hub genes from the PPI network. The high expression of miR-15b-5p could play an essential part in hepatocarcinogenesis through diverse regulation approaches.
Our previous study showed that parenteral anticoagulation therapy (PACT) in the context of aggressive antiplatelet therapy failed to improve clinical outcomes in patients undergoing percutaneous ...coronary intervention for non–ST‐segment elevation acute coronary syndrome (NSTE‐ACS). However, the role of PACT in patients managed medically remains unknown. This observational cohort study enrolled patients with NSTE‐ACS receiving medical therapy from November 2014 to June 2017 in the Improving Care for Cardiovascular Disease in China‐Acute Coronary Syndrome project. Eligible patients were included in the PACT group and non‐PACT group. The primary outcomes were in‐hospital all‐cause mortality and major bleeding. The secondary outcome included minor bleeding. Among 23,726 patients, 8,845 eligible patients who received medical therapy were enrolled. After adjusting the potential confounders, PACT was not associated with a lower risk of in‐hospital all‐cause mortality (adjusted odds ratio (OR), 1.25; 95% confidence interval (CI), 0.92–1.71; P = 0.151). Additionally, PACT did not increase the incidence of major bleeding or minor bleeding (major bleeding: adjusted OR, 1.04; 95% CI, 0.80–1.35; P = 0.763; minor bleeding: adjusted OR, 1.27; 95% CI, 0.91–1.75; P = 0.156). The propensity score analysis confirmed the primary analyses. In patients with NSTE‐ACS receiving antiplatelet therapy, PACT was not associated with a lower risk of in‐hospital all‐cause mortality or a higher bleeding risk in patients with NSTE‐ACS receiving non‐invasive therapies and concurrent antiplatelet strategies. Randomized clinical trials are warranted to reevaluate the safety and efficacy of PACT in all patients with NSTE‐ACS who receive noninvasive therapies and current antithrombotic strategies.
Chrome-free eco-leather production plays an important role in the sustainable development of the leather industry. Here, we established an eco-leather tanning system based on biomass-derived ...polycarboxylate–aluminum–zirconium complexes (PAZ). The tanning conditions, storage stability, and tanning mechanism of PAZ tanned leather were investigated, and then the industrial-scale application performance of the PAZ tanning system was compared with that of a conventional Cr tanning system from the aspects of collagen microstructure, leather properties, and environmental impacts. The PAZ tanning agent showed a high uptake rate of 95%, endowed the tanned leather with a shrinkage temperature of over 80 °C, and allowed the tanned leather to be stably stored for more than one year. The PAZ penetrated uniformly into the hierarchical structure of collagen fibers and mainly coordinated with the amino and carboxyl groups of collagen, thereby achieving intermolecular and intrafibril cross-linking in the leather matrix. The PAZ tanned leather possessed strong absorption capacity for post-tanning chemicals (over 85%) due to its high isoelectric point (7.2). Thus, the physical properties of PAZ crust leather were comparable to those of the Cr-tanned crust leather. The wastewater of the PAZ tanning system exhibited a reduction of 43.4% in total organic carbon load and better biodegradability than the Cr tanning system. The acute oral toxicity and acute dermal toxicity tests confirmed that the PAZ crust leather has low biotoxicity. This work not only offers insights into the PAZ tanning mechanism at the molecular level but also provides a sustainable and practical approach for manufacturing chrome-free eco-leather.
Display omitted
•Industrial-scale tanning trial verifies the practicability of PAZ tanning system.•PAZ crosslinks between collagen through coordination and non-covalent bonds.•PAZ penetrates into fibril hierarchy and increases the porosity of leather.•The comprehensive properties of PAZ leather are comparable to those of Cr leather.•The good biodegradability and low biotoxicity ensure the ecology of PAZ tanning system.
Unmanned aerial vehicle-assisted multi-access edge computing (UAV-MEC) plays an important role in some complex environments such as mountainous and disaster areas. Computation offloading problem ...(COP) is one of the key issues of UAV-MEC, which mainly aims to minimize the conflict goals between energy consumption and delay. Due to the time-varying and uncertain nature of the UAV-MEC system, deep reinforcement learning is an effective method for solving the COP. Different from the existing works, in this paper, the COP in UAV-MEC system is modeled as a multi-objective Markov decision process, and a multi-objective deep reinforcement learning method is proposed to solve it. In the proposed algorithm, the scalar reward of reinforcement learning is expanded into a vector reward, and the weights are dynamically adjusted to meet different user preferences. The most important preferences are selected by non-dominated sorting, which can better maintain the previously learned strategy. In addition, the Q network structure combines Double Deep Q Network (Double DQN) with Dueling Deep Q Network (Dueling DQN) to improve the optimization efficiency. Simulation results show that the algorithm achieves a good balance between energy consumption and delay, and can obtain a better computation offloading scheme.
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