Vonoprazan-amoxicillin dual regimen with Saccharomyces boulardii as a rescue therapy for Helicobacter pylori: Current perspectives and implications.

Yu et al's study in the World Journal of Gastroenterology (2023) introduced a novel regimen of Vonoprazan-amoxicillin dual therapy combined with Saccharomyces boulardii (S. boulardii) for the rescue therapy against Helicobacter pylori (H. pylori), a pathogen responsible for peptic ulcers and gastric cancer. Vonoprazan is a potassium-competitive acid blocker renowned for its rapid and long-lasting acid suppression, which is minimally affected by mealtime. Compared to proton pump inhibitors, which bind irreversibly to cysteine residues in the H+/K+-ATPase pump, Vonoprazan competes with the K+ ions, prevents the ions from binding to the pump and blocks acid secretion. Concerns with increasing antibiotic resistance, effects on the gut microbiota, patient compliance, and side effects have led to the advent of a dual regimen for H. pylori. Previous studies suggested that S. boulardii plays a role in stabilizing the gut barrier which improves H. pylori eradication rate. With an acceptable safety profile, the dual-adjunct regimen was effective regardless of prior treatment failure and antibiotic resistance profile, thereby strengthening the applicability in clinical settings. Nonetheless, S. boulardii comes in various formulations and dosages, warranting further exploration into the optimal dosage for supplementation in rescue therapy. Additionally, larger, randomized, double-blinded controlled trials are warranted to confirm these promising results.

Investigation on the mechanism of the combination of eremias multiocellata and cisplatin in reducing chemoresistance of gastric cancer based on in vitro and in vivo experiments.

BACKGROUND: Cisplatin (DDP) is one of the important chemotherapy drugs for patients with advanced gastric cancer and metastasis, but its resistance is a bottleneck problem that affects clinical efficacy and patient survival. Eremias multiocellata (EM) is a traditional Chinese herbal medicine, which has been used in the treatment of precancerous lesions, gastric cancer, liver fibrosis, and other digestive diseases. However, the mechanism of reducing chemotherapy resistance to gastric cancer is still unclear. METHODS: We used the MTT assay to evaluate the proliferative viability of gastric cancer parental cell line MKN45 and its drug-resistant cell line MKN45/DDP, and compared their drug-resistance indices. The migration and invasion abilities of MKN45/DDP drug-resistant cells were evaluated using the Transwell assay. Apoptosis in MKN45/DDP drug-resistant cells was detected using flow cytometry. The effect of a combination of EM and cisplatin on the levels of reactive oxygen species (ROS) and lipid peroxides (LPO) in cisplatin-resistant gastric cancer cells was detected using ROS fluorescent probes and a lipid peroxidation assay kit in conjunction with flow cytometry. The effect of EM combined with cisplatin on the level of iron ions was detected by fluorescence probe and confocal laser technique. Hematoxylin-eosin staining (HE staining) was used to detect the histopathologic morphology of drug-resistant gastric cancer in nude mice. Ferroptosis-related proteins were measured using immunohistochemistry. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was used to detect tumor drug resistance-related genes. The NF-κB/Snail pathway-related proteins, PI3K/AKT/mTOR pathway-related proteins, and drug resistance-related proteins were detected by Western blot. RESULTS AND CONCLUSIONS: The results of in vitro and in vivo experiments showed that EM combined with DDP could effectively inhibit the migration and invasive ability of MKN45/DDP cells, as well as induce apoptosis of MKN45/DDP cells; the combination of the two drugs could significantly increase the levels of ROS, lipid peroxidation and divalent ferric ions in MKN45/DDP cells, at the same time reducing the levels of Ferroptosis-related proteins, which could induce Ferroptosis. In addition, EM combined with DDP can also exert the effect of reversing DDP resistance and increasing the sensitivity of gastric cancer drug-resistant cells to DDP by regulating the NF-κB/Snail signaling pathway, PI3K/AKT/mTOR signaling pathway, and the expression of drug resistance-related proteins and genes.

Efficacy and toxicity of bimodal radiotherapy in WHO grade 2 meningiomas following subtotal resection with carbon ion boost: Prospective phase 2 MARCIE trial.

BACKGROUND: Novel radiotherapeutic modalities using carbon ions provide an increased relative biological effectiveness (RBE) compared to photons, delivering a higher biological dose while reducing radiation exposure for adjacent organs. This prospective phase 2 trial investigated bimodal radiotherapy using photons with carbon-ion (C12)-boost in patients with WHO grade 2 meningiomas following subtotal resection (Simpson grade 4 or 5). METHODS: A total of 33 patients were enrolled from July 2012 until July 2020. The study treatment comprised a C12-boost (18 Gy [RBE] in 6 fractions) applied to the macroscopic tumor in combination with photon radiotherapy (50 Gy in 25 fractions). The primary endpoint was the 3-year progression-free survival (PFS), and the secondary endpoints included overall survival, safety and treatment toxicities. RESULTS: With a median follow-up of 42 months, the 3-year estimates of PFS, local PFS and overall survival were 80.3%, 86.7%, and 89.8%, respectively. Radiation-induced contrast enhancement (RICE) was encountered in 45%, particularly in patients with periventricularly located meningiomas. Patients exhibiting RICE were mostly either asymptomatic (40%) or presented immediate neurological and radiological improvement (47%) after the administration of corticosteroids or bevacizumab in case of radiation necrosis (3/33). Treatment-associated complications occurred in 1 patient with radiation necrosis who died due to postoperative complications after resection of radiation necrosis. The study was prematurely terminated after recruiting 33 of the planned 40 patients. CONCLUSIONS: Our study demonstrates a bimodal approach utilizing photons with C12-boost may achieve a superior local PFS to conventional photon RT, but must be balanced against the potential risks of toxicities.

Chitosan-sodium alginate-polyethylene glycol-Ally isothiocyante nanocomposites ameliorates isoproterenol-induced myocardial infarction in rats.

Myocardial infarction (MI) is a common type of ischemic heart disease that affects millions of people worldwide. In recent times, nanotechnology has become a very promising field with immense applications. The current exploration was conducted to synthesize the chitosan-sodium alginate-polyethylene glycol-Ally isothiocyanate nanocomposites (CSP-AIso-NCs) and evaluate their beneficial roles against the isoproterenol (ISO)-induced MI in rats. The CSP-AIso-NCs were prepared and characterized by several characterization techniques. The MI was initiated in the rats by the administration of 85 mg/kg of ISO for 2 days and treated with 10 and 20 mg/kg of CSP-AIso-NCs for 1 month. The changes in heart weight and bodyweight were measured. The cardiac function markers were assessed with echocardiography. The lipid profiles, Na+, K+, and Ca2+ ions, cardiac biomarkers, antioxidant parameters, and inflammatory cytokines were assessed using corresponding assay kits. The histopathological study was done on the heart tissues. The UV spectral analysis revealed the maximum peak at 208 nm, which confirms the formation of CSP-AIso-NCs. The FT-IR analysis revealed the occurrence of different functional groups, and the crystallinity of the CSP-AIso-NCs was proved by the XRD analysis. DLS analysis indicated the size of the CSP-AIso-NCs at 146.50 nm. The CSP-AIso-NCs treatment increased the bodyweight and decreased the HW/BW ratio in the MI rats. The status of lipids was reduced, and HDL was elevated in the CSP-AIso-NCs administered to MI rats. CSP-AIso-NCs decreased the LVEDs, LVEDd, and NT-proBNP and increased the LVEF level. The oxidative stress markers were decreased, and the antioxidants were increased by the CSP-AIso-NCs treatment in the MI rats. The Na+ and Ca+ ions were reduced, and the K+ ions were increased by the CSP-AIso-NCs. The interleukin-1ß and tumor necrosis factor-α were also depleted, and Nrf-2 was improved in the CSP-AIso-NCs administered to MI rats. The histological study revealed the ameliorative effects of CSP-AIso-NCs. Overall, our outcomes revealed that the CSP-AIso-NCs are effective against the ISO-induced MI rats. Hence, it could be a hopeful therapeutic nanomedicine for MI treatment.

One-Pot Synthesis of Tumor-Microenvironment Responsive Degradable Nanoflower-Medicine for Multimodal Cancer Therapy with Reinvigorating Antitumor Immunity.

Multimodal cancer therapies show great promise in synergistically enhancing anticancer efficacy through different mechanisms. However, most current multimodal therapies either rely on complex assemblies of multiple functional nanomaterials and drug molecules or involve the use of nanomedicines with poor in vivo degradability/metabolizability, thus restricting their clinical translatability. Herein, a nanoflower-medicine using iron ions, thioguanine (TG), and tetracarboxylic porphyrin (TCPP) are synthesized as building blocks through a one-step hydrothermal method for combined chemo/chemodynamic/photodynamic cancer therapy. The resulting nanoflowers, consisting of low-density Fe2 O3 core and iron complex (Fe-TG and Fe-TCPP compounds) shell, exhibit high accumulation at the tumor site, desirable degradability in the tumor microenvironment (TME), robust suppression of tumor growth and metastasis, as well as effective reinvigoration of host antitumor immunity. Triggered by the low pH in tumor microenvironment, the nanoflowers gradually degrade after internalization, contributing to the effective drug release and initiation of high-efficiency catalytic reactions precisely in tumor sites. Moreover, iron ions can be eliminated from the body through renal clearance after fulfilling their mission. Strikingly, it is also found that the multimodal synergistic therapy effectively elicits the host antitumor immunity without inducing additional toxicity. This easy-manufactured and degradable multimodal therapeutic nanomedicine is promising for clinical precision oncology.

Carbon Ion Radiotherapy in the Treatment of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a highly lethal cancer with limited treatment options and poor prognosis. Carbon ion radiotherapy (CIRT) has emerged as a promising treatment modality for HCC due to its unique physical and biological properties. CIRT uses carbon ions to target and destroy cancer cells with a high precision and efficacy. The Bragg Peak phenomenon allows precise dose delivery to the tumor while minimizing damage to healthy tissues. In addition, the high relative biological effectiveness of carbon ions can be shown against radioresistant and hypoxic tumor areas. CIRT also offers a shorter treatment schedule than conventional radiotherapy, which increases patient convenience and compliance. The clinical outcomes of CIRT for HCC have shown excellent local control rates with minimal side effects. Considering its physical and biological properties, CIRT may be a viable option for complex clinical scenarios such as patients with poor liver function, large tumors, re-irradiation cases, and tumors close to critical organs. Further research and larger studies are needed to establish definitive indications for CIRT and to compare its efficacy with that of other treatment modalities. Nevertheless, CIRT offers a potential breakthrough in HCC management, providing hope for improved therapeutic outcomes and reduced treatment-related toxicities.

First evidence of in vivo effect of FLASH radiotherapy with helium ions in zebrafish embryos.

The ability to reduce toxicity of ultra-high dose rate (UHDR) helium ion irradiation has not been reported in vivo. Here, we tested UHDR helium ion irradiation in an embryonic zebrafish model. Our results show that UHDR helium ions spare body development and reduce spine curvature, compared to conventional dose rate.

Study on Doxorubicin Loading on Differently Functionalized Iron Oxide Nanoparticles: Implications for Controlled Drug-Delivery Application.

Nanoplatforms applied for the loading of anticancer drugs is a cutting-edge approach for drug delivery to tumors and reduction of toxic effects on healthy cells. In this study, we describe the synthesis and compare the sorption properties of four types of potential doxorubicin-carriers, in which iron oxide nanoparticles (IONs) are functionalized with cationic (polyethylenimine, PEI), anionic (polystyrenesulfonate, PSS), and nonionic (dextran) polymers, as well as with porous carbon. The IONs are thoroughly characterized by X-ray diffraction, IR spectroscopy, high resolution TEM (HRTEM), SEM, magnetic susceptibility, and the zeta-potential measurements in the pH range of 3-10. The degree of doxorubicin loading at pH 7.4, as well as the degree of desorption at pH 5.0, distinctive to cancerous tumor environment, are measured. Particles modified with PEI were shown to exhibit the highest loading capacity, while the greatest release at pH 5 (up to 30%) occurs from the surface of magnetite decorated with PSS. Such a slow release of the drug would imply a prolonged tumor-inhibiting action on the affected tissue or organ. Assessment of the toxicity (using Neuro2A cell line) for PEI- and PSS-modified IONs showed no negative effect. In conclusion, the preliminary evaluation of the effects of IONs coated with PSS and PEI on the rate of blood clotting was carried out. The results obtained can be taken into account when developing new drug delivery platforms.

Dual-infinite coordination polymer-engineered nanomedicines for dual-ion interference-mediated oxidative stress-dependent tumor suppression.

Recently, nanomedicine design has shifted from simple nanocarriers to nanodrugs with intrinsic antineoplastic activities for therapeutic performance optimization. In this regard, degradable nanomedicines containing functional inorganic ions have blazed a highly efficient and relatively safe ion interference paradigm for cancer theranostics. Herein, given the potential superiorities of infinite coordination polymers (ICPs) in degradation peculiarity and functional integration, a state-of-the-art dual-ICP-engineered nanomedicine is elaborately fabricated via integrating ferrocene (Fc) ICPs and calcium-tannic acid (Ca-TA) ICPs. Thereinto, Fc ICPs, and Ca-TA ICPs respectively serve as suppliers of ferrous iron ions (Fe2+) and calcium ions (Ca2+). After the acid-responsive degradation of ICPs, released TA from Ca-TA ICPs facilitated the conversion of released ferric iron (Fe3+) from Fc ICPs into highly active Fe2+. Owing to the dual-path oxidative stress and neighboring effect mediated by Fe2+ and Ca2+, such a dual-ICP-engineered nanomedicine effectively induces dual-ion interference against triple-negative breast cancer (TNBC). Therefore, this work provides a novel antineoplastic attempt to establish ICP-engineered nanomedicines and implement ion interference-mediated synergistic therapy.

A novel copper chelator for the suppression of colorectal cancer.

Copper ions play a crucial role in the progression of cancers. Tumor tissue is rich in copper ions, and copper chelators could potentially scavenge these copper ions and thus exert an antitumor effect. In this study, we report the synthesis of a novel thieno[3,2-c]pyridine compound we have called "JYFY-001" that can act as the copper chelator thanks to the inclusion of an N-(pyridin-2-yl)acetamide moiety that targets copper ions. JYFY-001 potently inhibited cancer proliferation, inducing cell apoptosis and impairing the extracellular acidification rate and oxygen consumption rate of colorectal cancer (CRC) cells. JYFY-001 also inhibited the growth of a CRC-transplanted tumor in a dose-dependent manner, inducing apoptosis of the tumor cells and promoting the infiltration of lymphocytes in the CRC-transplanted tumor tissues. JYFY-001 also enhanced the antitumor effects of the programmed cell death protein 1 (PD-1) inhibitor. The relatively benign nature of JYFY-001 was demonstrated by the effect on normal cell viability and acute toxicity tests in mice. Our findings suggest that JYFY-001 is a prospective copper chelator to be used as a targeted drug and a synergist of immunotherapy for CRC treatments.

Trends in iron oxide nanoparticles: a nano-platform for theranostic application in breast cancer.

Breast cancer (BC) is the deadliest malignant disorder globally, with a significant mortality rate. The development of tolerance throughout cancer treatment and non-specific targeting limits the drug's response. Currently, nano therapy provides an interdisciplinary area for imaging, diagnosis, and targeted drug delivery for BC. Several overexpressed biomarkers, proteins, and receptors are identified in BC, which can be potentially targeted by using nanomaterial for drug/gene/immune/photo-responsive therapy and bio-imaging. In recent applications, magnetic iron oxide nanoparticles (IONs) have shown tremendous attention to the researcher because they combine selective drug delivery and imaging functionalities. IONs can be efficaciously functionalised for potential application in BC therapy and diagnosis. In this review, we explored the current application of IONs in chemotherapeutics delivery, gene delivery, immunotherapy, photo-responsive therapy, and bio-imaging for BC based on their molecular mechanism. In addition, we also highlighted the effect of IONs' size, shape, dimension, and functionalization on BC targeting and imaging. To better comprehend the functionalization potential of IONs, this paper provides an outline of BC cellular development. IONs for BC theranostic are also reviewed based on their clinical significance and future aspects.Graphical Abstract[Formula: see text].

Current Breast cancer treatment resists due to the development of drug tolerance throughout cancer treatment and non-specific drug targeting.Magnetic IONs are being utilised for the therapy and bio-imaging of breast cancer by targeting overexpressed biomarkers, proteins, and receptors in breast cancer progression.Physical properties of IONs, such as size, shape, and dimensions, also alter their therapeutic and imaging responses.Iron oxide nanoparticles can be efficaciously functionalised based on breast cancer molecular mechanisms for potential application in breast cancer drug delivery, gene delivery, immunotherapy, photo responsive therapy, and bio-imaging.

Current understanding of the interactions between metal ions and Apolipoprotein E in Alzheimer's disease.

Alzheimer's disease (AD), the most common type of dementia in the elderly, is a chronic and progressive neurodegenerative disorder with no effective disease-modifying treatments to date. Studies have shown that an imbalance in brain metal ions, such as zinc, copper, and iron, is closely related to the onset and progression of AD. Many efforts have been made to understand metal-related mechanisms and therapeutic strategies for AD. Emerging evidence suggests that interactions of brain metal ions and apolipoprotein E (ApoE), which is the strongest genetic risk factor for late-onset AD, may be one of the mechanisms for neurodegeneration. Here, we summarize the key points regarding how metal ions and ApoE contribute to the pathogenesis of AD. We further describe the interactions between metal ions and ApoE in the brain and propose that their interactions play an important role in neuropathological alterations and cognitive decline in AD.

Neoadjuvant irradiation of extremity soft tissue sarcoma with ions (Extrem-ion): study protocol for a randomized phase II pilot trial.

BACKGROUND: The standard of care treatment for soft tissue sarcoma of the extremities is a wide resection in combination with pre- or postoperative radiotherapy with high local control rates, sparing patients the necessity of amputation without compromising on overall survival rates. The currently preferred timing of radiotherapy is under debate. Albeit having higher rates of acute wound complications, late side effects like fibrosis, joint stiffness or edema are less frequent in preoperative compared to postoperative radiotherapy. This can be explained in smaller treatment volumes and a lower dose in the preoperative setting. Particles allow better sparing of surrounding tissues at risk, and carbon ions additionally offer biologic advantages and are preferred in less radiosensitive tumors. Hypofractionation allows for a significantly shorter treatment duration. METHODS: Extrem-ion is a prospective, randomized, monocentric phase II trial. Patients with resectable or marginally resectable, histologically confirmed soft tissue sarcoma of the extremities will be randomized between neoadjuvant proton or neoadjuvant carbon ion radiotherapy in active scanning beam application technique (39 Gy [relative biological effectiveness, RBE] in 13 fractions [5-6 fractions per week] in each arm). The primary objective is the proportion of therapies without wound healing disorder the first 120 days after surgery or discontinuation of treatment for any reason related to the treatment. The secondary endpoints of the study consist of local control, local progression-free survival, disease-free survival, overall survival, and quality of life. DISCUSSION: The aim of this study is to confirm that hypofractionated, preoperative radiotherapy is safe and feasible. The potential for reduced toxicity by the utilization of particle therapy is the rational of this trial. A subsequent randomized phase III trial will compare the hypofractionated proton and carbon ion irradiation in regards to local control. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04946357 ; Retrospectively registered June 30, 2021.

A randomized controlled phase III study comparing hadrontherapy with carbon ions versus conventional radiotherapy - including photon and proton therapy - for the treatment of radioresistant tumors: the ETOILE trial.

BACKGROUND: Some cancers such as sarcomas (bone and soft tissue sarcomas) and adenoid cystic carcinomas are considered as radioresistant to low linear energy transfer radiation (including photons and protons) and may therefore beneficiate from a carbon ion therapy. Despite encouraging results obtained in phase I/II trials compared to historical data with photons, the spread of carbon ions has been limited mainly because of the absence of randomized medical data. The French health authorities stressed the importance of having randomized data for carbon ion therapy. METHODS: The ETOILE study is a multicenter prospective randomized phase III trial comparing carbon ion therapy to either advanced photon or proton radiotherapy for inoperable or macroscopically incompletely resected (R2) radioresistant cancers including sarcomas and adenoid cystic carcinomas. In the experimental arm, carbon ion therapy will be performed at the National Center for Oncological Hadrontherapy (CNAO) in Pavia, Italy. In the control arm, photon or proton radiotherapy will be carried out in referent centers in France. The primary endpoint is progression-free survival (PFS). Secondary endpoints are overall survival and local control, toxicity profile, and quality of life. In addition, a prospective health-economic study and a radiobiological analysis will be conducted. To demonstrate an absolute improvement in the 5-year PFS rate of 20% in favor of carbon ion therapy, 250 patients have to be included in the study. DISCUSSION: So far, no clinical study of phase III has demonstrated the superiority of carbon ion therapy compared to conventional radiotherapy, including proton therapy, for the treatment of radioresistant tumors. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02838602 . Date of registration: July 20, 2016. The posted information will be updated as needed to reflect protocol amendments and study progress.

Biological Dose Optimization for Particle Arc Therapy Using Helium and Carbon Ions.

PURPOSE: To present biological dose optimization for particle arc therapy using helium and carbon ions. METHODS AND MATERIALS: Treatment planning and optimization procedures were developed for spot-scanning hadron arc (SHArc) delivery using the RayStation treatment planning system and FRoG dose engine. The SHArc optimization algorithm is applicable for charged particle beams and determines angle dependencies for spot and energy selection with three main initiatives: (i) achieve standard clinical optimization goals and constraints for target and organs at risk (OARs), (ii) target dose robustness, and (iii) increase linear energy transfer (LET) in the target volume. Three patient cases previously treated at the Heidelberg Ion-beam Therapy Center (HIT) were selected for evaluation of conventional versus arc delivery for the two clinical particle beams (helium [4He] and carbon [12C] ions): glioblastoma, prostate adenocarcinoma, and skull-base chordoma. Biological dose and dose-averaged LET (LETd) distributions for SHArc were evaluated against conventional planning techniques (volumetric modulated arc therapy [VMAT] and 2-field intensity modulated particle therapy) applying the modified microdosimetric kinetic model with (α/ß)x = 2 Gy. Clinical viability and deliverability were assessed via evaluation of plan quality, robustness, and irradiation time. RESULTS: For all investigated patient cases, SHArc treatment optimizations met planning goals and constraints for target coverage and OARs, exhibiting acceptable target coverage and reduced normal tissue volumes, with effective dose >10-GyRBE compared with conventional 2F planning. For carbon ions, LETd was increased in the target volume from ∼40-60 to ∼80-140 keV/µm for SHArc compared with conventional treatments. Favorable LETd distributions were possible with the SHArc approach, with maximum LETd in clinical target volume/gross tumor volume and potential reductions of high-LET regions in normal tissues and OARs. Compared with VMAT, SHArc affords substantial reductions in normal tissue dose (40%-70%). CONCLUSIONS: SHArc therapy offers potential treatment benefits such as increased normal tissue sparing from higher doses >10-GyRBE, enhanced target LETd, and potential reduction in high-LET components in OARs. Findings justify further development of robust SHArc treatment planning toward potential clinical translation.

FLASH radiotherapy with carbon ion beams.

FLASH radiotherapy is considered a new potential breakthrough in cancer treatment. Ultra-high dose rates (>40 Gy/s) have been shown to reduce toxicity in the normal tissue without compromising tumor control, resulting in a widened therapeutic window. These high dose rates are more easily achievable in the clinic with charged particles, and clinical trials are, indeed, ongoing using electrons or protons. FLASH could be an attractive solution also for heavier ions such as carbon and could even enhance the therapeutic window. However, it is not yet known whether the FLASH effect will be the same as for sparsely ionizing radiation when densely ionizing carbons ions are used. Here we discuss the technical challenges in beam delivery and present a promising solution using 3D range-modulators in order to apply ultra-high dose rates (UHDR) compatible with FLASH with carbon ions. Furthermore, we will discuss the possible outcome of C-ion therapy at UHDR on the level of the radiobiological and radiation chemical effects.

Metal ion chelation enhances tissue plasminogen activator (tPA)-induced thrombolysis: an in vitro and in vivo study.

Stroke is the third leading cause of death in the United States and the leading cause of adult disability. Despite enormous research efforts including many clinical trials, tissue plasminogen activator (tPA) remains the only FDA-approved treatment for acute ischemic stroke. Unfortunately, only 1-3% of stroke patients in the US receive this therapy because of the narrow time window and severe side effects for using tPA. The most deadly and damaging side effect is the risk of intracranial bleeding or hemorrhage. For that reason, the dose of tPA and its overall administration are under tight control, which may compromise the effect of thrombolysis. Studies have been focused on improving the effectiveness of tPA for higher rate of reperfusion, and the safety for less adverse bleeding episode. We studied how metal ions (zinc & iron) affect tPA-induced thrombolysis in vitro and in vivo, and proposed a method to improve the rate of thrombolysis. The amount of hemoglobin in the blood clot lysis was measured by a spectrophotometer. The tPA-induced thrombolysis was measured in vivo in femoral artery. Our results showed that Zn2+, Fe3+ and Fe2+ inhibited tPA-induced thrombolysis, with Zn2+ and Fe2+ being the most effective. Metal ion chelating agent EDTA when it was co-applied with tPA significantly enhanced the tPA-induced thrombolysis. The chelation alone did not have noticeable thrombolytic effect. In in vivo study of tPA-induced thrombosis following femoral artery thrombosis, the co-application of tPA and EDTA achieved significant higher rate of reperfusion than that by tPA treatment alone, suggesting that ion chelation facilitates tPA-induced thrombolysis and potentially improves the safety of tPA application by reducing the necessary dose of tPA application. Our results suggest that the co-application of a chelator and tPA improves the efficacy and, potentially, safety of tPA application, by reducing the necessary dose of tPA for thrombolysis.

Synergistic effects of silver ions and metformin against enterococcus faecalis under high-glucose conditions in vitro.

BACKGROUND: This study aimed to evaluate the synergistic antibacterial activities of silver ions (Ag+) and metformin hydrochloride (Met) against Enterococcus faecalis (E. faecalis) under normal or high-glucose conditions. RESULTS: The minimum inhibitory concentration, minimum bactericidal concentration, growth curves, and colony-forming units were used to evaluate the antibacterial effects of Ag+ and Met on planktonic E. faecalis in Brain Heart Infusion broth with or without additional glucose. The influences of Ag+ and Met on four weeks E. faecalis biofilm on human dentin slices was also tested. Cytotoxicity was tested on MC3T3-E1 osteoblastic cells using CCK-8 assays. The results indicated that E. faecalis showed higher resistance to drug treatment under high-glucose conditions. Ag+ (40 µg/mL) plus Met (3.2% or 6.4%) showed enhanced antibacterial activities against both planktonic E. faecalis and biofilm on dentin slices, with low cytotoxicity. CONCLUSIONS: Met enhanced the bactericidal effects of Ag+ against both planktonic and biofilm E. faecalis under normal or high-glucose conditions with low cytotoxicity. Further molecular studies are needed to be conducted to understand the mechanisms underlying the synergistic activity between Met and Ag+.

CircZNF208 enhances the sensitivity to X-rays instead of carbon-ions through the miR-7-5p /SNCA signal axis in non-small-cell lung cancer cells.

BACKGROUND: Mounting evidence suggests that circular RNAs (circRNAs) are closely related to the regulation of gene expression during tumour development. However, the role of circRNAs in modulating the radiosensitivity of non-small cell lung cancer (NSCLC) cells has not been explored. METHODS: Transcriptome sequencing was used to explore the expression profiles of circRNAs in NSCLC. The expression level of circRNAs was changed by inducing instantaneous knockdown or overexpression. Changes in proliferation and radiosensitivity of NSCLC cells were investigated using CCK-8, EDU, and clonal survivals. RESULTS: By analysing the circRNA expression profile of NSCLC cells, we found that circRNA ZNF208 (circZNF208) was significantly upregulated in a radioresistant NSCLC cell line (A549-R11), which was acquired from the parental NSCLC cell line A549. Knockout experiments indicated that circZNF208 enhanced the radiosensitivity of A549 and A549-R11 cells to X-rays. Mechanistically, circZNF208 upregulated SNCA expression by acting as a sponge of miR-7-5p and subsequently promoted the resistance of NSCLC cells to low linear energy transfer (LET) X-rays. However, this effect was not observed in NSCLC cells exposed to high-LET carbon ions. CONCLUSIONS: Knockdown of circZNF208 altered the radiosensitivity of patients with NSCLC to X-rays but did not significantly change the sensitivity to carbon ions. Therefore, circZNF208 might serve as a potential biomarker and therapeutic target for NSCLC treatment with radiotherapy of different modalities.

Inter-fractional monitoring of [Formula: see text]C ions treatments: results from a clinical trial at the CNAO facility.

The high dose conformity and healthy tissue sparing achievable in Particle Therapy when using C ions calls for safety factors in treatment planning, to prevent the tumor under-dosage related to the possible occurrence of inter-fractional morphological changes during a treatment. This limitation could be overcome by a range monitor, still missing in clinical routine, capable of providing on-line feedback. The Dose Profiler (DP) is a detector developed within the INnovative Solution for In-beam Dosimetry in hadronthErapy (INSIDE) collaboration for the monitoring of carbon ion treatments at the CNAO facility (Centro Nazionale di Adroterapia Oncologica) exploiting the detection of charged secondary fragments that escape from the patient. The DP capability to detect inter-fractional changes is demonstrated by comparing the obtained fragment emission maps in different fractions of the treatments enrolled in the first ever clinical trial of such a monitoring system, performed at CNAO. The case of a CNAO patient that underwent a significant morphological change is presented in detail, focusing on the implications that can be drawn for the achievable inter-fractional monitoring DP sensitivity in real clinical conditions. The results have been cross-checked against a simulation study.