Risk Evaluation of Proton Pump Inhibitors for Panitumumab-Related Hypomagnesemia in Patients with Metastatic Colorectal Cancer.

Hypomagnesemia commonly occurs as a side effect of panitumumab treatment. In severe cases, temporary discontinuation or dose reduction of panitumumab may be necessary. Proton pump inhibitors (PPIs) are reportedly potential risk factors for hypomagnesemia. We conducted a multicenter study to assess the impact of PPIs on the risk of grade 3-4 hypomagnesemia in patients with metastatic colorectal cancer (mCRC) receiving panitumumab. We adjusted for potential bias using a propensity score-matched analysis and retrospectively reviewed the medical records of patients. Hypomagnesemia severity was graded according to the Common Terminology Criteria for Adverse Events, version 5.0. A total of 165 patients were enrolled in this study. The incidence of grade 3-4 hypomagnesemia was significantly higher in the PPI group than in the non-PPI group, both before (20.0% [30/60] vs. 8.0% [8/105], p = 0.026) and after propensity score matching (16.2% [6/37] vs. 0% [0/37], p = 0.025). In the propensity score-matched cohort, the risk of grade 3-4 hypomagnesemia was significantly higher in the PPI group (odds ratio, 2.19; 95% confidence interval, 1.69-2.84; p = 0.025). These findings suggest that concomitant use of PPIs significantly increases the risk of grade 3-4 hypomagnesemia in patients with mCRC receiving panitumumab. Therefore, close monitoring of these patients is imperative.

Synergistic antibacterial effect of copper and silver nanoparticles and their mechanism of action.

Bacterial infections are one of the leading causes of death worldwide. In the case of topical bacterial infections such as wound infections, silver (Ag) has historically been one of the most widely used antibacterials. However, scientific publications have demonstrated the adverse effects of silver on human cells, ecotoxicity and insufficient antibacterial effect for the complete elimination of bacterial infections. The use of Ag in the form of nanoparticles (NPs, 1-100 nm) allows to control the release of antibacterial Ag ions but is still not sufficient to eliminate infection and avoid cytotoxicity. In this study, we tested the potency of differently functionalized copper oxide (CuO) NPs to enhance the antibacterial properties of Ag NPs. The antibacterial effect of the mixture of CuO NPs (CuO, CuO-NH2 and CuO-COOH NPs) with Ag NPs (uncoated and coated) was studied. CuO and Ag NP combinations were more efficient than Cu or Ag (NPs) alone against a wide range of bacteria, including antibiotic-resistant strains such as gram-negative Escherichia coli and Pseudomonas aeruginosa as well as gram-positive Staphylococcus aureus, Enterococcus faecalis and Streptococcus dysgalactiae. We showed that positively charged CuO NPs enhanced the antibacterial effect of Ag NPs up to 6 times. Notably, compared to the synergy of CuO and Ag NPs, the synergy of respective metal ions was low, suggesting that NP surface is required for the enhanced antibacterial effect. We also studied the mechanisms of synergy and showed that the production of Cu+ ions, faster dissolution of Ag+ from Ag NPs and lower binding of Ag+ by proteins of the incubation media in the presence of Cu2+ were the main mechanisms of the synergy. In summary, CuO and Ag NP combinations allowed increasing the antibacterial effect up to 6 times. Thus, using CuO and Ag NP combinations enables to retain excellent antibacterial effects due to Ag and synergy and enhances beneficial effects, since Cu is a vital microelement for human cells. Thus, we suggest using combinations of Ag and CuO NPs in antibacterial materials, such as wound care products, to increase the antibacterial effect of Ag, improve safety and prevent and cure topical bacterial infections.

Antibacterial and Antiviral Effects of Ag, Cu and Zn Metals, Respective Nanoparticles and Filter Materials Thereof against Coronavirus SARS-CoV-2 and Influenza A Virus.

Due to the high prevalence of infectious diseases and their concurrent outbreaks, there is a high interest in developing novel materials with antimicrobial properties. Antibacterial and antiviral properties of a range of metal-based nanoparticles (NPs) are a promising means to fight airborne diseases caused by viruses and bacteria. The aim of this study was to test antimicrobial metals and metal-based nanoparticles efficacy against three viruses, namely influenza A virus (H1N1; A/WSN/1933) and coronaviruses TGEV and SARS-CoV-2; and two bacteria, Escherichia coli and Staphylococcus aureus. The efficacy of ZnO, CuO, and Ag NPs and their respective metal salts, i.e., ZnSO4, CuSO4, and AgNO3, was evaluated in suspensions, and the compounds with the highest antiviral efficacy were chosen for incorporation into fibers of cellulose acetate (CA), using electrospinning to produce filter materials for face masks. Among the tested compounds, CuSO4 demonstrated the highest efficacy against influenza A virus and SARS-CoV-2 (1 h IC50 1.395 mg/L and 0.45 mg/L, respectively), followed by Zn salt and Ag salt. Therefore, Cu compounds were selected for incorporation into CA fibers to produce antiviral and antibacterial filter materials for face masks. CA fibers comprising CuSO4 decreased SARS-CoV-2 titer by 0.38 logarithms and influenza A virus titer by 1.08 logarithms after 5 min of contact; after 1 h of contact, SARS-COV-2 virus was completely inactivated. Developed CuO- and CuSO4-based filter materials also efficiently inactivated the bacteria Escherichia coli and Staphylococcus aureus. The metal NPs and respective metal salts were potent antibacterial and antiviral compounds that were successfully incorporated into the filter materials of face masks. New antibacterial and antiviral materials developed and characterized in this study are crucial in the context of the ongoing SARS-CoV-2 pandemic and beyond.

Comparison of "click-to-sense" assay with frozen section analysis using simulated surgical margins in breast cancer patients.

PURPOSE: We have shown that "Click-to-sense" (CTS) assay based on the visualization of cancer cells by fluorescence probe targeted for acrolein is useful for differentiating between the malignant and benign lesions of the breast. In the present study, we aimed to apply CTS assay to the examination of the simulated surgical margins, being compared with frozen section (FS) analysis. EXPERIMENTAL DESIGN: The simulated surgical margin samples (n = 300) were obtained from 1 to 2 cm distant sites from the tumor margin in the mastectomy specimens of breast cancer patients, and divided into the training (n = 150) and validation (n = 150) set. The samples were subjected to CTS assay, subsequently to FS analysis and finally to permanent section (PS) analysis. RESULTS: Diagnostic accuracy of the CTS assay and FS analysis was evaluated in the examination of the simulated surgical margin status finally determined by the PS analysis. In the training set, sensitivity, specificity, and accuracy was 89.3%, 98.4%, and 96.7% for the CTS assay and 89.3%, 98.4%, and 96.7% for the FS analysis. In the validation set, sensitivity, specificity, and accuracy was 93.3%, 98.3%, and 97.3% for the CTS assay, and 93.3%, 99.2%, and 98.0% for the FS analysis. CONCLUSIONS: The CTS assay is as accurate as the FS analysis in the examination of the simulated surgical margins in breast cancer patients, and it seems to have a potential to replace the FS analysis for the intra-operative examination of surgical margins in breast-conserving surgery since it is less labor-intensive and more time-saving than the FS analysis.

Cubic Iron Core-Shell Nanoparticles Functionalized to Obtain High-Performance MRI Contrast Agents.

Nanoparticles with SiO2 coating were synthesized to have a cubic iron core. These were found to have saturation magnetization very close to the highest possible value of any iron-containing nanoparticles and the bulk iron saturation magnetization. The in vitro toxicology studies show that they are highly biocompatible and possess better MRI contrast agent potential than iron oxide NPs.

Detailed exploration of pathophysiology involving inflammatory status and bleeding symptoms between lipopolysaccharide- and tissue factor-induced disseminated intravascular coagulation in rats.

Lipopolysaccharide (LPS) and tissue factor (TF) have frequently been used to induce disseminated intravascular coagulation (DIC) in experimental animal models. We have previously reported that the pathophysiology of DIC differs according to the inducing agents. However, inflammatory status and bleeding symptoms have not been fully compared between rat models of the two forms of DIC. We attempted to evaluate detailed characteristic features of LPS- and TF-induced DIC models, especially in regard to inflammatory status and bleeding symptoms, in addition to selected hemostatic parameters and pathologic findings in the kidneys. The degree of hemostatic activation in both types of experimental DIC was identical, based on the results of thrombin-antithrombin complex levels. Markedly elevated tumor necrosis factor, interleukin-6, and high-mobility group box-1 concentrations were observed with severe organ dysfunction and marked fibrin deposition in the kidney on administration of LPS, whereas markedly elevated D-dimer concentration and bleeding symptoms were observed with TF administration. Pathophysiology such as fibrinolytic activity, organ dysfunction, inflammation status, and bleeding symptom differed markedly between LPS- and TF-induced DIC models in rats. We, therefore, recommend that these disease models be assessed carefully as distinct entities to determine the implications of their experimental and clinical use.

Colitis induced by Lenvatinib in a patient with advanced hepatocellular carcinoma.

Lenvatinib is a standard molecular targeted agent for the first-line treatment of unresectable hepatocellular carcinoma. Here, we report a case of colitis induced by Lenvatinib treatment in a patient with hepatocellular carcinoma. A 78-year-old man previously treated with Lenvatinib for unresectable hepatocellular carcinoma was admitted to our hospital complaining of right lateral abdominal pain without diarrhea. Our endoscopic findings showed multiple ulcers and erosions on his ascending colon, and he was diagnosed with colitis induced by Lenvatinib treatment. After the discontinuation of Lenvatinib, his colitis improved, and he resumed Lenvatinib at a lower dose. Colitis is a rare adverse event of Lenvatinib, and this is the first detailed report of colitis induced by Lenvatinib with endoscopic findings.

Docetaxel-induced fluid retention during adjuvant chemotherapy with S-1 plus docetaxel.

S-1 plus docetaxel is the standard postoperative adjuvant chemotherapy regimen for patients with stage III gastric cancer in Japan, which has increased the use of docetaxel. One of the most common adverse events of docetaxel, which is widely used to treat several malignancies, is fluid retention. Conversely, the most worrisome cause of ascites in patients who receive adjuvant chemotherapy is recurrence. Sometimes, the differential diagnosis of ascites is difficult if ascitic cytology is negative. In this study, we presented the case of a patient with massive ascites that appeared during adjuvant chemotherapy with S-1 plus docetaxel.

Surface carboxylation or PEGylation decreases CuO nanoparticles' cytotoxicity to human cells in vitro without compromising their antibacterial properties.

Clinical use of CuO nanoparticles (NPs) as antibacterials can be hampered by their toxicity to human cells. We hypothesized that certain surface functionalizations of CuO NPs may render NPs toxic to bacteria, but still be relatively harmless to human cells. To control this hypothesis, the toxicity of differently functionalized CuO NPs to bacteria Escherichia coli vs human cells (THP-1 macrophages and HACAT keratinocytes) was compared using similar conditions and end points. CuO NPs functionalized with polyethylene glycol (CuO-PEG), carboxyl (CuO-COOH, anionic), ammonium (CuO-NH4+, cationic) and unfunctionalized CuO NPs and CuSO4 (controls) were tested. In general, the toxicity of Cu compounds decreased in the following order: CuO-NH4+ > unfunctionalized CuO > CuSO4 > CuO-COOH > CuO-PEG. Positively charged unfunctionalized CuO and especially CuO-NH4+ proved most toxic (24-h EC50 = 21.7-47 mg/l) and had comparable toxicity to bacterial and mammalian cells. The multivariate analysis revealed that toxicity of these NPs was mostly attributed to their positive zeta potential, small hydrodynamic size, high Cu dissolution, and induction of reactive oxygen species (ROS) and TNF-α. In contrast, CuO-COOH and CuO-PEG NPs had lower toxicity to human cells compared to bacteria despite efficient uptake of these NPs by human cells. In addition, these NPs did not induce TNF-α and ROS. Thus, by varying the NP functionalization and Cu form (soluble salt vs NPs), it was possible to "target" the toxicity of Cu compounds, whereas carboxylation and PEGylation rendered CuO NPs that were more toxic to bacteria than to human cells envisaging their use in medical antibacterial products.

Antimicrobial potency of differently coated 10 and 50 nm silver nanoparticles against clinically relevant bacteria Escherichia coli and Staphylococcus aureus.

Silver nanoparticles (nanoAg) are effective antimicrobials and promising alternatives to traditional antibiotics. This study aimed at evaluating potency of different nanoAg against healthcare infections associated bacteria: Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus. A library of differently coated nanoAg of two different sizes (10 and 50 nm) were prepared using coating agents poly-L-Lysine (PLL), cetyltrimethyl-ammonium bromide (CTAB), citrate (CIT), polyvinyl-pyrrolidone (PVP), polysorbate 80 (Tween 80), and dioctyl-sodium sulfosuccinate (AOT). Stability evaluation by means of agglomeration and dissolution behaviour was performed for all nanoAg under conditions relevant for this study. Antibacterial properties of nanoAg were addressed by determining their minimal bactericidal concentrations (MBC) in deionised (DI) water to minimise the influence of silver speciation on its bioavailability. In parallel, AgNO3 was analysed as an ionic control. Studied nanoAg were efficient antimicrobials being remarkably more potent towards E. coli than to S. aureus (4 h MBC values for different nanoAg ranged from 0.08 to 5.0 mg Ag/L and 1.0-10 mg Ag/L, respectively). The toxicity of all nanoAg to S. aureus (but not to E. coli) increased with exposure time (4 h vs 24 h). 10 nm sized nanoAg released more Ag-ions and were more toxic than 50 nm nanoAg. Coating-dependent toxicity was more prominent for 50 nm nanoAg coated with Tween 80 or CTAB rendering the least toxic nanoAg. Obtained results showed that the antimicrobial effects of nanoAg were driven by shed Ag-ions, depended on target bacteria, exposure time and were the interplay of NP size, solubility and surface coating.

Antimicrobial Activity of Polyoxometalate Ionic Liquids against Clinically Relevant Pathogens.

The activity of a new class of antimicrobials-polyoxometalate ionic liquids (POM-ILs)-is systematically investigated. The prototype POM-ILs feature Keggin-type anions (α-SiW11 O39 8- ) and tetraalkylammonium ions as active cationic species. Antimicrobial tests of the POM-ILs against important human pathogens show that variation of the alkyl chain length of the cation leads to significant changes in antimicrobial activity against the medically relevant Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, and especially against the Gram-positive Staphylococcus aureus. Owing to the unique materials properties of the POM-ILs, such as high viscosity and water immiscibility, applications of antimicrobial surface coatings against airborne pathogens or for water decontamination can be envisaged. Furthermore, the combination of antimicrobially active cations with POM anions might afford new POM-ILs with two active components.

Solubility-driven toxicity of CuO nanoparticles to Caco2 cells and Escherichia coli: Effect of sonication energy and test environment.

Due to small size and high surface energy nanoparticles (NPs) tend to agglomerate and precipitate. To avoid/diminish that, sonication of NPs stock suspensions prior toxicity testing is often applied. Currently, there is no standardized particle sonication protocol available leading to inconsistent toxicity data, especially if toxicity is driven by NPs' dissolution that may be enhanced by sonication. In this study we addressed the effect of sonication on hydrodynamic size (Dh), dissolution and toxicity of copper oxide (CuO) NPs to mammalian cell line Caco-2 in vitro and bacteria Escherichia coli in the respective test environments (cell culture MEM medium, bacterial LB medium and deionised (DI) water). NPs were suspended using no sonication, water bath and probe sonication with different energy intensities. Increased sonication energy (i) decreased the Dh of CuO NPs in all three test environments; (ii) increased dissolution of NPs in MEM medium and their toxicity to Caco-2; (iii) increased dissolution of NPs in LB medium and their bioavailability to E. coli; and (iv) had no effect on dissolution and antibacterial effects of NPs in DI water. Thus, to reduce variations in dissolution and toxicity, we recommend sonication of NPs in DI water following the dilution into suitable test media.

Antibodies to Lactobacilli and Bifidobacteria in young children with different propensity to develop islet autoimmunity.

The intestinal microbiota is essential to the maturation and homeostasis of the immune system. Immunoblot assays were used to establish the prevalence of serum IgG, IgM, and IgA antibodies specific for Bifidobacterium adolescentis, Bifidobacterium longum, and Lactobacillus rhamnosus GG proteins in young children presenting with or without type 1 diabetes (T1D). We demonstrated that children between the ages of 6 and 12 months had a substantial increase in the frequency of IgG antibodies specific for L. rhamnosus GG proteins. We measured IgG, IgM, and IgA class antibody reactivity against B. adolescentis DSM 20083, B. adolescentis DSM 20086, and B. longum DSM 20088 proteins demonstrating significantly higher IgA responses against B. adolescentis DSM 20083 strain proteins in children who developed islet autoimmunity and T1D later in life. B. adolescentis strains showed more IgM type antibodies in children who developed T1D later in life, but the difference was not statistically significant. B. longum proteins were recognized by IgG and IgA antibodies to a higher extent compared to other bacteria studied. These results confirm that differences in immune reactivity against some commensal strains in young children may represent a different risk factor for developing T1D.

Comparison of serum exosome isolation methods for microRNA profiling.

OBJECTIVES: Exosomes are small membrane bound vesicles secreted by most cell types. Exosomes contain various functional proteins, mRNAs and microRNAs (miRNAs) that could be used for diagnostic and therapeutic purposes. Currently, a standard method for serum exosome isolation is differential ultracentrifugation, but a search for alternative, less time-consuming and labour extensive exosomal isolation method for use in clinical settings is ongoing. The effect of serum exosome isolation method on obtained miRNA profile is not yet clear. The aim of this study was to determine to which extent selected exosome isolation methods influence the serum exosomal miRNA profile. DESIGN AND METHODS: Exosomes were isolated from blood serum of healthy individuals by ultracentrifugation and ExoQuick Precipitation methods. The expression profile of 375 miRNAs was determined by real time PCR using Exiqon miRCURY LNA™ microRNA Human panel I assays. RESULTS: Although a strong correlation of exosomal miRNA profiles was observed between the two isolation methods, distinct clusters of miRNA levels between the used methods were identified. The detected levels of two miRNAs, miR-92a and miR-486-5p, were significantly influenced by the exosome isolation method used. CONCLUSIONS: Both exosome isolation methods are suitable for serum exosomal miRNA profiling. Differences found in miRNA patterns between the two methods indicate that the observed exosomal miRNA profile is slightly affected by the extracellular vesicle isolation method.

[Combination chemotherapy of docetaxel and UFT against hormone refractory prostate cancer].

Docetaxel-based chemotherapy has been shown to be effective and well tolerated by Japanese patients with metastatic hormone-refractory prostate cancer (HRPC). This study was undertaken to assess the feasibility of docetaxel in combination with UFT (a combination of tegafur and uracil) in Japanese patients with HRPC. Ten patients aged 60-86 years with HRPC, who were pre-treated with hormonal therapy and expected to have more than 3 month survival and without major organ dysfunction, were included in this study. Treatment consisted of docetaxel 70 mg/m2 every 3 weeks plus UFT 260 mg/m2 /day. The primary end point was prostate-specific antigen (PSA) response, and the secondary end points included progression-free survival and toxicity. Nine patients were evaluable for efficacy and toxicity. The PSA response rate was 50% (1 CR and 4 PR). The most common non-hematological adverse events (of any grade) possibly related to treatment were neutropenia and anorexia. Grade 3/4 neutropenia and anorexia occurred in 50 and 20% of patients, respectively. The combination of docetaxel and UFT was feasible and active in Japanese patients with HRPC, with a manageable adverse-event profile similar to that observed in lung cancer chemotherapy.

Immunoglobulin preparations attenuate organ dysfunction and hemostatic abnormality by suppressing the production of cytokines in lipopolysaccharide-induced disseminated intravascular coagulation in rats.

OBJECTIVE: We attempted to clarify the effect of immunoglobulin concentrates on the rat lipopolysaccharide (LPS)-induced disseminated intravascular coagulation (DIC) model. DESIGN: Prospective, comparative, experimental study. SETTING: Laboratory at a university hospital. SUBJECTS: Male Wistar rats, aged 6 to 7 wks and weighing 160 to 170 g. INTERVENTIONS: Two kinds of experiments were performed. In the first, experimental DIC was induced by sustained infusion of 30 mg/kg LPS for 4 hrs via the tail vein, and two doses of immunoglobulin (25 or 100 mg/kg/4.5 hrs) were administered to rats 30 mins before infusion of LPS, after which immunoglobulin infusion was continued for a further 4 hrs. In the second, experimental DIC was induced by sustained infusion (5 mg/kg/1 hr) of LPS for 1 hr, and one dose of immunoglobulin (100 mg/kg/4 hrs) was administered to rats after LPS induction. The parameters were estimated at 4 hrs and 8 hrs in the first experiment and at 1, 5, and 10 hrs in the second one. MEASUREMENT AND MAIN RESULTS: Similar results were observed in the two experiments. Consumption coagulopathy and hemostatic activation were attenuated, especially when immunoglobulin was administered before LPS infusion. Plasma levels of creatinine and alanine aminotransferase were significantly depressed by coadministration of immunoglobulin. Marked glomerular fibrin deposition was observed in the LPS-induced DIC model, but this deposition was reduced by immunoglobulin. In the first stage of the experiment, plasma levels of tumor necrosis factor (TNF) and interleukin (IL)-6 were suppressed by coadministration of immunoglobulin. In the second, plasma levels of IL-6 were significantly suppressed by immunoglobulin. CONCLUSION: It was concluded that plasma levels of TNF and IL-6 could be significantly suppressed by immunoglobulin in the LPS-induced DIC model. Moreover, hemostatic abnormality, organ dysfunction, and glomerular fibrin deposition in this model were all ameliorated by immunoglobulin.