Protecting the Antibacterial Coating of Urinal Catheters for Improving Safety.

Catheter-associated urinary tract infections (CAUTI) are among the most common bacterial infections associated with prolonged hospitalization and increased healthcare expenditures. Despite recent advances in the prevention and treatment of these infections, there are still many challenges remaining, among them the creation of a durable catheter coating, which prevents bacterial biofilm formation. The current work reports on a method of protecting medical tubing endowed with antibiofilm properties. Silicone catheters coated sonochemically with ZnO nanoparticles (NPs) demonstrated excellent antibiofilm effects. Toward approval by the European Medicines Agency, it was realized that the ZnO coating would not withstand the regulatory requirements of avoiding dissolution for 14 days in artificial urine examination. Namely, after exposure to urine for 14 days, the coating amount was reduced by 90%. Additional coatings with either carbon or silica maintained antibiofilm activity against Staphylococcus aureus while resisting dissolution in artificial urine for 14 days (C- or SiO2-protected catheters exhibited only 29% reduction). HR-SEM images of the protected catheters indicate the presence of the ZnO coating as well as the protective layer. Antibiofilm activity of all catheters was evaluated both before and after exposure to artificial urine. It was shown that before artificial urine exposure, all coated catheters showed high antibiofilm properties compared to the uncoated control. Exposure of ZnO-coated catheters, without the protective layer, to artificial urine had a significant effect exhibited by the decrease in antibiofilm activity by almost 2 orders of magnitude, compared to unexposed catheters. Toxicity studies performed using a reconstructed human epidermis demonstrated the safety of the improved coating. Exposure of the epidermis to ZnO catheter extracts in artificial urine affects tissue viability compared with control samples, which was not observed in the case of ZnO NPs coating with SiO2 or C. We suggest that silica and carbon coatings confer some protection against zinc ions release, improving ZnO coating safety.

'Secondary' acute lymphoblastic/lymphocytic leukemia - done playing second fiddle?

Acute lymphoblastic/lymphocytic leukemia (ALL) occurring post-cancer diagnosis (secondary ALL - sALL) is increasingly recognized as a discrete entity, constituting up to as much as 5-10% of all new ALL diagnoses, and carrying its own biologic, prognostic and therapeutic significance. In this review, we will outline the history and current state of research into sALL. We will explore the evidence for differences underlining its existence as a distinct subgroup, as well as examining what might be driving such differences etiologically, including prior chemotherapy. We will examine these distinctions on population-, chromosomal-, and molecular-levels, and we will consider whether they translate to differences in clinical outcome, and whether they do - or should - warrant differences in treatment selection.

Antibacterial Properties and Mechanisms of Action of Sonoenzymatically Synthesized Lignin-Based Nanoparticles.

In recent years, lignin has drawn increasing attention for different applications due to its intrinsic antibacterial and antioxidant properties, coupled with biodegradability and biocompatibility. However, chemical modification or combination with metals is usually required to increase its antimicrobial functionality and produce biobased added-value materials for applications wherein bacterial growth should be avoided, such as biomedical and food industries. In this work, a sonoenzymatic approach for the simultaneous functionalization and nanotransformation of lignin to prepare metal-free antibacterial phenolated lignin nanoparticles (PheLigNPs) is developed. The grafting of tannic acid, a natural phenolic compound, onto lignin was achieved by an environmentally friendly approach using laccase oxidation upon the application of high-intensity ultrasound to rearrange lignin into NPs. PheLigNPs presented higher antibacterial activity than nonfunctionalized LigNPs and phenolated lignin in the bulk form, indicating the contribution of both the phenolic content and the nanosize to the antibacterial activity. Studies on the antibacterial mode of action showed that bacteria in contact with the functionalized NPs presented decreased metabolic activity and high levels of reactive oxygen species (ROS). Moreover, PheLigNPs demonstrated affinity to the bacterial surface and the ability to cause membrane destabilization. Antimicrobial resistance studies showed that the NPs did not induce resistance in pathogenic bacteria, unlike traditional antibiotics.

Cuprous Oxide Nanoparticles Decorated Fabric Materials with Anti-biofilm Properties.

Considering the global spread of bacterial infections, the development of anti-biofilm surfaces with high antimicrobial activities is highly desired. This work unraveled a simple, sonochemical method for coating Cu2O nanoparticles (NPs) on three different flexible substrates: polyester (PE), nylon 2 (N2), and polyethylene (PEL). The introduction of Cu2O NPs on these substrates enhanced their surface hydrophobicity, induced ROS generation, and completely inhibited the growth of sensitive (Escherichia coli and Staphyloccocus aureus) and drug-resistant (MDR E. coli and MRSA) planktonic and biofilm. The experimental results confirmed that Cu2O-PE exhibited complete biofilm mass reduction ability for all four strains, whereas Cu2O-N2 showed more than 99% biomass inhibition against both drug-resistant and sensitive pathogens in 6 h. Moreover, Cu2O-PEL also indicated a 99.95, 97.73, 98.00, and 99.20% biomass reduction of MRSA, MDR E. coli, E. coli, and S. aureus, respectively. All substrates were investigated for time-dependent inhibitions, and the associated biofilm mass and log reduction were evaluated. The mechanisms of Cu2O NP action against the mature biofilms include the generation of reactive oxygen species (ROS) as well as electrostatic interaction between Cu2O NPs and bacterial membranes. The current study could pave the way for the commercialization of sonochemically coated Cu2O NP flexible substrates for the prevention of microbial contamination in hospitals and industrial environments.

Antibacterial, Antibiofilm, and Antiviral Farnesol-Containing Nanoparticles Prevent Staphylococcus aureus from Drug Resistance Development.

Multidrug antimicrobial resistance is a constantly growing health care issue associated with increased mortality and morbidity, and huge financial burden. Bacteria frequently form biofilm communities responsible for numerous persistent infections resistant to conventional antibiotics. Herein, novel nanoparticles (NPs) loaded with the natural bactericide farnesol (FSL NPs) are generated using high-intensity ultrasound. The nanoformulation of farnesol improved its antibacterial properties and demonstrated complete eradication of Staphylococcus aureus within less than 3 h, without inducing resistance development, and was able to 100% inhibit the establishment of a drug-resistant S. aureus biofilm. These antibiotic-free nano-antimicrobials also reduced the mature biofilm at a very low concentration of the active agent. In addition to the outstanding antibacterial properties, the engineered nano-entities demonstrated strong antiviral properties and inhibited the spike proteins of SARS-CoV-2 by up to 83%. The novel FSL NPs did not cause skin tissue irritation and did not induce the secretion of anti-inflammatory cytokines in a 3D skin tissue model. These results support the potential of these bio-based nano-actives to replace the existing antibiotics and they may be used for the development of topical pharmaceutic products for controlling microbial skin infections, without inducing resistance development.

Immunoglobulin repletion during blinatumomab therapy does not reduce the rate of secondary hypogammaglobulinemia and associated infectious risk.

Background: Blinatumomab has demonstrated efficacy in minimal residual disease (MRD) positive and relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) by inciting rapid and sustained B-cell depletion. Methods: Owing to its effect on B-cells, blinatumomab is associated with a higher rate of secondary hypogammaglobulinemia compared to chemotherapy. To mitigate blinatumomab-induced hypogammaglobulinemia, patients were pre-emptively repleted with intravenous immune globulin (IVIG) during blinatumomab therapy. In this retrospective study, we compared outcomes of 23 blinatumomab treated adults with ALL. Seventeen patients routinely received IVIG and 6 patients were in the control cohort. Results: Our findings demonstrated no difference between the two cohorts in immunoglobulin G (IgG) nadir (338 mg/dL vs. 337 mg/dL, P=0.641), days to IgG nadir (120.5 vs. 85.5 days, P=0.13), infection rate (82.4% vs. 66.7%, P=0.58), infections requiring ICU admission (23.5% vs. 16.7%, P=1), and infection related mortality (17.6% vs. 16.7%, P=1). Conclusion: Pre-emptive IVIG repletion during blinatumomab did not prevent hypogammaglobulinemia and associated infection risk.

An Engineered Nanocomplex with Photodynamic and Photothermal Synergistic Properties for Cancer Treatment.

Photodynamic therapy (PDT) and photothermal therapy (PTT) are promising therapeutic methods for cancer treatment; however, as single modality therapies, either PDT or PTT is still limited in its success rate. A dual application of both PDT and PTT, in a combined protocol, has gained immense interest. In this study, gold nanoparticles (AuNPs) were conjugated with a PDT agent, meso-tetrahydroxyphenylchlorin (mTHPC) photosensitizer, designed as nanotherapeutic agents that can activate a dual photodynamic/photothermal therapy in SH-SY5Y human neuroblastoma cells. The AuNP-mTHPC complex is biocompatible, soluble, and photostable. PDT efficiency is high because of immediate reactive oxygen species (ROS) production upon mTHPC activation by the 650-nm laser, which decreased mitochondrial membrane potential (∆ψm). Likewise, the AuNP-mTHPC complex is used as a photoabsorbing (PTA) agent for PTT, due to efficient plasmon absorption and excellent photothermal conversion characteristics of AuNPs under laser irradiation at 532 nm. Under the laser irradiation of a PDT/PTT combination, a twofold phototoxicity outcome follows, compared to PDT-only or PTT-only treatment. This indicates that PDT and PTT have synergistic effects together as a combined therapeutic method. Our study aimed at applying the AuNP-mTHPC approach as a potential treatment of cancer in the biomedical field.

PD-1 inhibition in advanced myeloproliferative neoplasms.

Myelofibrosis (MF) is a clonal stem cell neoplasm characterized by abnormal JAK-STAT signaling, chronic inflammation, cytopenias, and risk of transformation to acute leukemia. Despite improvements in the therapeutic options for patients with MF, allogeneic hematopoietic stem cell transplantation remains the only curative treatment. We previously demonstrated multiple immunosuppressive mechanisms in patients with MF, including increased expression of programmed cell death protein 1 (PD-1) on T cells compared with healthy controls. Therefore, we conducted a multicenter, open-label, phase 2, single-arm study of pembrolizumab in patients with Dynamic International Prognostic Scoring System category of intermediate-2 or greater primary, post-essential thrombocythemia or post-polycythemia vera myelofibrosis that were ineligible for or were previously treated with ruxolitinib. The study followed a Simon 2-stage design and enrolled a total of 10 patients, 5 of whom had JAK2V617mutation, 2 had CALR mutation, and 6 had additional mutations. Most patients were previously treated with ruxolitinib. Pembrolizumab treatment was well tolerated, but there were no objective clinical responses, so the study closed after the first stage was completed. However, immune profiling by flow cytometry, T-cell receptor sequencing, and plasma proteomics demonstrated changes in the immune milieu of patients, which suggested improved T-cell responses that can potentially favor antitumor immunity. The fact that these changes were not reflected in a clinical response strongly suggests that combination immunotherapeutic approaches rather than monotherapy may be necessary to reverse the multifactorial mechanisms of immune suppression in myeloproliferative neoplasms. This trial was registered at www.clinicaltrials.gov as #NCT03065400.

Fluorine-Free Superhydrophobic Coating with Antibiofilm Properties Based on Pickering Emulsion Templating.

This study presents antibiofilm coating formulations based on Pickering emulsion templating. The coating contains no bioactive material because its antibiofilm properties stem from passive mechanisms that derive solely from the superhydrophobic nature of the coating. Moreover, unlike most of the superhydrophobic formulations, our system is fluorine-free, thus making the method eminently suitable for food and medical applications. The coating formulation is based on water in toluene or xylene emulsions that are stabilized using commercial hydrophobic silica, with polydimethylsiloxane (PDMS) dissolved in toluene or xylene. The structure of the emulsions and their stability was characterized by confocal microscopy and cryogenic-scanning electron microscopy (cryo-SEM). The most stable emulsions are applied on polypropylene (PP) surfaces and dried in an oven to form PDMS/silica coatings in a process called emulsion templating. The structure of the resulting coatings was investigated by atomic force microscopy (AFM) and SEM. The surface of the coatings shows a honeycomb-like structure that exhibits a combination of micron-scale and nanoscale roughness, which endows it with its superhydrophobic properties. After tuning, the superhydrophobic properties of the coatings demonstrated highly efficient passive antibiofilm activity. In vitro antibiofilm trials with E. coli indicate that the coatings reduced the biofilm accumulation by 83% in the xylene-water-based surfaces and by 59% in the case of toluene-water-based surfaces.

Multimodal single-cell analysis of cutaneous T-cell lymphoma reveals distinct subclonal tissue-dependent signatures.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of mature T-cell neoplasms characterized by the accumulation of clonal malignant CD4+ T cells in the skin. The most common variant of CTCL, mycosis fungoides (MF ), is confined to the skin in early stages but can be accompanied by extracutaneous dissemination of malignant T cells to the blood and lymph nodes in advanced stages of disease. Sézary syndrome (SS), a leukemic form of disease, is characterized by significant blood involvement. Little is known about the transcriptional and genomic relationship between skin- and blood-residing malignant T cells in CTCL. To identify and interrogate malignant clones in matched skin and blood from patients with leukemic MF and SS, we combine T-cell receptor clonotyping with quantification of gene expression and cell surface markers at the single cell level. Our data reveal clonal evolution at a transcriptional and genetic level within the malignant populations of individual patients. We highlight highly consistent transcriptional signatures delineating skin- and blood-derived malignant T cells. Analysis of these 2 populations suggests that environmental cues, along with genetic aberrations, contribute to transcriptional profiles of malignant T cells. Our findings indicate that the skin microenvironment in CTCL promotes a transcriptional response supporting rapid malignant expansion, as opposed to the quiescent state observed in the blood, potentially influencing efficacy of therapies. These results provide insight into tissue-specific characteristics of cancerous cells and underscore the need to address the patients' individual malignant profiles at the time of therapy to eliminate all subclones.

Safety and Efficacy: Clinical Experience of Venetoclax in Combination With Hypomethylating Agents in Both Newly Diagnosed and Relapsed/Refractory Advanced Myeloid Malignancies.

Hypomethylating agents (HMAs) in combination with venetoclax have been widely adopted as the standard of care for patients who cannot tolerate induction chemotherapy and for patients who have relapsed/refractory (R/R) acute myeloid leukemia (AML). This study retrospectively analyzed the outcomes of all patients with AML (n = 65) or myelodysplastic syndrome (n = 7) who received the combination of HMA and venetoclax at our institution. Outcomes measured included complete remission (CR) and CR with incomplete hematologic recovery (CRi) rates, duration of response (DOR), and overall survival (OS). Patient mutational profiles and transfusion requirements were also assessed. Of 26 newly diagnosed AML patients, the CR/CRi rate was 53.8%. The median DOR and OS were 6.9 months and not reached, respectively. Of 39 R/R AML patients, the CR/CRi rate was 38.5%. The median DOR and OS were both 8.1 months. Responders to HMA and venetoclax were enriched for TET2, IDH1, and IDH2 mutations, while nonresponders were associated with FLT3 and RAS mutations. Adaptive resistance was observed through various mechanisms including acquired RAS pathway mutations. Of transfusion-dependent patients, 12.2% and 15.2% achieved red blood cell (RBC) and platelet transfusion independence, respectively, while 44.8% and 35.1% of RBC and platelet transfusion independent patients, respectively, became transfusion dependent. In total 59.1% of patients developed a ≥grade 3 infection and 46.5% neutropenic fever. HMA + venetoclax can lead to impressive response rates with moderately durable remissions and survival. However, the benefits of this combination are diminished by the significant toxicities from infection, persistent cytopenias, and transfusion requirements.

Severe COVID-19 virus reactivation following treatment for B cell acute lymphoblastic leukemia.

SARS-CoV-2 has infected millions of people worldwide, but little is known at this time about second infections or reactivation. Here, we report a case of a 55-year-old female undergoing treatment for CD20+ B cell acute lymphoblastic leukemia who experienced a viral reactivation after receiving rituximab, cytarabine, and dasatinib. She was initially hospitalized with COVID-19 in April and developed a high antibody titer with two negative nasal polymerase chain reaction (PCR) swabs for SARS-CoV-2 on discharge. After recovery, she resumed treatment in June for her leukemia, which included rituximab, cytarabine, and dasatinib. She promptly lost her COVID-19 antibodies, and her nasal PCR turned positive in June. She developed a severe COVID-19 pneumonia with lymphopenia, high inflammatory markers, and characteristic bilateral ground-glass opacities on chest CT, requiring high-flow nasal cannula and transfer to the intensive care unit. She received steroids, anticoagulation, and convalescent plasma, and within 48 h she was off oxygen. She was discharged home in stable condition several days later. Given the short time frame from leukemia treatment to PCR positivity and the low case rate in mid-June in New York City, reinfection appears to have been unlikely and SARS-CoV-2 reactivation is a possible explanation. This case illustrates the risks of treating recently recovered COVID-19 patients with immunosuppressive therapy, particularly lymphocyte- and antibody-depleting therapy, and raises new questions about the potential of SARS-CoV-2 reactivation.

Developing strategies to reduce the duration of therapy for patients with myeloproliferative neoplasms.

INTRODUCTION: All current treatment strategies for myeloproliferative neoplasms (MPN) patients with the exception of allogeneic stem cell transplant (ASCT) are continuously administered. Treatment approaches that reduce the degree of minimal residual disease (MRD) might permit possible drug holidays or potential cures. AREA COVERED: Authors discuss the presently available agents and those that are under clinical development that might induce a state of MRD and can be administered intermittently. Data extracted from a comprehensive search of peer review literature performed in Pubmed as well as information presented in scientific meetings. EXPERT OPINION: Currently, the only potential curative treatment for MPN is ASCT. ASCT requires a period of intense treatment but ultimately allows the patient to enjoy a period independent of continued treatment. There is evidence that intermittent use of busulfan or prolonged use of IFN-α can induce hematological remissions that are sustained for prolonged periods of time, allowing for drug holidays. The experimental drug Imetelstat is a promising drug that has been reported to prolong survival in very high-risk myelofibrosis patients after a limited period of time of administration. New experimental drugs and drug combinations that target the malignant clone and/or microenvironmental abnormalities have the potential to eliminate MRD, which might allow for drug holidays and reduction in the duration of therapy.

Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts.

The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic. We summarise key changes related to service allocation, clinical and supportive care, clinical trial participation, and ethical considerations regarding the use of lifesaving measures for these patients. We recognise that these recommendations might be more applicable to high-income countries and might not be generalisable because of regional differences in health-care infrastructure, individual circumstances, and a complex and highly fluid health-care environment. Despite these limitations, we aim to provide a general framework for the care of patients with acute leukaemias and myeloid neoplasms during the COVID-19 pandemic on the basis of recommendations from international experts.

Prevention and Treatment of Pseudomonas Aeruginosa-Based Biofilm with Ethanol.

BACKGROUND: Although indwelling catheters are increasingly used in modern medicine, they can be a source of microbial contamination and hard-to-treat biofilms, which jeopardize patient lives. At times 70% ethanol is used as a catheter-lock solution due to its bactericidal properties. However, high concentrations of ethanol can result in adverse effects and in malfunction of the catheters. OBJECTIVES: To determine whether low concentrations of ethanol can prevent and treat biofilms of Pseudomonas aeruginosa. METHODS: Ethanol was tested at a concentration range of 0.625-80% against laboratory and clinical isolates of P. aeruginosa for various time periods (2-48 hours). The following parameters were evaluated following ethanol exposure: prevention of biofilm formation, reduction of biofilm metabolic activity, and inhibition of biofilm regrowth. RESULTS: Exposing P. aeruginosa to twofold ethanol gradients demonstrated a significant biofilm inhibition at concentrations as low as 2.5%. Treating pre-formed biofilms of P. aeruginosa with 20% ethanol for 4 hours caused a sharp decay in the metabolic activity of both the laboratory and clinical P. aeruginosa isolates. In addition, treating mature biofilms with 20% ethanol prevented the regrowth of bacteria encased within it. CONCLUSIONS: Low ethanol concentrations (2.5%) can prevent in vitro biofilm formation of P. aeruginosa. Treatment of previously formed biofilms can be achieved using 20% ethanol, thereby keeping the catheters intact and avoiding complications that can result from high ethanol concentrations.

JAKs to STATs: A tantalizing therapeutic target in acute myeloid leukemia.

The Janus Associated Kinase-Signal Transducers and Activators of Transcription (JAK-STAT) signaling pathway plays a pivotal role in hematopoietic growth factor signaling. Hyperactive JAK-STAT signaling is implicated in the pathogenesis of myeloid malignancies, including acute myeloid leukemia (AML). The significant headway in understanding the biology of AML has led to an explosion of novel therapeutics with mechanistic rationale for the treatment of newly diagnosed and relapsed/refractory (R/R) AML. Most importantly, selective targeting of the JAK-STAT pathway has proven to be an effective therapeutic strategy in myeloproliferative neoplasms and is also being evaluated in related myeloid malignancies, including AML. This comprehensive review will focus on the apparent and evolving potential of JAK-STAT pathway inhibition in AML with emphasis on JAK inhibitors, highlighting both success and failure with this experimental approach in the clinic, and identifying rationally based combinatorial approaches.

Small molecule-decorated gold nanoparticles for preparing antibiofilm fabrics.

The increase in antibiotic resistance reported worldwide poses an immediate threat to human health and highlights the need to find novel approaches to inhibit bacterial growth. In this study, we present a series of gold nanoparticles (Au NPs) capped by different N-heterocyclic molecules (N_Au NPs) which can serve as broad-spectrum antibacterial agents. Neither the Au NPs nor N-heterocyclic molecules were toxic to mammalian cells. These N_Au NPs can attach to the surface of bacteria and destroy the bacterial cell wall to induce cell death. Sonochemistry was used to coat Au NPs on the surface of fabrics, which showed superb antimicrobial activity against multi-drug resistant (MDR) bacteria as well as excellent efficacy in inhibiting bacterial biofilms produced by MDR bacteria. Our study provides a novel strategy for preventing the formation of MDR bacterial biofilms in a straightforward, low-cost, and efficient way, which holds promise for broad clinical applications.

Antibacterial Activity Against Methicillin-Resistant Staphylococcus aureus of Colloidal Polydopamine Prepared by Carbon Dot Stimulated Polymerization of Dopamine.

A simple one-step process for the polymerization of dopamine has been developed using nitrogen-doped carbon dots (N@C-dots) as the sole initiator. The synthesized amorphous polydopamine (PDA)-doped N@C-dots (PDA-N@C-dots composite) exhibited a negative charge of -39 mV with particle sizes ranging from 200 to 1700 nm. The stable colloidal solution was active against methicillin-resistant Staphylococcus aureus (MRSA), a Gram-negative bacterium. The strong adhesion of the polymer to the bacterial membrane resulted in a limited diffusion of nutrients and wastes in and out of the cell cytosol, which is a generic mechanism to trigger cell death. Another possible route is the autoxidation of the catechol moiety of PDA to form quinone and release reactive oxygen species (ROS) such as superoxide radicle and hydrogen peroxide, two well-known ROS with antimicrobial properties against both Gram-negative and Gram-positive bacteria.