Insufficient Efficacy Research Articles

Myoglobin-loaded gadolinium nanotexaphyrins for oxygen synergy and imaging-guided radiosensitization therapy

Gadolinium (Gd3+)-coordinated texaphyrin (Gd-Tex) is a promising radiosensitizer that entered clinical trials, but temporarily fails largely due to insufficient radiosensitization efficacy. Little attention has been given to using nanovesicles to improve its efficacy. Herein, Gd-Tex is transformed into building blocks “Gd-Tex-lipids” to self-assemble nanovesicles called Gd-nanotexaphyrins (Gd-NTs), realizing high density packing of Gd-Tex in a single nanovesicle and achieving high Gd-Tex accumulation in tumors. To elucidate the impact of O2 concentration on Gd-Tex radiosensitization, myoglobin (Mb) is loaded into Gd-NTs (Mb@Gd-NTs), resulting in efficient relief of tumor hypoxia and significant enhancement of Gd-Tex radiosensitization, eventually inducing the obvious long-term antitumor immune memory to inhibit tumor recurrence. In addition to Gd3+, the versatile Mb@Gd-NTs can also chelate 177Lu3+ (Mb@177Lu/Gd-NTs), enabling SPECT/MRI dual-modality imaging for accurately monitoring drug delivery in real-time. This “one-for-all” nanoplatform with the capability of chelating various trivalent metal ions exhibits broad clinical application prospects in imaging-guided radiosensitization therapy.

Variability of Measurement and Feasibility of Assessing Changes in Brachiocepahlic Atherosclerotic Plaque After Acute Coronary Syndrome.

Aim Analysis of inter- and intra-study variability of changes in the atherosclerotic plaque (ASP) total height and total area, the main quantitative indexes that were planned to be used in the present study for assessment of the atherosclerotic load of carotid arteries.Material and methods The incidence of recurrent cardiovascular complications (CVC) within 1 year after acute coronary syndrome (ACS) ranges from 7-9 % (in studies) to 34 % (in clinical practice). This indicates insufficient efficacy of traditional approaches to secondary prevention of coronary heart disease. We proposed a study to test a hypothesis that the dynamics of ASP parameters in carotid and subclavian regions can serve as an alternative criterion for the adequacy of secondary prevention after ACS. The analysis was performed on subgroups of main study participants. These patients had ACS of any type documented by coronary angiography with an ASP confirmed by ultrasound of the brachiocephalic arteries (BCA) during the index hospitalization. BCA ultrasound was performed to analyze the inter- and intra-study variability of BCA atherosclerotic load, the ASP total height (Hsum) and total area (ASPTA), in 20 and 24 patients of the main study, respectively. Results of the repeated ultrasound were evaluated in 30 patients of the main study after 6 months of follow-up.Results The inter-study variability of each index was significantly higher than the intra-study variability which was consistent with results of previous studies. The intra-study variability of Hsum was 0.10 (95 % confidence interval, CI - 0.23-0.44) mm and ASPTA, 1.05 (95 % CI, - 0.54-2.63) mm2. The variability values were considerably smaller than the changes for 6 months: Hsum, 0.92 (95 % CI, - 0.64-2.49) mm and ASPTA, 3.67 (95 % CI, 0.42-6.91) mm2, although the difference did not reach statistical significance. The above results were obtained at an early stage of the study during the adaptation of specialists to the protocol.Conclusion The study results suggest a possibility of a fairly reliable assessment of the dynamics of quantitative indexes of carotid ultrasound 6 months after ACS.

Multi-functional monodispersed SiO2–TiO2 core-shell nanostructure and TEOS in the consolidation of archaeological lime mortars surfaces

Archaeological traditional lime mortars are susceptible to many environmental conditions such as the impact of water (rain, humidity, groundwater, etc.), variation of temperatures' degrees, wind and/or pollution. Accordingly, this research aims to provide newly assessed multifunctional Nano-coating for the purpose of archaeological lime mortar protection. For this, the study combined physicochemical and mechanical characterizations in performance assessment of 3%, 5%, and 7% of the synthesized SiO2–TiO2 core-shell nanostructure and TEOS as consolidants on the surfaces of the experimental lime mortars. A series of techniques and tests were fulfilled for the evaluation. For analysis, X-ray diffraction and UV–Vis along with scanning electron microscopy were used to identify microstructure. Furthermore, wettability, colorimetric, self-cleaning, petrophysical, Nano-indentation, and uniaxial compressive strength tests were performed to select the most durable consolidant between 3%, 5%, and 7% SiO2–TiO2/TEOS. Durability assessments were carried out through salt weathering, thermal and UV aging tests. The results showed that 3% and 5% of SiO2–TiO2/TEOS enhanced the physical and mechanical properties of the lime mortars. On the other hand, 7% SiO2–TiO2/TEOS proved their insufficient efficacy in improving the surfaces of lime mortars for the high amount of TiO2 and its behavior for aggregation.

Red Light-Triggered Anti-Angiogenic and Photodynamic Combination Therapy of Age-Related Macular Degeneration.

Choroidal neovascularization (CNV) is the key pathological event of wet age-related macular degeneration (wAMD) leading to irreversible vision loss. Currently, anti-angiogenic therapy with anti-vascular endothelial growth factor (VEGF) agents has become the standard treatment for wAMD, while it is still subject to several limitations, including the safety concerns of monthly intravitreal administration and insufficient efficacy for neovascular occlusion. Combined therapy with photodynamic therapy (PDT) and anti-angiogenic agents has emerged as a novel treatment paradigm. Herein, a novel and less-invasive approach is reported to achieve anti-angiogenic and photodynamic combination therapy of wAMD by intravenous administration of a photoactivatable nanosystem (Di-DAS-VER NPs). The nanosystem is self-assembled by reactive oxygen species (ROS)-sensitive dasatinib (DAS) prodrug and photosensitizer verteporfin (VER). After red-light irradiation to the diseased eyes, intraocular release of anti-angiogenic DAS is observed, together with selective neo-vessels occlusion by VER-generated ROS. Notably, Di-DAS-VER NPs demonstrates promising therapeutic efficacy against CNV with minimized systemic toxicity. The study enables an efficient intravenous wAMD therapy by integrating a photoactivation process with combinational therapeutics into one simple nanosystem.

Resolution of the Expert council “Unsolved problems of targeted therapy for paroxysmal nocturnal hemoglobinuria in Russia”

On June 24, 2023, an Expert Council was held in St. Petersburg, during which leading experts in the field of hematology discussed current achievements and answered a number of unresolved issues of targeted therapy of paroxysmal nocturnal hemoglobinuria (APG) in order to further improve treatment results in Russia. During the Expert Council, the following aspects of targeted APG therapy were considered: • criteria for the suboptimal response of patients with APG to therapy with inhibitors of the 5th component of complement (C5); • efficacy and safety of the use of pegcetacoplan in APG in patients with insufficient efficacy of inhibitors of the C5 component of complement; • vaccination issues before starting therapy with complement inhibitors and the possibility of conducting treatment with pegcetacoplan at home.

Real-World Safety and Efficacy of Biosimilar CT-P13 in Patients with Immune-Mediated Inflammatory Diseases: Integrated Analysis of Three Japanese Prospective Observational Studies.

Biosimilar CT-P13 was approved with limited data from clinical trials compared to the originator infliximab in biologic-naïve patients with rheumatoid arthritis. Three prospective post-marketing surveillance studies have been conducted in Japanese biologic-naïve patients and switched patients from biologics including the originator infliximab. We performed an integrated analysis of final data from three post-marketing studies to provide long-term safety and efficacy data of CT-P13 in a real-world clinical setting. A total of 1816 patients consisting of 987 patients with rheumatoid arthritis, 342 patients with Crohn's disease, 322 patients with ulcerative colitis, and 165 patients with psoriasis were evaluated for safety. Efficacy was assessed in 1150 patients whose disease parameter values were serially collected. Adverse drug reactions were reported in 24.2% of all patients. The incidence of adverse drug reactions differed by the prior treatment status with biologics: 30.5% in patients naïve to biologics, 17.0% in patients switched from the originator infliximab, and 33.5% in patients switched from other biologics. Infusion reactions were the most frequent adverse drug reactions (8.2%), and its incidence was significantly higher in patients with ulcerative colitis and an allergy history in a multivariable Cox regression analysis. Infection was the second most frequent (6.1%), but tuberculosis only occurred in four patients (0.2%). The incidence of infection was low in patients with Crohn's disease and psoriasis, and significant risk factors were an allergy history, comorbidities, and concomitant steroid use. Interstitial lung disease occurred in 16 patients (0.9%), including 11 patients with rheumatoid arthritis. With CT-P13 therapy, disease activity parameters decreased similarly in all four diseases, although long-term drug discontinuation rates because of inefficacy varied by disease. In naïve patients, the disease activity parameters decreased rapidly and the proportion of patients in remission increased. Patients switched from infliximab maintained lowered parameter levels with infliximab pretreatment. Decreases were also observed in patients switched from other biologics, but discontinuations were most often because of insufficient efficacy. The integrated analysis of a large number of patients detected no new safety signals with long-term CT-P13 treatment. Efficacy in rheumatoid arthritis, psoriasis, Crohn's disease, and ulcerative colitis cases was confirmed in biologic-naïve patients and switched patients from the originator infliximab or other biologics.

Is Aducanumab treatment developed to prevent progression of Alzheimer's disease cost-effective in Turkey?

BackgroundAlzheimer's Disease (AD), the most common type of dementia, is a chronic, progressive, and neurodegenerative brain discomfort that causes the be damage to brain cells. Although there is no definitive treatment for AD, various drug treatments are used to reduce and control the symptoms of the disease. Developed for the treatment of mild-stage Alzheimer's patients, Aducanumab is the only drug approved by the Food and Drug Administration (FDA) in the past two decades. However, the cost is very high and, in many countries, Aducanumab has not been approved due to insufficient clinical efficacy and lack of evidence yet. This study aims to analyze the cost-effectiveness of Aducanumab, which was developed for the treatment of mild-stage AD, from the patient's perspective.MethodsIn the study, the Markov model was developed to determine the cost-effectiveness of Aducanumab compared to Standard of Care (SoC) therapy over a 5-year horizon. Cost and effectiveness data were taken from the literature. In the study, the discount rate was determined as 6%. The results were presented as the incremental cost-effectiveness ratio (ICER), which represents the cost per quality-adjusted life years (QALY). The results were retested with a one-way and probabilistic sensitivity analysis (PSA) due to possible uncertainties in the research parameters. The results were presented with the tornado diagram and the scatter plots.ResultsWith the Markov model, the total costs of Aducanumab and SoC treatments over a 5-year horizon were found to be 98.068 $ and 21.292 $, respectively. Aducanumab treatment had an incremental gain of 0.64 QALY and an incremental cost of 76.776 $ compared to the SoC treatment. The ICER value, which shows the additional cost per QALY of Aducanumab, was 119.408 $/QALY. As a result of the study, it was determined that Aducanumab was not cost-effective when compared to SoC treatment. Sensitivity analysis results showed stability against uncertainties. Aducanumab was confirmed not to be cost-effective with its current price and potential clinical benefit.ConclusionThe result of the research is considered important in terms of providing evidence-based information on the cost-effectiveness of Aducanumab in Turkey. However, further, research is needed to evaluate Aducanumab's clinical efficacy and cost-effectiveness.

Silver electroceutical technology to treat sarcopenia

While the world is rapidly transforming into a superaging society, pharmaceutical approaches to treat sarcopenia have hitherto not been successful due to their insufficient efficacy and failure to specifically target skeletal muscle cells (skMCs). Although electrical stimulation (ES) is emerging as an alternative intervention, its efficacy toward treating sarcopenia remains unexplored. In this study, we demonstrate a silver electroceutical technology with the potential to treat sarcopenia. First, we developed a high-throughput ES screening platform that can simultaneously stimulate 15 independent conditions, while utilizing only a small number of human-derived primary aged/young skMCs (hAskMC/hYskMC). The in vitro screening showed that specific ES conditions induced hypertrophy and rejuvenation in hAskMCs, and the optimal ES frequency in hAskMCs was different from that in hYskMCs. When applied to aged mice in vivo, specific ES conditions improved the prevalence and thickness of Type IIA fibers, along with biomechanical attributes, toward a younger skMC phenotype. This study is expected to pave the way toward an electroceutical treatment for sarcopenia with minimal side effects and help realize personalized bioelectronic medicine.

Plasma-Derived Nanoclusters for Site-Specific Multimodality Photo/Magnetic Thrombus Theranostics.

Traditional thrombolytic therapeutics for vascular blockage are affected by their limited penetration into thrombi, associated off-target side effects, and low bioavailability, leading to insufficient thrombolytic efficacy. It is hypothesized that these limitations can be overcome by the precisely controlled and targeted delivery of thrombolytic therapeutics. A theranostic platform is developed that is biocompatible, fluorescent, magnetic, and well-characterized, with multiple targeting modes. This multimodal theranostic system can be remotely visualized and magnetically guided toward thrombi, noninvasively irradiated by near-infrared (NIR) phototherapies, and remotely activated by actuated magnets for additional mechanical therapy. Magnetic guidance can also improve the penetration of nanomedicines into thrombi. In a mouse model of thrombosis, the thrombosis residues are reduced by ≈80% and with no risk of side effects or of secondary embolization. This strategy not only enables the progression of thrombolysis but also accelerates the lysis rate, thereby facilitating its prospective use in time-critical thrombolytic treatment.

Current Advances in Nanotechnology-Mediated Delivery of Herbal and Plant-Derived Medicines.

Phytomedicine has been used by humans since ancient times to treat a variety of diseases. However, herbal medicines face significant challenges, including poor water and lipid solubility and instability, which lead to low bioavailability and insufficient therapeutic efficacy. Recently, it has been shown that nanotechnology-based drug delivery systems are appropriate to overcome the above-mentioned limitations. The present review study first discusses herbal medicines and the challenges involved in the formulation of these drugs. The different types of nano-based drug delivery systems used in herbal delivery and their potential to improve therapeutic efficacy are summarized, and common techniques for preparing nanocarriers used in herbal drug delivery are also discussed. Finally, a list of nanophyto medicines that have entered clinical trials since 2010, as well as those that the FDA has approved, is presented.

Multifunctional CuFe2O4@HA as a GSH-depleting nanoplatform for targeted photothermal/enhanced-chemodynamic synergistic therapy

Chemodynamic therapy (CDT), which converts overexpressed hydrogen peroxide (H2O2) in tumor cells to hydroxyl radicals (•OH) by Fenton reactions, is considered a prospective strategy in anticancer therapy. However, the high level of glutathione (GSH) and poor Fenton catalytic efficiency contribute to the suboptimal efficiency of CDT. Herein, we present a multifunctional nanoplatform (CuFe2O4@HA) that can induce GSH depletion and combine with photothermal therapy (PTT) to enhance antitumor efficacy. CuFe2O4@HA nanoparticles could release Cu2+ and Fe3+ after entering tumor cells by targeting hyaluronic acid (HA). Subsequently, Cu2+ and Fe3+ were reduced to Cu+ and Fe2+ by GSH, where Cu+/Fe2+ significantly catalyzed H2O2 to produce a higher level of •OH, and the depletion of GSH disrupted the antioxidant capacity of the tumor. Therefore, depleting GSH substantially enhances the level of •OH in tumor cells. In addition, CuFe2O4@HA nanoparticles have considerable absorption in the near-infrared (NIR) region, which can stimulate excellent PTT effects. More importantly, the heat generated by PTT can further enhance the Fenton catalysis efficiency. In vitro and in vivo experiments have demonstrated the excellent tumor-killing effect of CuFe2O4@HA nanoparticles. This strategy overcomes the problem of insufficient CDT efficacy caused by GSH overexpression and poor catalytic efficiency. Moreover, this versatile nanoplatform provides a reference for self-enhanced CDT and PTT/CDT synergistic targeted therapy.

Design of a Multi-Epitope Vaccine against Tuberculosis from Mycobacterium tuberculosis PE_PGRS49 and PE_PGRS56 Proteins by Reverse Vaccinology.

Tuberculosis is a disease caused by Mycobacterium tuberculosis, representing the second leading cause of death by an infectious agent worldwide. The available vaccine against this disease has insufficient coverage and variable efficacy, accounting for a high number of cases worldwide. In fact, an estimated third of the world's population has a latent infection. Therefore, developing new vaccines is crucial to preventing it. In this study, the highly antigenic PE_PGRS49 and PE_PGRS56 proteins were analyzed. These proteins were used for predicting T- and B-cell epitopes and for human leukocyte antigen (HLA) protein binding efficiency. Epitopes GGAGGNGSLSS, FAGAGGQGGLGG, GIGGGTQSATGLG (PE_PGRS49), and GTGWNGGKGDTG (PE_PGRS56) were selected based on their best physicochemical, antigenic, non-allergenic, and non-toxic properties and coupled to HLA I and HLA II structures for in silico assays. A construct with an adjuvant (RS09) plus each epitope joined by GPGPG linkers was designed, and the stability of the HLA-coupled construct was further evaluated by molecular dynamics simulations. Although experimental and in vivo studies are still necessary to ensure its protective effect against the disease, this study shows that the vaccine construct is dynamically stable and potentially effective against tuberculosis.

UNDERGROUND UTILITY LOCATOR EQUIPPED WITH A TWO-STROKE PULSE TRANSDUCER

With detailed large-scale topographic surveys of cities, especially when photographing executive master plans of industrial facilities, geodetic services perform work on measuring not only ground sites, but also - on detecting and localizing of underground utilities: water, oil and gas metal pipelines, power and telephone cables, etc. The search for underground communications by various services is carried out at use of special electronic devices for searching of underground communications: tracers, cable detectors. A number of shortcomings have been identified when operating these devices, including difficulties in detecting and fixing of pipes or cables in conditions of increased industrial interference, insufficient efficacy and accuracy of the search process, high energy consumption, low level of ease of operation, due to relatively large weight and size parameters. A comparative analysis of currently used search devices has proven technical defects of circuit solutions, and has formed the basis for developing of an electronic circuit. A working model of an underground utility finder with a pulse converter has been produced. Main technical characteristics were obtained after testing. The technical solution has been patented in the GU of the Intellectual Property Center of the Republic of Uzbekistan.

Targeting G protein-coupled receptors for heart failure treatment.

Heart failure remains a leading cause of morbidity and mortality worldwide. Current treatment for patients with heart failure include drugs targeting G protein-coupled receptors such as β-adrenoceptor antagonists (β-blockers) and angiotensin II type 1 receptor antagonists (or angiotensin II receptor blockers). However, many patients progress to advanced heart failure with persistent symptoms, despite treatment with available therapeutics that have been shown to reduce mortality and mortality. GPCR targets currently being explored for the development of novel heart failure therapeutics include adenosine receptor, formyl peptide receptor, relaxin/insulin-like family peptide receptor, vasopressin receptor, endothelin receptor and the glucagon-like peptide 1 receptor. Many GPCR drug candidates are limited by insufficient efficacy and/or dose-limiting unwanted effects. Understanding the current challenges hindering successful clinical translation and the potential to overcome existing limitations will facilitate the future development of novel heart failure therapeutics. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc.

Differential target multiplexed spinal cord stimulation using a paddle-type lead placed at the appropriate site for neuropathic pain after spinal cord injury in patients with past spinal surgical histories: study protocol for an exploratory clinical trial

BackgroundNeuropathic pain after spinal cord injury (SCI), both traumatic and non-traumatic, is refractory to various treatments. Spinal cord stimulation (SCS) is one of the neuromodulation therapies for neuropathic pain, although SCS has insufficient efficacy for neuropathic pain after SCI. The reasons are presumed to be inappropriate locations of SCS leads and conventional tonic stimulation itself does not have a sufficient analgesic effect for the pain. In patients with past spinal surgical histories, the cylinder-type leads are likely to be placed on the caudal side of the SCI because of surgical adhesions. Differential target multiplexed (DTM) stimulation is one of the latest new stimulation patterns that is superior to conventional stimulation.MethodsA single-center, open-label, randomized, two-way crossover trial is planned to investigate the efficacy of SCS using DTM stimulation placing a paddle lead at the appropriate site for neuropathic pain after SCI in patients with spinal surgical histories. The paddle-type lead delivers energy more efficiently than a cylinder-type lead. This study consists of two steps: SCS trial (first step) and SCS system implantation (second step). The primary outcome is rates of achieving pain improvement with more than 33% reduction 3 months after SCS system implantation. The secondary outcomes are to be evaluated as follows: (1) effectiveness of DTM and tonic stimulations during the SCS trial; (2) changes of assessment items from 1 to 24 months; (3) relationships between the result of the SCS trial and the effects 3 months after SCS system implantation; (4) preoperative factors associated with a long-term effect, defined as continuing for more than 12 months; and (5) whether gait function improves from 1 to 24 months.DiscussionA paddle-type lead placed on the rostral side of SCI and using DTM stimulation may provide significant pain relief for patients with intractable neuropathic pain after SCI in patients with past spinal surgical histories.Trial registrationJapan Registry of Clinical Trials (jRCT) jRCT 1042220093. Registered on 21 November 2022, and last modified on 6 January 2023. jRCT is approved as a member of the Primary Registry Network of WHO ICTRP.

Targeting the Hedgehog pathway with novel Gli1 hydrophobic tagging degraders

The Hedgehog/Glioma-associated oncogene (Hh/Gli) signaling pathway plays an essential role in embryonic development and tissue homeostasis. Aberrant regulation of this pathway has been linked to various human malignancies. Gli1, the downstream transcription factor of the Hh pathway, is the ultimate effector of the canonical Hh pathway and has been identified as a common regulator of several tumorigenic pathways prevalent in Hh-independent cancers. Thus Gli1 represents a unique and promising drug target for a wide range of cancers. However, the identification and development of small molecules that directly target Gli1 protein have progressed slowly, due to an insufficient efficacy and selectivity. Herein, we developed novel small-molecule Gli1 degraders based on the hydrophobic tagging (HyT) strategy. The Gli1 HyT degrader 8e potently inhibited the proliferation of Gli1-overexpressed HT29 colorectal cancer cells, induced Gli1 degradation with a DC50 value of 5.4 μM in HT29 and achieved 70% degradation at 7.5 μM in MEFPTCH1−/− and MEFSUFU−/−cell lines, via proteasome pathway. Compared to the canonical Hh antagonist Vismodegib, 8e exhibited much stronger potency in suppressing the mRNA expression of Hh target genes in Hh-overactivated MEFPTCH1−/− and Vismodegib resistant MEFSUFU−/− cells. Our study provides small molecule Gli1 degraders effectively interfering with both canonical and noncanonical Hh signaling and overcoming current Smoothened (SMO) antagonists resistance, which might pave a new avenue for developing therapeutic modalities targeting Hh/Gli1 signaling pathway.

Deep brain stimulation (DBS) as a therapeutic approach in gait disorders: What does it bring to the table?

Gait deficits are found in various degenerative central nervous system conditions, and are particularly a hallmark of Parkinson's disease (PD). While there is no cure for such neurodegenerative disorders, Levodopa is considered as the standard medication in PD patients. Often times, the therapy of severe PD consists of deep brain stimulation (DBS) of the subthalamic nucleus. Earlier research exploring the effect of gait have reported contradictory results or insufficient efficacy. A change in gait includes various parameters, such as step length, cadence, Double-stance phase duration which may be positively affected by DBS. DBS could also be effective in correcting the levodopa-induced postural sway abnormalities. Moreover, during normal walking, interaction among the subthalamic nucleus and cortex -essential regions which exert a role in locomotion- are coupled. However, during the freezing of gait, the activity is desynchronized. The mechanisms underlying DBS-induced neurobehavioral improvements in such scenarios requires further study. The present review discusses DBS in the context of gait, the benefits associated with DBS compared to standard pharmacotherapy options, and provides insights into future research.

Content of CD4<sup>+</sup>T cell subpopulations in predicting the efficacy of biological therapy for psoriasis in children

Psoriasis is a chronic inflammatory skin disease characterized by increased proliferation of epidermal cells, impaired keratinization and an inflammatory reaction in dermis caused by activation of T lymphocytes and synthesis of pro-inflammatory cytokines. The pathophysiology of psoriasis is also associated with a decrease in anti-inflammatory functions of immunosuppressive cells. Recently, there are more cases of development of resistance to ongoing therapy with biologics in children, requiring cancellation of drug or its replacement. The aim of the study was to evaluate the content of T helper subpopulations in prognosis of effectiveness of biologics in children with psoriasis. Immunophenotyping of T helper populations was performed in 110 children with psoriasis vulgaris before appointment of biologics, at 16 and 52 weeks. Age of children ranged from 6 to 18 years. Severity of psoriasis and effectiveness of therapy were assessed by index PASI, which varied 0-68. Content of Tregs, Thact and Th17 was determined by flow cytometry. In group with a sufficient effect of biologics, a decrease in PASI was obtained, both at week 16 of therapy (p = 0.000) and by year of treatment, p = 0.017. In children with psoriasis, regardless of duration and effectiveness of biologics, percentage of Thact was increased relative to normal values. In group 1 before prescription of biologics was increased percentage of Thact (p = 0.005) and Th17 (p = 0.001). Analysis of dynamics of content of small populations of T helper during 1 year of use of biologics in children with different efficacy of therapy showed that significant changes were found in content of Th17 and Treg, as well as their Th17/Treg. ROC analysis showed that when Th17 deviation was above 53%, Thact above 181% and Th17/Treg above 2.6 before biologics were prescribed, insufficient efficacy of therapy could be expected in 75% of cases by year. By the end of induction course, with a Th17 deviation above 102% and a Th17/Treg above 2.6, probability of ineffective treatment was already 82%. The study shows the informative value of assessment of Thact before appointment of biologics, dynamics of Th17 by the end of induction course and Treg after 16 weeks of therapy in prognosis of effectiveness of biologics in children with psoriasis.

Antibacterial mechanism of the novel antimicrobial peptide Jelleine-Ic and its efficacy in controlling Pseudomonas syringae pv. actinidiae in kiwifruit.

Bacterial canker caused by Pseudomonas syringae pv. actinidiae (Psa) poses a severe threat to kiwifruit production. Because of the insufficient efficacy and environmental safety of available treatments, novel antibacterial agents should be urgently developed. Antimicrobial peptides (AMPs) can be used as antimicrobials for disease control. In this study, we designed a novel AMP, Jelleine-Ic, and evaluated its antibacterial activity and mechanism of action against Psa. Jelleine-Ic with a half maximal effective concentration of 1.67 μg/mL exhibited stronger antibacterial activity than did parent Jelleine-I. Jelleine-Ic targeted the Psa membrane, increased membrane permeabilization, and dissipated membrane potential, resulting in calcium leakage. Electron microscopy revealed that Jelleine-Ic disrupted cell morphology and caused intracellular alterations. Moreover, this AMP penetrated the cell membrane, bound to DNA, and reduced the expression of genes related to DNA replication and repair. Jelleine-Ic also reduced esterase activity and induced intracellular reactive oxygen species generation. This peptide inhibited the development of Psa canker. The control efficiency of Jelleine-Ic against Psa in the leaf discs and leaves of kiwifruit was 81.83% and 70.53%, respectively, which was superior to that of the commercial agricultural streptomycin. Furthermore, Jelleine-Ic upregulated the expression of kiwifruit defense genes (PR-10 and WRKY70a). Jelleine-Ic effectively controls Psa in vitro and in vivo, and may be developed as a bactericide for plant disease control. This article is protected by copyright. All rights reserved.

Epigenetic priming improves salvage chemotherapy in diffuse large B-cell lymphoma via endogenous retrovirus-induced cGAS-STING activation

BackgroundAlthough most patients with diffuse large B-cell lymphoma (DLBCL) achieve complete remission after first-line rituximab-containing immunochemotherapy, up to 40% of patients relapse and require salvage therapy. Among those patients, a substantial proportion remain refractory to salvage therapy due to insufficient efficacy or intolerance of toxicities. A hypomethylating agent, 5-azacytidine, showed a chemosensitizing effect when primed before chemotherapy in lymphoma cell lines and newly diagnosed DLBCL patients. However, its potential to improve outcomes of salvage chemotherapy in DLBCL has not been investigated.ResultsIn this study, we demonstrated the mechanism of 5-azacytidine priming as a chemosensitizer in a platinum-based salvage regimen. This chemosensitizing effect was associated with endogenous retrovirus (ERV)-induced viral mimicry responses via the cGAS-STING axis. We found deficiency of cGAS impaired the chemosensitizing effect of 5-azacytidine. Furthermore, combining vitamin C and 5-azacytidine to synergistically activate STING could be a potential remedy for insufficient priming induced by 5-azacytidine alone.ConclusionsTaken together, the chemosensitizing effect of 5-azacytidine could be exploited to overcome the limitations of the current platinum-containing salvage chemotherapy in DLBCL and the status of cGAS-STING has the potential to predict the efficacy of 5-azacytidine priming.