The level of macrophage migration inhibitory factor is negatively correlated with the efficacy of PD-1 blockade immunotherapy combined with chemotherapy as a neoadjuvant therapy for esophageal squamous cell carcinoma.

PURPOSE: This study aimed to screen biomarkers to predict the efficacy of programmed cell death 1 (PD-1) blockade immunotherapy combined with chemotherapy as neoadjuvant therapy for esophageal squamous cell carcinoma (ESCC). METHODS: In the first stage of the study, the baseline concentrations of 40 tumor-related chemokines in the serum samples of 50 patients were measured to screen for possible biomarkers. We investigated whether the baseline concentration of the selected chemokine was related to the therapeutic outcomes and tumor microenvironment states of patients treated with the therapy. In the second stage, the reliability of the selected biomarkers was retested in 34 patients. RESULTS: The baseline concentration of macrophage migration inhibitory factor (MIF) was negatively correlated with disease-free survival (DFS) and overall survival (OS) in patients treated with the therapy. In addition, a low baseline expression level of MIF is related to a better tumor microenvironment for the treatment of ESCC. A secondary finding was that effective treatment decreased the serum concentration of MIF. CONCLUSION: Baseline MIF levels were negatively correlated with neoadjuvant therapy efficacy. Thus, MIF may serve as a predictive biomarker for this therapy. The accuracy of the prediction could be improved if the serum concentration of MIF is measured again after the patient received several weeks of treatment.

Discovery of the First Irreversible HDAC6 Isoform Selective Inhibitor with Potent Anti-Multiple Myeloma Activity.

In our previous research, a series of phenylsulfonylfuroxan-based hydroxamates were developed, among which compound 1 exhibited remarkable in vitro and in vivo antitumor potency due to its histone deacetylase (HDAC) inhibitory and nitric oxide (NO)-donating activities. Herein, the in-depth study of compound 1 revealed that this HDAC inhibitor-NO donor hybrid could enduringly increase the intracellular levels of acetyl histones and acetyl α-tubulin, which could be ascribed to its irreversible inhibition toward class I HDACs and HDAC6. Structural modification of compound 1 led to a novel phenylsulfonylfuroxan-based hydroxamate 4, which exhibited considerable HDAC6 inhibitory activity and selectivity. Furthermore, compound 4 could inhibit intracellular HDAC6 both selectively and irreversibly. To the best of our knowledge, this is the first research reporting the irreversible inhibition of HDAC6. It was also demonstrated that compared with ACY-241 (a reversible HDAC6 inhibitor in clinical trials), the irreversible HDAC6 selective inhibitor 4 exhibited not only superior anti-multiple myeloma activity but also improved therapeutic index.

A Dual-Enzyme Amplification Loop for the Sensitive Biosensing of Endopeptidases.

A rapid and sensitive approach for the detection of endopeptidases via a new analyte-triggered mutual emancipation of linker-immobilized enzymes (AMELIE) mechanism has been developed and demonstrated using a matrix metallopeptidase, a collagenase, as the model endopeptidase analyte. AMELIE involves an autocatalytic loop created by a pair of selected enzymes immobilized on solid substrates via linkers with specific sites that can be proteolyzed by one another. These bound enzymes are spatially separated so that they cannot act upon their corresponding substrates until the introduction of the target endopeptidase analyte that can also cleave one of the linkers. This triggers the self-sustained loop of enzymatic activities to emancipate all the immobilized enzymes. In this proof of concept, signal transduction was achieved by a colorimetric horseradish peroxidase-tetramethylbenzidine (HRP-TMB-H2O2) reaction with HRP that are also being immobilized by one of the linkers. The pair of immobilized enzymes were collagenase and alginate lyase, and they were immobilized by an alginate linker and a short peptide chain containing the amino acid sequence of Leu-Gly-Pro-Ala for collagenase. A detection limit of 2.5 pg collagenase mL-1 with a wide linear range up to 4 orders of magnitude was achieved. The AMELIE biosensor can detect extracellular collagenase in the supernatant of various bacteria cultures, with a sensitivity as low as 103 cfu mL-1 of E. coli. AMELIE can readily be adapted to provide the sensitive detection of other endopeptidases.

Prevalence and diversity of mycoviruses occurring in Chinese Lentinula edodes germplasm resource.

Incidence and banding patterns of virus-like dsRNA elements in 215 Chinese genetically diverse Lentinula edodes strains collected from wide geographic distribution (or producing areas) were first investigated, and 17 viruses were identified including eight novel viruses. The results revealed a 63.3% incidence of dsRNA elements in the cultivated strains and a 67.2% incidence in the wild strains. A total of 10 distinguishable dsRNAs ranging from 0.6 to 12 kbp and 12 different dsRNA patterns were detected in the positive strains. The molecular information of these dsRNA elements was characterized, and the molecular information of the other 12 different viral sequences with (+) ssRNA genome was revealed in four L. edodes strains with complex dsRNA banding patterns. RT-PCR was also done to verify the five dsRNA viruses and 12 (+) ssRNA ones. The results presented may enrich our understanding of L. edodes virus diversity, and will promote further research on virus-host interactions. IMPORTANCE: Viral infections involve complicated interactions including benign, harmful or possibly beneficial to hosts. Sometimes environment could lead to a transition in lifestyles from persistent to acute, resulting in a disease phenotype. The quality of spawn, such as the vulnerability to infection of viruses, is therefore important for mushroom production. Lentinula edodes, a wood rot basidiomycete fungus, was widely cultivated in the world for its edible and medicinal properties. In this study, the profile of dsRNA elements from Chinese genetically diverse L. edodes strains collected from wide geographic distribution or producing areas was first investigated. The molecular information of the dsRNA elements was characterized. Additionally, 12 different viral sequences with (+) ssRNA genome from four L. edodes strains with complex dsRNA banding patterns were identified. The results presented here will broaden our knowledge about mushroom viruses, and promote further studies of L. edodes production and the interaction between viruses and L. edodes.

MiR-26a-5p Heightens Breast Cancer Cell Sensitivity to Paclitaxel via Targeting Flap Endonuclease 1.

OBJECTIVE: Flap endonuclease 1 (FEN1) has been confirmed to involve the drug resistance of multiple cancers including breast cancer. However, the effect of miRNA-mediated FEN1 on breast cancer cell resistance is still ambiguous and needs further research. METHODS: Firstly, we used GEPIA2 to predict the FEN1 expression in breast cancer. Next, we used quantitative real-time polymerase chain reaction (qRT-PCR) and western blot to evaluate the FEN1 level of cells. After parental cells or MDA-MB-231-paclitaxel (PTX) cells being transfected with or without siFEN1, the apoptosis, migration, and protein levels of FEN1, Bcl-2, and resistance-related genes were examined by flow cytometry, wound healing assay, and western blot, respectively. Then, the putative miRNA targeting FEN1 was predicted using StarBase V3.0, and further confirmed by qRT-PCR. The targeted binding of FEN1 to miR-26a-5p was detected by dual-luciferase reporter assay. After parental cells or MDA-MB-231-PTX cells being transfected with or without miR-26a-5p mimic, the apoptosis, migration, and protein levels of FEN1, Bcl-2, and resistance-related genes were tested again. RESULTS: FEN1 expression was enhanced in breast cancer and MDA-MB-231-PTX cells. The combined application of FEN1 knockdown and PTX enhanced apoptosis in MDA-MB-231-PTX cells but suppressed cell migration and expressions of FEN1, Bcl-2, and resistance-related genes. Then, we confirmed that FEN1 was targeted by miR-26a-5p. The combined application of miR-26a-5p mimic and PTX largely facilitated apoptosis in MDA-MB-231-PTX cells but restrained cell migration and expressions of FEN1, Bcl-2, and resistance-related genes. CONCLUSION: MiR-26a-5p contributes to the sensitivity of breast cancer cells to paclitaxel via restraining FEN1.

Open versus laparoscopic Hartmann's procedure: a systematic review and meta-analysis.

PURPOSE: Hartmann's procedure is traditionally performed in emergency situations where single-step procedures with immediate anastomosis may be unsafe. However, it can be associated with significant morbidity and low colostomy reversal rate. Whilst randomised controlled trials and a Cochrane review have reported strong evidence of laparoscopic over open colectomies, no such reviews have been performed for Hartmann's procedure. Hence, this paper aims to summarise the existing evidence to determine the efficacy of laparoscopic Hartmann's procedure over its open counterpart. METHODS: Embase, Medline and Cochrane databases were searched from inception to 15 November 2020 for keywords relating to 'laparoscopy' and 'Hartmann' using strict inclusion and exclusion criteria. Odds ratio was estimated for dichotomous outcomes and weighted mean difference was estimated for continuous outcomes. RESULTS: From the 836 articles yielded from the search strategy, 12 articles were selected for meta-analysis. Pooled analysis revealed that laparoscopic Hartmann's procedure (LHP) allows for a shorter length of stay, and a lower risk of overall surgical site infections and superficial surgical site infections. There was no significant difference in other outcomes. Single-arm analysis of LHP also showed an unprecedented high colostomy reversal rate of over 80%. CONCLUSION: In clinically suitable patients, laparoscopic Hartmann's procedure has benefits over open Hartmann's procedure. Despite the selection bias of single-arm studies, LHP has reported a high stoma reversal rate of over 80%. Future well-controlled studies should be done to affirm the findings.

Experimental Analysis of Temperature-Control Curtain Regulating Outflow Temperature in a Thermal-Stratified Reservoir.

The construction of reservoir dams has changed the environment and natural properties of the river course, and deep-water reservoirs present an obvious phenomenon of thermal stratification. Low-temperature outflow water in spring and summer will have a negative impact on the downstream ecological environment. Therefore, it is necessary to take selective withdrawal measures to regulate low-temperature outflow water. The temperature-control curtain project has the advantages of low cost, convenient construction and wide application. Based on the topographic data, a laboratory test model for regulating outflow temperature by a temperature-control curtain is established. A high-power electric heating system is adopted to form a nonlinear thermal stratification. The accuracy of the test data is verified by the prototype observed water temperature. The main parameters affecting the outflow temperature are investigated, including thermal stratification, flow height above the temperature-control curtain, water level, and discharge flow. The results show the following: firstly, the outflow temperature mainly depends on the thermal stratification, decreases with the increase of water level, and increases with the increase of discharge flow; secondly, the effect of a temperature-control curtain on improving the outflow temperature is directly related to the thermal stratification in different months, and the improvement effect is better in spring and summer; finally, the improvement effect increases with the decrease of flow height above the temperature-control curtain, increases with the increase of water level, and decreases with the increase of discharge flow.

The development of a redox-sensitive curcumin conjugated chitosan oligosaccharide nanocarrier for the efficient delivery of docetaxel to glioma cells.

Background: A redox-sensitive nanoscale delivery system was developed, based on the hydrophilic chitosan oligosaccharide-ss-hydrophobic curcumin conjugate (CSO-ss-CUR) loaded with docetaxel (DTX), for the targeting and synergistic treatment of gliomas. Methods: Redox-sensitive nanoparticles were loaded with DTX (DTX/CSO-ss-CUR) using the improved ultrasonic-dialysis approach. The morphology and particle size of the loaded nanoparticles were examined by transmission electron microscopy (TEM) and dynamic light scattering (DLS), respectively. The cytotoxicity and cellular uptake of the nanoparticles were assessed in vitro using the C6 glial cell line. The in vivo antitumor efficacy and in vivo biodistribution studies were evaluated using the C6 tumor-bearing Balb/c female mouse model. Results: The DTX/CSO-ss-CUR nanoparticles were generally spherical in shape and exhibited desirable particle size (under 250 nm) with high drug loading efficiency (DL) (8.96%±0.56%) and encapsulation efficiency (EE) (35.23%±3.26%). In vitro, the drug was released from the nanoparticles in a redox-sensitive manner. The DTX/CSO-ss-CUR nanoparticles exhibited superior hemocompatibility in the hemolytic test and in vitro cytotoxicity and live/dead cell staining experiments revealed a higher cytotoxicity to glioma cells compared to the free drug. Furthermore, in vitro uptake experiments using C6 glioma cells demonstrated that the CSO-ss-CUR nanoparticles had good cell penetration ability. The in vivo antitumor efficacy and in vivo biodistribution studies suggested that the CSO-ss-CUR nanoparticles could effectively inhibit C6 tumor growth. More importantly, after intravenous injection, more CSO-ss-CUR nanoparticles were concentrated in the brain of the mice than free 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide (DiR) group. Conclusions: A unique drug delivery system formed by the self-assembly of CSO-ss-CUR was developed and shown to effectively cross the blood-brain barrier (BBB), enriching the abundance of the drug in the brain tissues. This may represent a potential therapeutic strategy for the treatment of gliomas. Keywords: Chitosan oligosaccharide (CSO); curcumin (CUR); docetaxel (DTX); glioma.

Irinotecan/scFv co-loaded liposomes coaction on tumor cells and CAFs for enhanced colorectal cancer therapy.

BACKGROUND: Cancer-associated fibroblasts (CAFs), as an important component of stroma, not only supply the "soils" to promote tumor invasion and metastasis, but also form a physical barrier to hinder the penetration of therapeutic agents. Based on this, the combinational strategy that action on both tumor cells and CAFs simultaneously would be a promising approach for improving the antitumor effect. RESULTS: In this study, the novel multifunctional liposomes (IRI-RGD/R9-sLip) were designed, which integrated the advantages including IRI and scFv co-loading, different targets, RGD mediated active targeting, R9 promoting cell efficient permeation and lysosomal escape. As expected, IRI-RGD/R9-sLip showed enhanced cytotoxicity in different cell models, effectively increased the accumulation in tumor sites, as well as exhibited deep permeation ability both in vitro and in vivo. Notably, IRI-RGD/R9-sLip not only exhibited superior in vivo anti-tumor effect in both CAFs-free and CAFs-abundant bearing mice models, but also presented excellent anti-metastasis efficiency in lung metastasis model. CONCLUSION: In a word, the novel combinational strategy by coaction on both "seeds" and "soils" of the tumor provides a new approach for cancer therapy, and the prepared liposomes could efficiently improve the antitumor effect with promising clinical application prospects.

Reconfigurable Antenna Array Direction Finding System Based on a Fast Search Algorithm.

In a traditional antenna array direction finding system, all the antenna sensors need to work or shut down at the same time, which often leads to signal crosstalk, signal distortion, and other electromagnetic compatibility problems. In addition, the direction-finding algorithm in a traditional system needs a tremendous spectral search, which consumes considerable time. To compensate for these deficiencies, a reconfigurable antenna array direction finding system is established in this paper. This system can dynamically load part or all of the antennas through microwave switches (such as a PIN diode) and conduct a fast direction of arrival (DOA) search. First, the hardware structure of the reconfigurable antenna is constructed. Then, based on the conventional spatial domain search algorithm, an improved transform domain (TD) search algorithm is proposed. The effectiveness of the system has been proven by real experiments, and the advantage of the system has been verified by detailed simulations.

Recent advances in photodegradation of antibiotic residues in water.

Antibiotics are widely present in the environment due to their extensive and long-term use in modern medicine. The presence and dispersal of these compounds in the environment lead to the dissemination of antibiotic residues, thereby seriously threatening human and ecosystem health. Thus, the effective management of antibiotic residues in water and the practical applications of the management methods are long-term matters of contention among academics. Particularly, photocatalysis has attracted extensive interest as it enables the treatment of antibiotic residues in an eco-friendly manner. Considerable progress has been achieved in the implementation of photocatalytic treatment of antibiotic residues in the past few years. Therefore, this review provides a comprehensive overview of the recent developments on this important topic. This review primarily focuses on the application of photocatalysis as a promising solution for the efficient decomposition of antibiotic residues in water. Particular emphasis was laid on improvement and modification strategies, such as augmented light harvesting, improved charge separation, and strengthened interface interaction, all of which enable the design of powerful photocatalysts to enhance the photocatalytic removal of antibiotics.

Synthesis and biological study of class I selective HDAC inhibitors with NO releasing activity.

Based on the multi-mechanism antitumor strategy and the regulatory effect of nitric oxide (NO) on histone deacetylases (HDACs), a series of N-acyl-o-phenylenediamine-based HDAC inhibitors equipped with the phenylsulfonylfuroxan module as NO donor was designed, synthesized and biologically evaluated. The in vitro HDAC inhibitory assays revealed that compared with the clinical class I selective HDAC inhibitor MS275, compounds 7c, 7d and 7e possessed similar HDAC inhibitory potency and selective profile, which were confirmed by the results of western blot analysis. The western blot analysis also showed that NO scavenger N-acetyl cysteine (NAC) could weaken the intracellular HDAC inhibitory ability of compound 7c, supporting the HDAC inhibitory effect of NO generated by 7c. It is worth noting that compounds 7c, 7d and 7e exhibited more potent in vitro antiproliferative activities than MS275 against all four tested solid tumor cell lines. The promising in vivo antitumor potency of 7c was demonstrated in a HCT116 xenograft model.

Discovery of a Novel Hybrid of Vorinostat and Riluzole as a Potent Antitumor Agent.

Vorinostat (suberoylanilide hydroxamic acid) was the first approved histone deacetylase (HDAC) inhibitor in a group of validated cancer therapeutic agents targeting epigenetics. Riluzole is a drug used to treat amyotrophic lateral sclerosis, the antitumor potency of which has been recently revealed. Herein, a novel hybrid of vorinostat and riluzole (compound 1) was rationally designed, synthesized, and evaluated. Compared with vorinostat, compound 1 exhibited superior total HDAC inhibitory activity and similar HDAC isoform selective profiles. The intracellular HDAC inhibition of compound 1 was confirmed by Western blot analysis. Moreover, compound 1 possessed more potent in vitro antiproliferative activity against all tested solid and hematological tumor cell lines than vorinostat. In vitro metabolic stability evaluation of compound 1 revealed better human plasma stability and comparable human liver microsomal stability than vorinostat. Additionally, compound 1 demonstrated more significant in vivo antitumor activity in a MDA-MB-231 xenograft model than vorinostat, which could be attributed to its superior in vitro antiproliferative activity and metabolic stability. Taken together, the results presented here support further research and development of compound 1 as a promising antitumor agent.

Synthesis of Novel 1T/2H-MoS2 from MoO3 Nanowires with Enhanced Photocatalytic Performance.

Metallic 1T-phase MoS2 is a newly emerging and attractive catalyst since it has more available active sites and high carrier mobility in comparison with its widely used counterpart of semiconducting 2H-MoS2. Herein, 1T/2H-MoS2(N) (N: MoO3 nanowires were used to prepare 1T/2H-MoS2) was synthesized by using molybdenum trioxide (MoO3) nanowires as the starting material and applied in the photodegradation of antibiotic residue in water. Enhanced photocatalytic performance was observed on the obtained 1T/2H-MoS2(N), which was 2.8 and 1.3 times higher than those on 1T/2H-MoS2(P) (P: commercial MoO3 powder was used to prepare 1T/2H-MoS2) and 2H-MoS2, respectively. The active component responsible for the photodegradation was detected and a reaction mechanism is proposed.

Facile Construction of All-Solid-State Z-Scheme g-C3N4/TiO2 Thin Film for the Efficient Visible-Light Degradation of Organic Pollutant.

The increasing discharge of dyes and antibiotic pollutants in water has brought serious environmental problems. However, it is difficult to remove such pollutants effectively by traditional sewage treatment technologies. Semiconductor photocatalysis is a new environment-friendly technique and is widely used in aqueous pollution control. TiO2 is one of the most investigated photocatalysts; however, it still faces the main drawbacks of a poor visible-light response and a low charge-separation efficiency. Moreover, powder photocatalyst is difficult to be recovered, which is another obstacle limiting the practical application. In this article, g-C3N4/TiO2 heterojunction is simply immobilized on a glass substrate to form an all-solid-state Z-scheme heterojunction. The obtained thin-film photocatalyst was characterized and applied in the visible-light photodegradation of colored rhodamine B and tetracycline hydrochloride. The photocatalytic performance is related to the deposited layers, and the sample with five layers shows the best photocatalytic efficiency. The thin-film photocatalyst is easy to be recovered with stability. The active component responsible for the photodegradation is identified and a Z-scheme mechanism is proposed.

SOX9 is a dose-dependent metastatic fate determinant in melanoma.

BACKGROUND: In this research, we aimed to resolve contradictory results whether SOX9 plays a positive or negative role in melanoma progression and determine whether SOX9 and its closely related member SOX10 share the same or distinct targets in mediating their functions in melanoma. METHODS: Immunofluorescence, TCGA database and qPCR were used to analyze the correlation between the expression patterns and levels of SOX9, SOX10 and NEDD9 in melanoma patient samples. AlamarBlue, transwell invasion and colony formation assays in melanoma cell lines were conducted to investigate the epistatic relationship between SOX10 and NEDD9, as well as the effects of graded SOX9 expression levels. Lung metastasis was determined by tail vein injection assay. Live cell imaging was conducted to monitor dynamics of melanoma migratory behavior. RHOA and RAC1 activation assays measured the activity of Rho GTPases. RESULTS: High SOX9 expression was predominantly detected in patients with distant melanoma metastases whereas SOX10 was present in the different stages of melanoma. Both SOX9 and SOX10 exhibited distinct but overlapping expression patterns with metastatic marker NEDD9. Accordingly, SOX10 was required for NEDD9 expression, which partly mediated its oncogenic functions in melanoma cells. Compensatory upregulation of SOX9 expression in SOX10-inhibited melanoma cells reduced growth and migratory capacity, partly due to elevated expression of cyclin-dependent kinase inhibitor p21 and lack of NEDD9 induction. Conversely, opposite phenomenon was observed when SOX9 expression was further elevated to a range of high SOX9 expression levels in metastatic melanoma specimens, and that high levels of SOX9 can restore melanoma progression in the absence of SOX10 both in vitro and in vivo. In addition, overexpression of SOX9 can also promote invasiveness of the parental melanoma cells by modulating the expression of various matrix metalloproteinases. SOX10 or high SOX9 expression regulates melanoma mesenchymal migration through the NEDD9-mediated focal adhesion dynamics and Rho GTPase signaling. CONCLUSIONS: These results unravel NEDD9 as a common target for SOX10 or high SOX9 to partly mediate their oncogenic events, and most importantly, reconcile previous discrepancies that suboptimal level of SOX9 expression is anti-metastatic whereas high level of SOX9 is metastatic in a heterogeneous population of melanoma.

Circulating and tumor-infiltrating myeloid-derived suppressor cells in cervical carcinoma patients.

Myeloid-derived suppressor cells (MDSCs) serve an immunosuppressive role in human tumors. Human Lin-/low human leukocyte antigen-antigen D related (HLA-DR-) cluster of differentiation (CD)-11b+CD33+ MDSCs are closely linked with tumor staging, progression, clinical therapeutic efficacy and prognosis for various types of tumors. The present study employed multiparametric flow cytometry to measure the proportion of Lin-/lowHLA-DR-CD11b+CD33+ MDSCs in the peripheral blood of 105 cervical cancer patients and 50 healthy subjects. The level of MDSC was higher in tumor patients than in the normal control group and this was closely associated with clinical staging. Further analysis of tumor-infiltrating MDSCs was performed in 22 patients. The MDSC proportions in tumor tissue were significantly higher than those in the corresponding adjacent tissue. The phenotypic characteristics of Lin-/lowHLA-DR-CD11b+CD33+ MDSCs were then evaluated and the results revealed that they express high CD13 and CD39, and low CD115, CD117, CD124 and programmed cell death ligand 1; they were also devoid of CD14, CD15 and CD66b. MDSCs and T-cells from peripheral blood were sorted by flow cytometry for co-culture experiments. Lin-/lowHLA-DR-CD11b+CD33+ MDSCs from patients significantly inhibited the proliferation of CD4 and CD8 T-cells. Furthermore, functional analysis verified that MDSCs from cervical cancer patients could inhibit interleukin-2 and interferon-γ production from T-cells. In addition, the associations between peripheral circulating MDSCs and tumor infiltrating MDSCs, and tumor relapse and metastasis were analyzed. The number of peripheral MDSCs and MDSCs in tumor tissue were observed to be associated with relapse-free survival. Thus, MDSCs in the peripheral blood and tumors of cervical cancer patients have a significant immunosuppressive effect, and are associated with cervical cancer staging and metastasis. These results suggest that targeting MDSCs may increase antitumor immunity and increase the efficacy of cervical cancer therapies.

Evaluation of the potential of a simplified co-delivery system with oligodeoxynucleotides as a drug carrier for enhanced antitumor effect.

BACKGROUND: We previously developed a simple effective system based on oligodeoxynucleotides with CGA repeating units (CGA-ODNs) for Dox and siRNA intracellular co-delivery. METHODS: In the present study, the in vitro cytotoxicity, gene transfection and in vivo safety of the co-delivery system were further characterized and discussed. RESULTS: Compared with poly(ethyleneimine) (PEI), both CGA-ODNs and the pH-sensitive targeted coating, o-carboxymethyl-chitosan (CMCS)-poly(ethylene glycol) (PEG)-aspargine-glycine-arginine (NGR) (CMCS-PEG-NGR, CPN) showed no obvious cytotoxicity in 72 h. The excellent transfection capability of CPN coated Dox and siRNA co-loaded nanoparticles (CPN-PDR) was confirmed by real-time PCR and Western blot analysis. It was calculated that there was no significant difference in silencing efficiency among Lipo/siRNA, CPN-modified siRNA-loaded nanoparticles (CPN-PR) and CPN-PDR. Furthermore, CPN-PDR was observed to be significantly much more toxic than Dox- and CPN-modified Dox-loaded nanoparticles (CPN-PD), implying their higher antitumor potential. Both hemolysis tests and histological assessment implied that CPN-PDR was safe for intravenous injection with nontoxicity and good biocompatibility in vitro and in vivo. CONCLUSION: The results indicated that CPN-PDR could be a potentially promising co-delivery carrier for enhanced antitumor therapy.

Progress of CDK4/6 Inhibitor Palbociclib in the Treatment of Cancer.

The Cyclin-Dependent Kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. These kinases are closely related to oncogenesis and have been proved to be attractive targets for designing novel anticancer agents. The CDK inhibitors can effectively suppress the excessive proliferation of tumor cells by inducing cell cycle arrest. In recent years, a large number of CDK inhibitors have entered pre-clinical and/or clinical trials. Among these compounds, the selective CDK4/6 inhibitor Palbociclib has been approved by FDA for breast cancer treatment. Moreover, Palbociclib demonstrated promising antitumor potential as monotherapy or combined therapy in numerous clinical trials. Herein, we provide a brief review focused on the recent progress of clinical studies about Palbociclib.

Suppression of cortical TRPM7 protein attenuates oxidative damage after traumatic brain injury via Akt/endothelial nitric oxide synthase pathway.

Neuronal death after traumatic brain injury (TBI) is a complex process resulting from a combination of factors, many of which are still unknown. Transient receptor potential melastatin 7 (TRPM7) is a transient receptor potential channel that has been demonstrated to mediate ischemic and traumatic neuronal injury in vitro. In the present study, TRPM7 was suppressed in the rat cerebral cortex by intracortical injections of viral vectors bearing shRNA specific for TRPM7 to investigate its potential role in an in vivo TBI model. We found that TRPM7 suppression significantly reduced brain edema, brain contusion volume and motor functional deficits, which was sustained for at least 2 weeks after the insult. These protective effects were accompanied by inhibited apoptosis in injured cortex. Also, TRPM7 suppression attenuated lipid peroxidation, decreased the expression of protein carbonyl, and preserved the endogenous antioxidant enzyme activities. The results of western blot analysis showed that TRPM7 suppression markedly increased the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS). In addition, blocking Akt/eNOS pathway activation by the specific inhibitor LY294002 (LY, 10 µL, 10 mmol/L) or L-NIO (0.5 mg/kg) partially reversed the protective effects of TRPM7 suppression and its anti-oxidative activities. Taken together, these findings demonstrated that regional inhibition of TRPM7 in cerebral cortex exerts neuroprotective effects against TBI through activation of Akt/eNOS pathway. Thus, TRPM7 might represent a potential drug development target for the treatment of TBI.