Low Efficacy Research Articles

Combination of Bacillus tequilensis with difenoconazole to control pear black spot and the related synergistic mechanism.

Pear black spot (PBS) is caused by Alternaria alternata and causes severe damage worldwide. It is particularly important to screen for synergistic fungicide combinations to address issues associated with the low efficacy of biocontrol agents, high dosage requirements and poor sustained effectiveness of chemical fungicides. In vitro and in vivo studies were performed to determine the efficacy of a treatment for this important disease. Additionally, transcriptomic and metabolomic analyses were performed to determine the main molecular and biochemical mechanisms involved in the interaction. Bacillus tequilensis 2_2a has a significant synergistic effect with difenoconazole, causing hyphal entanglement and spore lysis and inhibiting the formation of PBS lesions in vitro. In the field, the control effect of the combination was greater than 95%. The pathways associated with the synergistic effect on the mycelia of A. alternata were divided into two main types: one included glycolysis, oxidative phosphorylation, and MAPK signal transduction, while the other included glycolysis, the TCA cycle, coenzyme A biosynthesis, sterol synthesis, and fatty acid degradation. Both types of pathways jointly affect the cell cycle. The main functions of the key genes and metabolites that have been verified as being affected are glucose synthesis and oxidative respiration, as well as citric acid synthesis, acetyl-CoA synthesis, and sterol synthesis. Both functions involve intracellular pyridine nucleotide metabolism and adenine nucleotide transformation. This study helps to reveal the synergistic mechanisms underlying the combined efficacy of biological and chemical agents, providing a scientific basis for field applications.

TME-Triggered Degradable Phototheranostic Nanoplatform for NIR-II Fluorescence Bioimaging-Guided Phototherapies and Immune Activation.

The low therapeutic efficacy and potential long-term toxicity of antitumor treatments seriously limit the clinical application of phototherapies. Herein, we develop a degradable phototheranostic nanoplatform for NIR-II fluorescence bioimaging-guided synergistic photothermal (PTT) and photodynamic therapies (PDT) and immune activation to inhibit tumor growth. The phototheranostic nanoplatform (CX@PSS) consists of multidisulfide-containing polyurethane loaded with a photosensitizer CX, which can be specifically degraded in the GSH overexpressed tumor microenvironment (TME) and exhibits good NIR-II fluorescence, photodynamic, and photothermal properties. Under 808 nm light irradiation, CX@PSS exhibits efficient photothermal conversion and ROS generation, which further induces immunogenic cell death (ICD), releasing tumor-associated antigens and activating the immune response. In vitro and in vivo studies confirm the potential of CX@PSS in NIR II FL imaging-guided tumor treatments by synergistic PTT, PDT, and immune activation. This work is expected to provide a new pathway for clinical applications of imaging-guided tumor diagnosis and treatments.

ANALYSIS OF FACTORS RELATED TO THE SELF-EFFICACY OF INDONESIAN RED CROSS (IRC) MEMBER STUDENTS IN CARRYING OUT AHA 2020 STANDARD CARDIOPULMONARY RESUSCITATION IN DENPASAR CITY

Abstract Background: Cardiac arrest is a condition of the heart that loses its function suddenly to pump blood throughout the body. Cardiac Arrest has events that take place very quickly and cannot be predicted so that it becomes an important concern in the world of health. Cardiopulmonary Resusitatiom (CPR) training programs for IRC students are increasingly emphasized to increase bystander CPR which is very low, while some cause low interest of students in doing CPR, especially mouth to mouth because they are afraid to do CPR because they feel wrong if they do CPR incorrectly, physically cannot do CPR, fear of harming the individuals helped, fear of contracting diseases contagious, the belief that the person has died. Objective: Analyze the factors of self- physicalizing (knowledge, attitude, motivation and awareness) of IRC students in providing cardiopulmonary resuscitation (CPR) in cardiac arrest patients Method: This research is a type of quantitative research with a cross sectional approach with purposive sampling. Data collection was carried out for 2 months once using a direct questionnaire. The number of samples in this study was 300 respondents of IRC member students in Denpasar City. The inclusion criteria in this study are IRC member students from universities who are active in lectures, active as members of IRC Denpasar City, attending basic training IRC members are young and willing to be respondents. Process research directly and also written on the consent sheet becomes a research respondent and is given informed consent. After getting approval, participants can do the entire questionnaire for 30 minutes. The analysis test carried out is univariate analysis, which describes the characteristics of research respondents, analysis using sperm, multivariate analysis using logistic regression tests. Results: The results of the study obtained that knowledge P value = 0.022, attitude p value 0.026, motivation p value 0.017 and awareness p value 0.050. Awareness is the most influential variable with student preparedness (OR= 1,192), which means that poor awareness will cause low efficacy of undergraduate nursing students in helping patients with cardiac arrest by 1 time compared to the efficacy of IRC member students who have good awareness after the variables of knowledge, attitude, and motivation are controlled. Conclusion: There is a significant relationship between knowledge, attitudes, motivation and awareness with the efficacy of PMI member students in conducting CPR AHA 2020 where awareness is the most influential variable on the efficacy of IRC member students in conducting CPR AHA 2020.

FDA analysis of immune checkpoint inhibitors in combination with vascular endothelial growth factor tyrosine kinase inhibitors in the second-line treatment of patients with advanced non-small cell lung cancer.

8595 Background: Immune checkpoint inhibitors (ICIs) targeting PD-(L)1 in combination with platinum-based chemotherapy is standard first-line therapy for patients with advanced non-small cell lung cancer (NSCLC). The majority of these patients progress and there remains a high unmet medical need in the second-line setting given the limited FDA approved available therapies. The ICI plus vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI) combination, successful across several tumor types, was studied in NSCLC as a potential treatment option. Methods: The FDA identified 3 randomized trials conducted between June 2019 and August 2023, comparing the combination regimen ICI plus VEGF TKI to docetaxel in patients with advanced NSCLC who had progressed on both platinum-based chemotherapy and an ICI. All 3 trials were publicly reported to have not met their primary endpoint. Topline results for key efficacy and safety outcomes from each of the 3 trials were provided by the commercial sponsors. Results: 1317 total patients across 3 trials (LEAP-008, SAPPHIRE and CONTACT-01) were randomized to receive either an ICI plus VEGF TKI or docetaxel. The results are presented (Table). Efficacy parameters demonstrated similar results across trials between arms. There was no clear signal that the combination is more effective than single agent docetaxel. Safety parameters across trials consistently demonstrated higher rates of toxicity with the combination. Conclusions: ICI plus oral VEGF TKI combinations have not demonstrated an advantage over docetaxel in randomized trials of patients with advanced NSCLC. In 2 of the 3 trials, response rate data did not demonstrate superior efficacy compared to docetaxel. Additionally, any observed PFS benefit was small in magnitude. The relatively low efficacy, in combination with the additive toxicity of the regimen, may curtail a potential OS benefit. There remains a high unmet medical need in this patient population and further analysis is necessary to explore potential NSCLC subgroups which may derive benefit. [Table: see text]

4CAST: A phase 1b dose exploration, open-label, single-center study evaluating the safety of INO-464 in combination with chemotherapy in patients with metastatic breast cancer.

e13112 Background: Metastatic triple negative breast cancer (TNBC) has a poor prognosis and the development of new targeted therapies is an area of unmet need. The androgen receptor (AR) antagonist, INO-464, but not abiraterone or enzalutamide, blocks chemotherapy induced cell plasticity to inhibit and primary and metastatic breast cancer (MBC) growth. Single agent INO-464 at a dose of 450mg/d is well tolerated but has low efficacy. Laboratory data demonstrates suppression of metastatic TNBC and an increase in survival with the combination of INO-464 and taxane chemotherapy. Methods: We designed a Phase 1b open-label, single center dose exploration (Part 1) and dose expansion (Part 2) clinical trial of INO-464 450mg/d with docetaxel (IV 75mg/m2 q3wkly) or nab-paclitaxel (IV 100mg/m2 D1/8/15 q4wkly) in any subtype of MBC. The primary objective was to assess the safety and tolerability of INO-464 (450mg/d) and docetaxel or nab-paclitaxel utilizing a rolling 6 design, as well as to determine the maximum tolerated dose (MTD) and the recommended dose of INO-464 to be given with a taxane in the dose expansion study. Secondary objectives included anti-tumor activity and testosterone levels. Results: Recruitment began in August 2022. The cut-off date for this analysis was 19 January 2024. Eight patients have been treated to date and 6 patients were DLT evaluable. All were women with MBC with mean age of 56 (range 48-64) years. Patients had received a median of 5 (range 2 to 7) lines of chemotherapy for MBC. Patient 001 had G3 anaphylaxis due to docetaxel that resolved with adrenaline but came off study and was not DLT evaluable. The protocol was amended to give INO-464 with 1mg of dexamethasone. No DLTs were subsequently observed. Adverse events (AEs) were mostly low grade and chemotherapy related although G2 pneumonitis occurred beyond the DLT period in two patients, one of whom had prior sacituzimab govotecan-related pneumonitis. INO-464-related AEs were G1 fatigue/headache in 4/6 patients. Seven of seven patients had a best response (RECIST1.1) SD, and CA15.3 stability was seen in 4/7 patients. Baseline serum testosterone was detectable in 4/6 patients (range 0.5-1.3 nmol/L, lower limit of detection of <0.5), and remained undetectable or at the lower limit of detection throughout treatment. Conclusions: The MTD of INO-464 is 450mg daily with 0.5mg dexamethasone in combination with docetaxel or nab-paclitaxel chemotherapy. The combination is well tolerated with early efficacy signals. Dose expansion will test the combination in metastatic TNBC with nuclear AR positive breast cancer. Clinical trial information: NCT04947189 .

Test the effectiveness of some medications and vitamin D3 used against COVID-19 on Gram-positive and Gram-negative bacteria isolated from people infected with the Coronavirus

The COVID-19 pandemic has led to a search for effective pharmaceuticals and vitamins to combat the virus. These therapies have antiviral capabilities and can affect both gram-negative and gram-positive bacteria. This study aims to assess the effectiveness of various medications and nutrients in treating bacterial infections linked to COVID-19. In vitro, tests will be conducted to evaluate these therapies' antibacterial efficacy against both gram-negative and gram-positive bacteria. In the current study, we test a group of antibiotics commonly used in treating Coronavirus on different types of Gram-positive and Gram-negative bacteria. They found that Azithromycin was highly effective against both positive and negative bacteria, but its effectiveness decreased when combined with vitamin D. Levofloxacin was the most effective antibiotic, and its efficacy was not affected by the addition of zinc or vitamin D. Acyclovir had a slight effect on bacteria when used alone, but its efficacy improved with zinc. Zinc and Vitamin D had a high degree of effectiveness, but Vitamin D had relatively low efficacy, except against one type of bacteria. The study aims to evaluate the effectiveness of drugs and vitamins against bacterial infections in COVID-19 patients. The results will provide a better understanding of the potential advantages of these medications in controlling bacterial infections. (The abstract should have one paragraph) The study aims to evaluate the effectiveness of drugs and vitamins against bacterial infections in COVID-19 patients. The results will provide a better understanding of the potential advantages of these medications in controlling bacterial infections.

Extramedullary Intracranial Plasmacytomas: A Systematic Review of Literature.

Extramedullary plasmacytoma (EMP) is an uncommon disorder characterized by the development of abnormal plasma cell tumors outside the bone marrow. These tumors are typically observed in various locations, including the upper respiratory tract, gastrointestinal tract, and other soft tissues. Among the less explored manifestations of EMP is intracranial EMP, which remains poorly understood due to the limited literature available on the subject. The objective was to comprehend the population characteristics, localization, type, treatment, and outcomes of intracranial EMP. A systematic review of the literature for EMPs was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The strategy "extramedullary plasmacytoma AND multiple myeloma" was used for the search. The search terms were queried using PubMed, Embase, Scopus, Cochrane, and Web of Science databases. We included only those studies that presented clinical studies with patients diagnosed with intracranial plasmacytomas. In this study, a total of 84 patients from 25 studies were analyzed. The average age of diagnosis was 57.25 years, with a slightly higher proportion of females (57%) compared to male patients (43%). The most common locations of intracranial plasmacytomas were the clivus (29.7%), frontal lobe (18.9%), parietal lobe (8.1%), occipital lobe (6.7%), temporal lobe (6.7%), and sphenoid (4%). Chordoma and meningioma were the most common differential diagnoses encountered during clinical investigations. Treatment modalities included radiotherapy (RT), chemotherapy (QT), surgical resection (SR), and conservative approaches. The most frequent treatment combinations were SR + RT (19%) and RT only (17.8%). Mortality was reported in 48% of the cases, with complete resolution observed in 10 cases and partial resolution in 3 cases. The average follow-up duration was 37.5 months. The clivus is the most frequently reported site of extramedullary intracranial plasmacytoma (EMIP) occurrence, representing 29.7% of cases. Chordomas were commonly observed alongside EMIPs and emerged as the primary differential diagnosis. RT was the predominant treatment modality, with SR considered when feasible. RT alone demonstrated the highest effectiveness in managing EMIPs (30%), while QT as a sole intervention showed lower efficacy. However, a combination of dexamethasone, lenalidomide, and targeted RT displayed promising results, offering improved tumor response and increased safety.

Immune-related adverse events in patients treated with immunotherapy according to corticosteroid exposure.

e14709 Background: Patients with cancer require treatment with corticosteroids for multiple reasons, including prevention of chemotherapy-related side effects. Although corticosteroid use has been associated with lower efficacy of immune checkpoint inhibitors (ICI) in some studies, whether corticosteroid exposure affects the presence and severity of immune-related adverse events (irAEs) remains unclear. Methods: Retrospective single-center study of patients diagnosed with solid tumors treated with ICI. Eligible patients were those who received at least one cycle of ICI and had at least 1 month of follow-up post-ICI initiation. Patient data were extracted from electronic medical records. Comparisons between groups were made based on steroid exposure (defined as the administration of >10 mg of prednisone or its equivalent for >10 days within a 30-day period or at any point during ICI treatment, excluding steroid treatment for irAEs). Associations between variables were assessed using independent samples T-test, Chi-square, and Fisher’s exact tests. Results: We included 135 patients (mean age 61 years, SD 13); 72 (54%) were male. Forty-two (31%) had been exposed to steroids (mean prednisone equivalent of 427 mg, SD 298). Most patients received ICI as palliative treatment for advanced disease (105/135; 78%), primarily as first-line therapy (79/105; 75%). Patients exposed to corticosteroids were more likely to have received ICI with chemotherapy (76% vs 1%, p<0.001), were younger (56 vs. 63 years, p=0.009), more likely to be female (62% vs. 39, p=0.014), and had lower median Charlson Comorbidity Index scores (2 vs. 3, p=0.026). Steroid-exposed patients were more likely to have employed ICI in the neoadjuvant or adjuvant settings (36 vs. 16%, p=0.024) or as third or subsequent line therapy (26 vs. 8%, p=0.044). There were no statistically significant differences in the frequency of irAEs of any grade based on steroid exposure (31% vs 41%, p=0.252). However, patients who were exposed to steroids were significantly less likely to delay or suspend ICI (10% vs. 32%, p=0.005). No other parameters were associated with the rate or severity of irAEs. Conclusions: Our findings suggest that corticosteroid exposure does not increase the frequency of irAEs in patients treated with ICI, but it is associated with a reduced likelihood of discontinuing ICI due to irAEs. These observations suggest that corticosteroids may play a beneficial role in managing patients undergoing immunotherapy, particularly in sustaining treatment continuity despite irAEs. This study underscores the need for further investigation into optimal steroid use strategies to enhance patient outcomes with immunotherapy, especially in situations when they are commonly prescribed, such as premedication for chemotherapy.

Microbial pesticides – challenges and future perspectives for testing and safety assessment with respect to human health

Plant protection measures are necessary to prevent pests and diseases from attacking and destroying crop plants and to meet consumer demands for agricultural produce. In the last decades the use of chemical pesticides has largely increased. Farmers are looking for alternatives. Biopesticides should be considered a sustainable solution. They may be less toxic than chemical pesticides, be very specific to the target pest, decompose quickly, and be less likely to cause resistance. On the other hand, lower efficacy and higher costs are two disadvantages of many biopesticides. Biopesticides include macroorganisms, natural compounds and microorganisms. Microbial pesticides are the most widely used and studied class of biopesticides. The greatest difference between microbial and chemical pesticides is the ability of the former to potentially multiply in the environment and on the crop plant after application. The data requirements for the European Union and the United States Environmental Protection Agency are highlighted, as these regulatory processes are the most followed in regions where local regulations for biopesticide products are not available or vague. New Approach Methods already proposed or harmonized for chemical pesticides are presented and discussed with respect to their use in evaluating microbial pesticide formulations. Evaluating the microbials themselves is not as simple as using the same validated New Approach Methods as for synthetic pesticides. Therefore, the authors suggest considering New Approach Method strategies specifically for microbials and global harmonization with acceptability with the advancements of such approaches. Further discussion is needed and greatly appreciated by the experts.

Synthesis and structural characterization of new macrocyclic inhibitors of the Zika virus NS2B-NS3 protease.

Three new series of macrocyclic active site-directed inhibitors of the Zika virus (ZIKV) NS2B-NS3 protease were synthesized. First, attempts were made to replace the basic P3 lysine residue of our previously described inhibitors with uncharged and more hydrophobic residues. This provided numerous compounds with inhibition constants between 30 and 50 nM. A stronger reduction of the inhibitory potency was observed when the P2 lysine was replaced by neutral residues, all of these inhibitors possess Ki values >1 µM. However, it is possible to replace the P2 lysine with the less basic 3-aminomethylphenylalanine, which provides a similarly potent inhibitor of the ZIKV protease (Ki = 2.69 nM). Crystal structure investigations showed that the P2 benzylamine structure forms comparable interactions with the protease as lysine. Twelve additional structures of these inhibitors in complex with the protease were determined, which explain many, but not all, SAR data obtained in this study. All individual modifications in the P2 or P3 position resulted in inhibitors with low antiviral efficacy in cell culture. Therefore, a third inhibitor series with combined modifications was synthesized; all of them contain a more hydrophobicd-cyclohexylalanine in the linker segment. At a concentration of 40 µM, two of these compounds possess similar antiviral potency as ribavirin at 100 µM. Due to their reliable crystallization in complex with the ZIKV protease, these cyclic compounds are very well suited for a rational structure-based development of improved inhibitors.

Lab on a chip (LOC) platform for drug screening against the intracellular forms of Trypanosoma cruzi

Trypanosoma cruzi is the etiological agent of Chagas disease, endemic in Latin America with recent spreading to non-endemic areas due to human migration. The low efficacy and substantial prevalence of side effects of the approved medications benznidazole (BZN) and nifurtimox observed mainly during the chronic phase of Chagas disease, when most patients receive their diagnosis, demonstrate the need to find new therapeutic compounds to address this neglected global health disease. Here, we developed a platform for screening the antitrypanosomal activity of compounds over intracellular amastigotes using microfluidics, LOC devices, and advanced image analysis algorithms. This platform allows the simultaneous testing of six different concentrations of a compound and the automatic and high-precision processing of the images obtained during the experimental phase, providing quickly and easily a multitude of statistical data for the screening of new drugs. To assess the developed platform, we analyzed the effects of BZN as a reference drug and compared the dose–response curves with those obtained with a flow cytometry-based method, obtaining similar IC50 results. Furthermore, a collection of compounds obtained by chemical synthesis from a combinatorial library was tested over intracellular amastigotes in infected Vero cells.

Spearmint targets microtubules by (-)-carvone.

Allelopathy can provide sustainable alternatives to herbicides because it is based on specific signals rather than generic toxicity. We show that the allelopathic activity of Spearmint and Watermint is linked with their main compounds, (-)-carvone and (+)-menthofuran, both deriving from (-)-limonene. Germination of Poppy and Cress, and root growth of Arabidopsis thaliana are inhibited by very low concentrations of (-)-carvone, acting even through the gas phase. (+)-Menthofuran is active as well, but at lower efficacy. Using fluorescently tagged marker lines in tobacco BY-2 cells and Arabidopsis roots, we demonstrate a rapid degradation of microtubules and a remodeling of actin filaments in response to (-)-carvone and, to a milder extent, to (+)-menthofuran. This cytoskeletal response is followed by cell death. By means of a Root Chip system, we can follow the tissue dependent response of the cytoskeleton and show a cell-type dependent gradient of sensitivity between meristem and distal elongation zone, accompanied by programmed cell death.

Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate for Preventing Vertical Transmission in Chronic Hepatitis B Mothers: A Systematic Review and Meta-Analysis.

International guidelines recommend maternal tenofovir disoproxil fumarate (TDF) therapy accompanied by infant immunoprophylaxis to prevent hepatitis B virus (HBV) mother-to-child transmission (MTCT) in highly viremic mothers. However, pooled analyses for tenofovir alafenamide (TAF) effects and comparisons between the 2 regimens are lacking. In this meta-analysis, pairs of independent reviewers performed multiple database searches from inception to 31 March 2024 and extracted data from cohort studies and randomized controlled trials (RCTs) in highly viremic mothers. The outcomes of interest were the reduction of MTCT and safety in the TDF-treated, TAF-treated, and control groups. We included 31 studies with 2588 highly viremic mothers receiving TDF, 280 receiving TAF, and 1600 receiving no treatment. Compared to the control, TDF therapy reduced the MTCT rate in infants aged 6-12 months (risk ratio: 0.10, 95% confidence interval [CI] .07-.16). Pairwise meta-analysis between TAF and TDF revealed similar effects on reducing MTCT (risk ratio: 1.09, 95% confidence interval .16-7.61). Network meta-analysis showed equal efficacy of the 2 regimens in reducing MTCT (risk ratio: 1.09, 95% CI .15-7.65). The surface under the cumulative ranking curve revealed TDF as the best regimen compared with TAF (probability ranking: .77 vs .72), while receiving a placebo during pregnancy had the lowest efficacy (probability ranking 0.01). There were no safety concerns for mothers and infants in all regimens. Compared to placebo or no treatment, maternal TDF and TAF prophylaxis are equally effective and without safety concerns in reducing MTCT in highly viremic mothers.

Nanomedicines: Nano based Drug Delivery Systems Challenges and Future of nanomedicines

Over the past ten years, the research and delivery of drugs has emerged as a rapidly expanding, highly capital-intensive, and demanding industry. This procedure is costly and time-consuming, and it has to deal with issues with rapid excretion, degradability, toxicity, low efficacy, biocompatibility, and low bioavailability. Nanomaterial are superior to conventional drug because they have remarkable qualities such as a high invasion rate, regulated, targeted, and gradual drug release, as well as easy receptor accessibility. Despite all of its importance, one of the main issues with different nanoparticles utilized as medication delivery systems is their toxicity. This review discusses the issue surrounding conventional drugs, the importance of nanomedicines in medication administration, and their potential for toxicity and also their future aspect that helps to improve health.

Trastuzumab-emtansine versus other anti-HER2 regimens in early or unresectable or metastatic HER-2 positive breast cancer: systematic review and network meta-analysis.

Motivation for the study. Treatment options for HER2-positive breast cancer were evaluated, focusing on the efficacy and safety of trastuzumab-emtansine (T-DM1) compared to other anti-HER2 therapies. Main findings. Trastuzumab-deruxtecan (T-DXd) and PyroCap emerged as promising alternatives, showing substantial improvements in progression-free survival for locally advanced or metastatic breast cancer. T-DM1 showed superior efficacy to the other treatments. Implications. Our findings could inform healthcare decision-making processes to optimize strategies for HER2-positive breast cancer, and potentially improve health outcomes and quality of life. We aimed to study the efficacy and safety of trastuzumab-emtansine (T-DM1) versus other anti-HER2 therapies in HER2+ breast cancer (BC). We performed a network meta-analysis (NMA) of randomized controlled trials (RCTs). Our study focused on patients undergoing treatment for unresectable locally advanced breast cancer (LABC) or metastatic breast cancer (mBC), which included regimens involving trastuzumab and taxanes. Additionally, we considered cases within the first 6 months of treatment for HER2+ early breast cancer (EBC). A total of 23 RCTs and 41 reports were included in our analysis. LABC and mBC showed no statistically significant difference in any of the comparisons of T-DM1 versus the other anti-HER2+ therapies. When assessing progression-free survival (PFS), trastuzumab-deruxtecan (T-DXd) and PyroCap demonstrated greater efficacy compared to other treatments (Hazard Ratio [HR]: 3.57; 95% confidence interval [CI]: 2.75-4.63 and HR: 1.82; 95% CI: 1.35-2.44; respectively), while T-DM1 alone exhibited superior effectiveness compared to LapCap (HR: 0.65; 95% CI: 0.55-0.77), TrasCap (HR: 0.65; 95% CI: 0.46-0.91), LapCapCitu (HR: 0.60; 95% CI: 0.33-1.10), Nera (HR: 0.55; 95% CI: 0.39-0.77), and Cap (HR: 0.37; 95% CI: 0.28-0.49). NMA allows a ranking based on the comparative efficacy and safety among the interventions available. Although superior to other schemes, T-DM1 showed a lower efficacy performance in PFS and overall response rate and a trend towards worse overall survival than T-DXd.

Detection of active compounds in Aloe vera leaf extract and their inhibitory effect on Pseudomonas aeruginosa.

In the study, two types of Aloe vera leaf extracts were prepared: aqueous and alcoholic extract. The research was conducted at the Department of Life Sciences, Faculty of Science, Tikrit University. From October to January. The active compounds in these alcoholic extracts were detected as tannins, cladosides, saponins, and flavonoids, all of which gave a positive result. The antibacterial activity of the aqueous and alcoholic extracts were estimated at concentrations ranging from (200-12. 5) mg/ml, where the alcoholic extract gave a high efficacy of (34.5) mm, while the aqueous extract had a lower efficacy (29.6) mm at the same concentration. Microbial tests were evaluated using different combinations of the extracts on Pseudomonas aeruginosa isolates, where the alcoholic extract gave the highest inhibitory efficacy to the bacteria.

Hybrid Microneedle-Mediated Transdermal Delivery of Atorvastatin Calcium-Loaded Polymeric Micelles for Hyperlipidemia Therapy.

Hyperlipidemia has been a huge challenge to global health, leading to the cardiovascular disease, hypertension, and diabetes. Atorvastatin calcium (AC), a widely prescribed drug for hyperlipidemia, faces huge challenges with oral administration due to poor water solubility and hepatic first-pass effects, resulting in low therapeutic efficacy. In this work, we designed and developed a hybrid microneedle (MN) patch system constructed with soluble poly(vinyl alcohol) (PVA) and AC-loaded polymeric micelles (AC@PMs) for transdermal delivery of AC to enhance the hyperlipidemia therapy. We first prepared various AC@PM formulations self-assembled from mPEG-PLA and mPEG-PLA-PEG block copolymers using a dialysis method and evaluated the physicochemical properties in combination with experiment skills and dissipative particle dynamics (DPD) simulations. Then, we encapsulated the AC@PMs into the PVA MN patch using a micromold filling method, followed by characterizing the performances, especially the structural stability, mechanical performance, and biosafety. After conducting in vivo experiments using a hyperlipidemic rat model, our findings revealed that the hybrid microneedle-mediated administration exhibited superior therapeutic efficacy when compared to oral delivery methods. In summary, we have successfully developed a hybrid microneedle (MN) patch system that holds promising potential for the efficient transdermal delivery of hydrophobic drugs.

Foveal atrophy in patients with active central serous chorioretinopathy at first presentation: characteristics and treatment outcomes

Background/aimsThis study aimed to investigate the clinical characteristics and treatment outcomes of patients with active central serous chorioretinopathy (CSC) and foveal atrophy.MethodsPatients diagnosed with active idiopathic CSC using multimodal imaging...

Efficacy of immunotherapy in advanced gastric cancer: preliminary results of a multicenter observational study

Background: Due to the low efficacy of PD-L1 antibodies in second and subsequent lines of metastatic gastric cancer (mGC), the optimal treatment strategy of such patients and appropriate choice of predictive biomarkers remain challenging. The aim of our study is to assess the efficacy of immune checkpoint inhibitors monotherapy in patients with mGC in routine clinical practice, especially in heavily-pretreated patients. Materials and methods: We retrospectively analyzed data of patients treated in five oncology centers in Moscow between 2018 and 2023, who received nivolumab or pembrolizumab for advanced gastric cancer. Primary end-point of our study was 6-months PFS. Secondary end-points were overall survival (OS), objective respons e rate (ORR), and disease control rate (DCR). Toxicity was assessed using CTC AE v5.0 scale. Results: 122 patients with mGC who received immune checkpoint inhibitors were included between 1 January 2018 and 28 February 2023. 6-months PFS rate was 31,6 %. The median OS was 7 months (95 % CI: 2–20), the median PFS was 3 months (95 % CI: 1,5–9,5). A statistically significant difference in OS was detected in patients with MSI compared to MSS (25 months vs 6 months; 95 % CI: 0,21–0,86; HR: 0,43). A trend towards higher PFS was observed as well (10 months in MSI vs 3 months in MSS; 95 % CI:0,26–1,01; HR: 0,51). No statistical significance in PFS and OS according to PD-L1 CPS was found among patients with MSS. ORR and DCR were 36,6 % and 10,6 %, respectively. No cases of pseudoprogression or fatal immune-related AEs were observed. Conclusion: Our real-world data is consistent with published literature and the results from clinical trials. Further studies are needed to determine prognostic factors and to establish prognostic model of patients receiving ICIs for optimal treatment strategy of mGC.

In vitro and in vivo efficacy of the amiodarone and praziquantel combination against the blood fluke Schistosoma mansoni.

Schistosomiasis, a widespread parasitic disease caused by the blood fluke of the genus Schistosoma, affects over 230 million people, primarily in developing countries. Praziquantel, the sole drug currently approved for schistosomiasis treatment, demonstrates effectiveness against patent infections. A recent study highlighted the antiparasitic properties of amiodarone, an anti-arrhythmic drug, exhibiting higher efficacy than praziquantel against prepatent infections. This study assessed the efficacy of amiodarone and praziquantel, both individually and in combination, against Schistosoma mansoni through comprehensive in vitro and in vivo experiments. In vitro experiments demonstrated synergistic activity (fractional inhibitory concentration index ≤0.5) for combinations of amiodarone with praziquantel. In a murine model of schistosomiasis featuring prepatent infections, treatments involving amiodarone (200 or 400 mg/kg) followed by praziquantel (200 or 400 mg/kg) yielded a substantial reduction in worm burden (60%-70%). Given the low efficacy of praziquantel in prepatent infections, combinations of amiodarone with praziquantel may offer clinical utility in the treatment of schistosomiasis.