RESUMEN

Postoperative radiotherapy remains the gold standard for malignant glioma treatment. Clinical limitations, including tumor growth between surgery and radiotherapy and the emergence of radioresistance, reduce treatment effectiveness and result in local disease progression. This study aimed to develop a local drug delivery system to inhibit tumor growth before radiotherapy and enhance the subsequent anticancer effects of limited-dose radiotherapy. We developed a compound of carboplatin-loaded hydrogel (CPH) incorporated with carboplatin-loaded calcium carbonate (CPCC) to enable two-stage (peritumoral and intracellular) release of carboplatin to initially inhibit tumor growth and to synergize with limited-dose radiation (10 Gy in a single fraction) to eliminate malignant glioma (ALTS1C1 cells) in a C57BL/6 mouse subcutaneous tumor model. The doses of carboplatin in CPH and CPCC treatments were 150 µL (carboplatin concentration of 5 mg/mL) and 15 mg (carboplatin concentration of 4.1 µg/mg), respectively. Mice receiving the combination of CPH-CPCC treatment and limited-dose radiation exhibited significantly reduced tumor growth volume compared to those receiving double-dose radiation alone. Furthermore, combining CPH-CPCC treatment with limited-dose radiation resulted in significantly longer progression-free survival than combining CPH treatment with limited-dose radiation. Local CPH-CPCC delivery synergized effectively with limited-dose radiation to eliminate mouse glioma, offering a promising solution for overcoming clinical limitations.

Asunto(s)

RESUMEN

A series of supramolecular hydrogels are constructed through selective metal coordination to a mannose-grafted Anderson-type polyoxometalate under sonication. The crosslinked helical nanofibers in the hydrogels are characterized by the synthesized hybrid clusters adopting a half-overlapped head-to-tail packing while the chirality of the mannose group directs the preferential assembly.

RESUMEN

CDK4/6 inhibitors combined with endocrine therapy prolonged survival in hormone receptor (HR)-positive and HER2-negative advanced breast cancer. We investigated whether CDK4/6 inhibitors enhance radiosensitivity and their underlying mechanisms of this subtype of breast cancer. In vitro and in vivo experiments were conducted using two HR-positive and HER2-negative breast cancer cell lines (MCF-7 and T-47D), CDK4/6 inhibitors (ribociclib and palbociclib) and radiotherapy (RT) to assess the biological functions and mechanisms. The radiation-enhancing effect was assessed using clonogenic assays; γH2AX and 53BP1 levels were assessed by immunofluorescence to evaluate DNA damage. The levels of phospho (p)-ERK, c-Myc, and DNA-double strand break (DSB)-related molecules, p-DNA-PKcs, Rad51, and p-ATM, were assessed by western blotting. We used an NF-κB p65 transcription factor assay kit to evaluate NF-κB activity. We evaluated the antitumor effect of the combination of RT and ribociclib through the MCF-7 orthotopic xenograft model. The synergistic effects of combining RT with ribociclib and palbociclib pretreatment were demonstrated by clonogenic assay. CDK4/6 inhibitors synergistically increased the numbers of RT-induced γH2AX and 53BP1, downregulated the expression of p-DNA-PKcs, Rad51 and p-ATM activated by RT, and reduced RT-triggering p-ERK expression, NF-κB activation, and its down-streaming gene, c-Myc. Combined ribociclib and RT reduced the growth of MCF-7 cell xenograft tumors, and downregulated the immunohistochemical expression of p-ERK, p-NF-κB p65, and c-Myc compared to that in the control group. Combining CDK4/6 inhibitors enhanced radiosensitivity of HR-positive and HER2-negative breast cancer cells at least by reducing DNA-DSB repair and weakening the activation of ERK and NF-κB signaling by RT.

RESUMEN

Dynamic reversible noncovalent interactions make supramolecular framework (SF) structures flexible and designable. A three-dimensional (3D) growth of such frameworks is beneficial to improve the structure stability while maintaining unique properties. Here, through the ionic interaction of the polyoxometalate cluster, coordination of zinc ions with cationic terpyridine, and hydrogen bonding of grafted carboxyl groups, the construction of a 3D SF at a well-crystallized state is realized. The framework can grow in situ on the Zn surface, further extending laterally into a full covering without defects. Relying on the dissolution and the postcoordination effects, the 3D SF layer is used as an artificial solid electrolyte interphase to improve the Zn-anode performance. The uniformly distributed clusters within nanosized pores create a negatively charged nanochannel, accelerating zinc ion transfer and homogenizing zinc deposition. The 3D SF/Zn symmetric cells demonstrate high stability for over 3000 h at a current density of 5 mA cm-2.

Asunto(s)

RESUMEN

A two-dimensional supramolecular framework with a tetragonal structure is constructed via host-guest interaction of a pillar[5]arene grafted polyanion with a modified porphyrin. The membrane of the framework with a chiral counterion exhibits enantiomeric selectivity during the filtration of racemic molecules with amino groups, demonstrating broadened potential in chiral separations.

RESUMEN

PURPOSE: In this study, we assessed whether the overexpression of MAP3K1 promotes the proliferation, migration, and invasion of breast cancer cells, which affect the prognosis of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early stage breast cancer. METHODS: Two HR-positive, HER2-negative breast cancer cell lines (MCF7 and T-47D) overexpressing MAP3K1 were transfected with two MAP3K1 short hairpin RNA plasmids (shMAP3K1 [#3] and shMAP3K1 [#5]). The proliferation, migration, and invasion of these cells were then examined. We assessed whether shMAP3K1 affects the cell cycle, levels of downstream signaling molecules (ERK, JNK, p38 MAPK, and NF-κB), and sensitivity to chemotherapeutic and hormonal agents. To assess the anti-tumor effect of MAP3K1 knockdown in the breast cancer orthotopic model, MCF7 and T-47D cells treated with or without shMAP3K1 (#3) and shMAP3K1 (#5) were inoculated into the mammary fat pads of mice. In total, 182 patients with HR-positive, HER2-negative T1 and T2 breast cancer and 0-3 nodal metastases were included. Additionally, 73 patients with T1 and T2 breast cancer and negative nodes who received adjuvant endocrine therapy alone were selected as an independent validation cohort. RESULTS: In both cell lines, shMAP3K1 (#3) and shMAP3K1 (#5) significantly reduced cell growth, migration, and invasion by downregulating MMP-9 and by blocking the G2/M phase of the cell cycle and its regulatory molecule cyclin B1. Moreover, both shMAP3K1 (#3) and shMAP3K1 (#5) downregulated ERK-, JNK-, p38 MAPK-, and NF-κB-dependent gene transcription and enhanced the sensitivity of both cell lines to doxorubicin, docetaxel, and tamoxifen. We observed that both shMAP3K1 (#3) and shMAP3K1 (#5) inhibited tumor growth compared with that in the scrambled group of MCF7 and T-47D cell orthotopic tumors. Patients with MAP3K1 overexpression exhibited significantly poorer 10-year disease-free survival (DFS) (70.4% vs. 88.6%, p = 0.003) and overall survival (OS) (81.9% vs. 96.3%, p = 0.001) than those without MAP3K1 overexpression. Furthermore, phospho-ERK (p < 0.001) and phospho-JNK (p < 0.001) expressions were significantly associated with MAP3K1 expression, and both phospho-ERK and phospho-JNK expressions were significantly correlated with poor 10-year DFS and OS. These biological findings, including a significant association between DFS and OS, and the expressions of MAP3K1, phospho-ERK, and phospho-JNK were further validated in an independent cohort. Multivariate analysis identified MAP3K1 expression as an independent poor prognostic factor for DFS and OS. CONCLUSION: Our results indicate that the overexpression of MAP3K1 plays a major role in the poor prognosis of HR-positive, HER2-negative early stage breast cancer.

Asunto(s)

RESUMEN

Supramolecular framework (SF) encourages the emergence of porous structures with molecular flexibility while the dimension and morphology controls are less involved even though critical factors are vital for various utilizations. Targeting this purpose, two isolated components are designed and their stepped combinations via ionic interaction, metal coordination, and hydrogen bond into framework assembly with two morphologic states are realized. The zinc coordination to an ionic complex of polyoxometalate with three cationic terpyridine ligands constructs 2D hexagonal SF structure. A further growth along perpendicular direction driven by hydrogen bonding between grafted mannose groups leads to 3D SF assemblies, providing a modulation superiority in one framework for multiple utilizations. The large area of multilayered SF sheet affords a filtration membrane for strict separation of nanoparticles/proteins under gently reduced pressures while the granular SF assembly demonstrates an efficient carrier to load and fix horse radish peroxidase with maintained activity for enzymatic catalysis.

Asunto(s)

RESUMEN

Synthetic framework materials have been cherished as appealing candidates for separation membranes in daily life and industry, while the challenges still remain in precise control of aperture distribution and separation threshold, mild processing methods, and extensive application aspects. Here, we show a two-dimensional (2D) processible supramolecular framework (SF) by integrating directional organic host-guest motifs and inorganic functional polyanionic clusters. The thickness and flexibility of the obtained 2D SFs are tuned by the solvent modulation to the interlayer interactions, and the optimized SFs with limited layers but micron-sized areas are used to fabricate the sustainable membranes. The uniform nanopores allow the membrane composed of layered SF to exhibit strict size retention for substrates with the rejection value of 3.8 nm, and the separation accuracy within 5 kDa for proteins. Furthermore, the membrane performs high charge selectivity for charged organics, nanoparticles, and proteins, due to the insertion of polyanionic clusters in the framework skeletons. This work displays the extensional separation potentials of self-assembled framework membranes comprising of small-molecules and provides a platform for the preparation of multifunctional framework materials due to the conveniently ionic exchange of the counterions of the polyanionic clusters.

RESUMEN

Dendrite growth and side reactions of Zn metal anodes remain unresolved obstacles for practical application of aqueous Zn ion batteries. Herein, a two-dimensional (2D) organic-inorganic heterostructure with controlled thickness was constructed as a protective layer for a Zn metal anode. The reduction of uniformly distributed polyoxometalate in the layer causes a negative charge density gradient, which can accelerate zinc ion transfer, homogenize zinc deposition, and shield sulfates at the electrode interface, while the exposed hydrophobic alkyl chain of the layer can isolate the direct contact of water with the Zn anode. As a result of the synergetic effect, this 2D organic-inorganic heterostructure enables high Zn plating/stripping reversibility, with high average Coulombic efficiencies of 99.97% for 3700 cycles at 2 mA cm-2. Under high Zn utilization conditions, a high areal-capacity full cell with hundreds of cycles was demonstrated.

Asunto(s)

RESUMEN

Abdominal or pelvic radiotherapy (RT) often results in small intestinal injury, such as apoptosis of epithelial cells and shortening of the villi. Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has many biological effects including cholesterol reduction, protection from cell damage, and autophagy activation. To reduce the extent of radiotherapy- (RT-) induced enteritis, we investigated the protective effects of atorvastatin against RT-induced damage of the intestinal tract. In this study, C57BL/6 mice were randomly distributed into the following groups (n = 8 per group): (1) control group: mice were fed water only, (2) atorvastatin group (Ator): mice were administered atorvastatin, (3) irradiation group (IR): mice received abdominal RT, (4) Ator+IR group: mice received abdominal RT following atorvastatin administration, and (5) Ator+IR+3-MA group: abdominal RT following atorvastatin and 3-methyladenine (an autophagy inhibitor) administration. Based on the assessment of modified Chiu's injury score and villus/crypt ratio, we found that atorvastatin administration significantly reduced intestinal mucosal damage induced by RT. Atorvastatin treatment reduced apoptosis (cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase), DNA damage (γH2AX and 53BP1), oxidative stress (OS, 4-hydroxynonenal), inflammatory molecules (phospho-NF-κB p65 and TGF-ß), fibrosis (collagen I and collagen III), barrier leakage (claudin-2 and fluorescein isothiocyanate-dextran), disintegrity (fatty acid-binding protein 2), and dysfunction (lipopolysaccharide) caused by RT in small intestinal tissue. In addition, atorvastatin upregulated the expression of autophagy-active molecules (LC3B), antioxidants (heme oxygenase 1 and thioredoxin 1), and tight junction proteins (occludin and zonula occludens 1). However, the biological functions of atorvastatin in decreasing RT-induced enteritis were reversed after the administration of 3-MA; the function of antioxidant molecules and activity of thioredoxin reductase were independent of autophagy activation. Our results indicate that atorvastatin can effectively relieve RT-induced enteritis through autophagy activation and associated biological functions, including maintaining integrity and function and decreasing apoptosis, DNA damage, inflammation, OS, and fibrosis. It also acts via its antioxidative capabilities.

Asunto(s)

RESUMEN

Enhanced conversion of carbon dioxide (CO2) for cycloaddition with epoxide derivatives is highly desired in organic synthesis and green chemistry, yet it is still a challenge to obtain satisfactory activity under mild reaction conditions of temperature and pressure. For this purpose, an unexploited strategy is proposed here by incorporating near-infrared (NIR) photothermal properties into multicomponent catalysts. Through the electrostatic adsorption of Co- or Ce-substituted polyoxometalate (POM) clusters on the surface of graphene oxide (GO) with covalently grafted polyethyleneimine (PEI), a series of composite catalysts POMs@GO-PEI are prepared. The structural and property characterizations demonstrate the synergistic advantages of the catalysts bearing Lewis acids and bases and local NIR photothermal heating from the GO matrix for dramatically enhanced CO2 cycloaddition. Noticeably, while the turnover frequency increases up to 2718 h-1, the heterogeneous catalysts exhibit photothermal stability and recyclability. With this method, the onsite NIR photothermal transformation becomes extendable to more green reaction processes.

RESUMEN

BACKGROUND: We previously demonstrated that nuclear BCL10 translocation participates in the instigation of NF-κB in breast cancer and lymphoma cell lines. In this study, we assessed whether nuclear BCL10 translocation is clinically significant in advanced and metastatic pancreatic ductal adenocarcinoma (PDAC). METHOD AND MATERIALS: We analyzed the expression of BCL10-, cell cycle-, and NF-κB- related signaling molecules, and the DNA-binding activity of NF-κB in three PDAC cell lines (mutant KRAS lines: PANC-1 and AsPC-1; wild-type KRAS line: BxPC-3) using BCL10 short hairpin RNA (shBCL10). To assess the anti-tumor effect of BCL10 knockdown in PDAC xenograft model, PANC-1 cells treated with or without shBCL10 transfection were inoculated into the flanks of mice. We assessed the expression patterns of BCL10 and NF-κB in tumor cells in 136 patients with recurrent, advanced, and metastatic PDAC using immunohistochemical staining. RESULTS: We revealed that shBCL10 transfection caused cytoplasmic translocation of BCL10 from the nuclei, inhibited cell viability, and enhanced the cytotoxicities of gemcitabine and oxaliplatin in three PDAC cell lines. Inhibition of BCL10 differentially blocked cell cycle progression in PDAC cell lines. Arrest at G1 phase was noted in wild-type KRAS cell lines; and arrest at G2/M phase was noted in mutant KRAS cell lines. Furthermore, shBCL10 transfection downregulated the expression of phospho-CDC2, phospho-CDC25C, Cyclin B1 (PANC-1), Cyclins A, D1, and E, CDK2, and CDK4 (BxPC-3), p-IκBα, nuclear expression of BCL10, BCL3, and NF-κB (p65), and attenuated the NF-κB pathway activation and its downstream molecule, c-Myc, while inhibition of BCL10 upregulated expression of p21, and p27 in both PANC-1 and BxPC-3 cells. In a PANC-1-xenograft mouse model, inhibition of BCL10 expression also attenuated the tumor growth of PDAC. In clinical samples, nuclear BCL10 expression was closely associated with nuclear NF-κB expression (p < 0.001), and patients with nuclear BCL10 expression had the worse median overall survival than those without nuclear BCL10 expression (6.90 months versus 9.53 months, p = 0.019). CONCLUSION: Nuclear BCL10 translocation activates NF-κB signaling and contributes to tumor progression and poor prognosis of advanced/metastatic PDAC.

RESUMEN

Polyoxometalates (POMs), as a typical class of discrete metal oxide clusters that are known in inorganic and structural chemistry since long, have displayed more and more interesting applications over recent years. However, in comparison to the chemical synthesis, the photochemical, electrochemical, and magnetic properties, the structural asymmetry, and relative characteristic investigations arising therefrom are far behind even if they are very important for functional materials, especially in solution systems. One of the main reasons is that it is hard to control and maintain a stable chiral state of POMs to carry out further corresponding performances. Aiming to overcome these disadvantages, the main concerns of this review are to discuss the generation of the chirality for discrete metal oxide clusters, chirality transfer via a supramolecular approach, chirality amplification in self-assemblies, and the related functional properties such as photochromism, catalysis, and bioactivities in solutions. Considering that some previous reviews dealt with chiral structures and packing architectures in the crystalline solids of POMs, this article only concentrates on the induced chirality and material properties in solution systems, which have been more active recently but no review article has been involved in this interesting area.

RESUMEN

The psyllid Cacopsylla chinensis (Yang & Li) (Hemiptera: Psyllidae) is a serious pest of pears in China. To determine and contrast the fitness of the psyllid on two endemic cultivars of Pyrus bretschneideri (i.e., BHXS and BSL) and two introduced cultivars of Pyrus communis (i.e., CB and CRB), we analyzed data on the development, survival, and fecundity from C. chinensis individuals reared on the four cultivars. The age-stage, two-sex life table theory was used in order to enable the inclusion of males in the analysis as well as a means of identifying the variation in developmental durations among individuals. Results indicated that C. chinensis can successfully develop and reproduce on all four pear cultivars. However, based on the lower preadult survival rate, longer preadult duration, longer total preoviposition period (TPOP), and lower fecundity that occurred on both cultivars of P. communis, these two cultivars are less favorable hosts for C. chinensis than the P. bretschneideri cultivars. The lower intrinsic rate of increase (r), finite rate of increase (λ), and net reproduction rate (R0) on CB and CRB pears showed these two introduced cultivars are more resistant to C. chinensis than the endemic BHXS and BSL pears. These resistant cultivars would be appropriate candidates for managing C. chinensis. We used the bootstrap technique to estimate the uncertainty of the population parameters (r, λ, R0, etc.), while also demonstrating that it can be used for estimating the 0.025 and 0.975 percentile confidence intervals of the age of survival rate.

Asunto(s)

RESUMEN

Our previous study demonstrated that administration of NVP-BEZ235 (BEZ235), a dual PI3K/mTOR inhibitor, before radiotherapy (RT) enhanced the radiotherapeutic effect in colorectal cancer (CRC) cells both in vitro and in vivo. Here, we evaluated whether maintenance BEZ235 treatment, after combinatorial BEZ235 + RT therapy, prolonged the antitumor effect in CRC. K-RAS mutant CRC cells (HCT116 and SW480), wild-type CRC cells (HT29), and HCT116 xenograft tumors were separated into the following six study groups: (1) untreated (control); (2) RT alone; (3) BEZ235 alone; (4) RT + BEZ235; (5) maintenance BEZ235 following RT + BEZ235 (RT + BEZ235 + mBEZ235); and (6) maintenance BEZ235 following BEZ235 (BEZ235 + mBEZ235). RT + BEZ235 + mBEZ235 treatment significantly inhibited cell viability and increased apoptosis in three CRC cell lines compared to the other five treatments in vitro. In the HCT116 xenograft tumor model, RT + BEZ235 + mBEZ235 treatment significantly reduced the tumor size when compared to the other five treatments. Furthermore, the expression of mTOR signaling molecules (p-rpS6 and p-eIF4E), DNA double-strand break (DSB) repair-related molecules (p-ATM and p-DNA-PKcs), and angiogenesis-related molecules (VEGF-A and HIF-1α) was significantly downregulated after RT + BEZ235 + mBEZ235 treatment both in vitro and in vivo when compared to the RT + BEZ235, RT, BEZ235, BEZ235 + mBEZ235, and control treatments. Cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP), 53BP1, and γ-H2AX expression in the HCT116 xenograft tissue and three CRC cell lines were significantly upregulated after RT + BEZ235 + mBEZ235 treatment. Maintenance BEZ235 treatment in CRC cells prolonged the inhibition of cell viability, enhancement of apoptosis, attenuation of mTOR signaling, impairment of the DNA-DSB repair mechanism, and downregulation of angiogenesis that occurred due to concurrent BEZ235 and RT treatment.

RESUMEN

BACKGROUND: Carboplatin, an antineoplastic agent, binds DNA and enhances radiotherapy (RT) effects. Carboplatin-loaded hydrogel (oxidized hyaluronic acid/adipic acid dihydrazide) enables the sustained drug release and facilitates the synergistic effect with RT. PURPOSE: We investigated the effectiveness and convenience of hydrogel carboplatin combined with RT for mice glioma. MATERIALS AND METHODS: Mouse glioma cells (ALTS1C1) were subcutaneously implanted in the right thigh of C57BL/6 mice on Day 0. The mice were categorized by treatments: sham, hydrogel, hydrogel carboplatin, aqueous carboplatin, RT, hydrogel carboplatin/RT, and aqueous carboplatin/RT. Hydrogel carboplatin (300 µg single dose on Day 7) or aqueous carboplatin (100 µg daily dose on Days 7, 8, and 9) was administered via intratumoral injection. RT was delivered a daily dose of 10 Gy on Days 8 and 9. RESULTS: For mice administered hydrogel carboplatin/RT versus those administered aqueous carboplatin/RT, the 24-day tumor growth control rate and 104-day recurrence-free survival rate were 100% and 50% versus 100% and 66.7% (p = 0.648), respectively. However, mice receiving other treatments showed tumor progression by Day 24 and died within 40 days of tumor cell implantation. CONCLUSIONS: Hydrogel carboplatin simplified intratumoral drug delivery and remained the synergistic effects with RT, which is potential for clinical applications.

Asunto(s)

RESUMEN

First-line antibiotic treatment for eradicating Helicobacter pylori (HP) infection is effective in HP-positive low-grade gastric mucosa-associated lymphoid tissue lymphoma (MALToma), but its role in HP-negative cases is uncertain. In this exploratory retrospective study, we assessed the outcome and potential predictive biomarkers for 25 patients with HP-negative localized gastric MALToma who received first-line HP eradication (HPE) therapy. An HP-negative status was defined as negative results on histology, rapid urease test, 13C urea breath test, and serology. We observed an antibiotic response (complete remission [CR], number = 8; partial remission, number = 1) in 9 (36.0%) out of 25 patients. A t(11;18)(q21;q21) translocation was detected in 7 (43.8%) of 16 antibiotic-unresponsive cases, but in none of the 9 antibiotic-responsive cases (P = 0.027). Nuclear BCL10 expression was significantly higher in antibiotic-unresponsive tumors than in antibiotic-responsive tumors (14/16 [87.5%] vs. 1/9 [11.1%]; P = 0.001). Nuclear NF-κB expression was also significantly higher in antibiotic-unresponsive tumors than in antibiotic-responsive tumors (12/16 [75.0%] vs. 1/9 [11.1%]; P = 0.004). A substantial portion of patients with HP-negative gastric MALToma responded to first-line HPE. In addition to t(11;18)(q21;q21), BCL10 and NF-κB are useful immunohistochemical biomarkers to predict antibiotic-unresponsive status in this group of tumors.

Asunto(s)