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Scientific Reports Jun 2024This study aimed to compare the clinical efficacy and investigate patients' preferences for two mucin secretagogues in the treatment of dry eye disease (DED). Thirty... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
This study aimed to compare the clinical efficacy and investigate patients' preferences for two mucin secretagogues in the treatment of dry eye disease (DED). Thirty patients with DED were randomly treated with either 3% diquafosol or 2% rebamipide ophthalmic solution for 4 weeks, followed by an additional 4-week treatment using the other eye drop after a 2-week washout period. Objective and subjective assessments, including the corneal and conjunctival staining score, tear breakup time (TBUT), Schirmer 1 test, tear osmolarity, tear matrix metalloproteinase-9 (MMP-9), lipid layer thickness (LLT) and ocular surface disease index (OSDI), were performed at baseline, 4 weeks, 6 weeks, and 10 weeks. Patient preferences were assessed based on four categories (comfort, efficacy, convenience, willingness to continue) using a questionnaire and the overall subjective satisfaction score for each drug was obtained at the end of the trial. In total, 28 eyes from 28 patients were included in the analysis. Both diquafosol and rebamipide significantly improved the OSDI (p = 0.033 and 0.034, respectively), TBUT (p < 0.001 and 0.026, respectively), and corneal (p < 0.001 and 0.001, respectively) and conjunctival (p = 0.017 and 0.042, respectively) staining after 4 weeks of treatment. An increase in Schirmer test scores was observed only after rebamipide treatment (p = 0.007). No significant changes were detected in tear osmolarity, MMP-9, and LLT following both treatments. The patients' preference was slightly greater for diquafosol (46.4%) than rebamipide (36.7%), presumably due to rebamipide's bitter taste. The self-efficacy of both drugs and overall satisfaction scores were comparable. These findings indicate that two mucin secretagogues showed comparable effects in ameliorating symptoms and improving signs (TBUT, corneal and conjunctival staining) in patients with DED.
Topics: Humans; Dry Eye Syndromes; Female; Male; Middle Aged; Quinolones; Prospective Studies; Mucins; Uracil Nucleotides; Alanine; Aged; Tears; Cross-Over Studies; Ophthalmic Solutions; Polyphosphates; Treatment Outcome; Adult; Matrix Metalloproteinase 9
PubMed: 38858411
DOI: 10.1038/s41598-024-63784-4 -
Journal of Hazardous Materials Aug 2024Pancreatic ductal adenocarcinoma (PDAC)/pancreatic cancer, is a highly aggressive malignancy with poor prognosis. Gemcitabine-based chemotherapy remains the cornerstone...
Pancreatic ductal adenocarcinoma (PDAC)/pancreatic cancer, is a highly aggressive malignancy with poor prognosis. Gemcitabine-based chemotherapy remains the cornerstone of PDAC treatment. Nonetheless, the development of resistance to gemcitabine among patients is a major factor contributing to unfavorable prognostic outcomes. The resistance exhibited by tumors is modulated by a constellation of factors such as genetic mutations, tumor microenvironment transforms, environmental contaminants exposure. Currently, comprehension of the relationship between environmental pollutants and tumor drug resistance remains inadequate. Our study found that PFOS/6:2 Cl-PFESA exposure increases resistance to gemcitabine in PDAC. Subsequent in vivo trials confirmed that exposure to PFOS/6:2 Cl-PFESA reduces gemcitabine's efficacy in suppressing PDAC, with the inhibition rate decreasing from 79.5 % to 56.7 %/38.7 %, respectively. Integrative multi-omics sequencing and molecular biology analyses have identified the upregulation of ribonucleotide reductase catalytic subunit M1 (RRM1) as a critical factor in gemcitabine resistance. Subsequent research has demonstrated that exposure to PFOS and 6:2 Cl-PFESA results in the upregulation of the RRM1 pathway, consequently enhancing chemotherapy resistance. Remarkably, the influence exerted by 6:2 Cl-PFESA exceeds that of PFOS. Despite 6:2 Cl-PFESA being regarded as a safer substitute for PFOS, its pronounced effect on chemotherapeutic resistance in PDAC necessitates a thorough evaluation of its potential risks related to gastrointestinal toxicity.
Topics: Gemcitabine; Deoxycytidine; Pancreatic Neoplasms; Humans; Fluorocarbons; Alkanesulfonic Acids; Cell Line, Tumor; Carcinoma, Pancreatic Ductal; Drug Resistance, Neoplasm; Animals; Ribonucleoside Diphosphate Reductase; Tumor Suppressor Proteins; Antimetabolites, Antineoplastic; Female; Mice; Male; Mice, Nude
PubMed: 38850938
DOI: 10.1016/j.jhazmat.2024.134790 -
Journal of Nanobiotechnology Jun 2024Myeloid-derived suppressor cells (MDSCs) have played a significant role in facilitating tumor immune escape and inducing an immunosuppressive tumor microenvironment....
Myeloid-derived suppressor cells (MDSCs) have played a significant role in facilitating tumor immune escape and inducing an immunosuppressive tumor microenvironment. Eliminating MDSCs and tumor cells remains a major challenge in cancer immunotherapy. A novel approach has been developed using gemcitabine-celecoxib twin drug-based nano-assembled carrier-free nanoparticles (GEM-CXB NPs) for dual depletion of MDSCs and tumor cells in breast cancer chemoimmunotherapy. The GEM-CXB NPs exhibit prolonged blood circulation, leading to the preferential accumulation and co-release of GEM and CXB in tumors. This promotes synergistic chemotherapeutic activity by the proliferation inhibition and apoptosis induction against 4T1 tumor cells. In addition, it enhances tumor immunogenicity by immunogenic cell death induction and MDSC-induced immunosuppression alleviation through the depletion of MDSCs. These mechanisms synergistically activate the antitumor immune function of cytotoxic T cells and natural killer cells, inhibit the proliferation of regulatory T cells, and promote the M2 to M1 phenotype repolarization of tumor-associated macrophages, considerably enhancing the overall antitumor and anti-metastasis efficacy in BALB/c mice bearing 4T1 tumors. The simplified engineering of GEM-CXB NPs, with their dual depletion strategy targeting immunosuppressive cells and tumor cells, represents an advanced concept in cancer chemoimmunotherapy.
Topics: Animals; Gemcitabine; Deoxycytidine; Myeloid-Derived Suppressor Cells; Mice; Immunotherapy; Mice, Inbred BALB C; Female; Nanoparticles; Cell Line, Tumor; Tumor Microenvironment; Breast Neoplasms; Cell Proliferation
PubMed: 38849938
DOI: 10.1186/s12951-024-02598-y -
Nature Communications Jun 2024Inherited cardiomyopathies are common cardiac diseases worldwide, leading in the late stage to heart failure and death. The most promising treatments against these...
Inherited cardiomyopathies are common cardiac diseases worldwide, leading in the late stage to heart failure and death. The most promising treatments against these diseases are small molecules directly modulating the force produced by β-cardiac myosin, the molecular motor driving heart contraction. Omecamtiv mecarbil and Mavacamten are two such molecules that completed phase 3 clinical trials, and the inhibitor Mavacamten is now approved by the FDA. In contrast to Mavacamten, Omecamtiv mecarbil acts as an activator of cardiac contractility. Here, we reveal by X-ray crystallography that both drugs target the same pocket and stabilize a pre-stroke structural state, with only few local differences. All-atom molecular dynamics simulations reveal how these molecules produce distinct effects in motor allostery thus impacting force production in opposite way. Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine.
Topics: Myocardial Contraction; Molecular Dynamics Simulation; Crystallography, X-Ray; Humans; Urea; Cardiac Myosins; Ventricular Myosins; Animals; Benzylamines; Uracil
PubMed: 38849353
DOI: 10.1038/s41467-024-47587-9 -
Cell Jun 2024Resmetirom is an oral selective THR-β agonist conditionally approved for the treatment of patients with noncirrhotic MASH with moderate to advanced fibrosis. Resmetirom...
Resmetirom is an oral selective THR-β agonist conditionally approved for the treatment of patients with noncirrhotic MASH with moderate to advanced fibrosis. Resmetirom restores mitochondrial and hepatic metabolic function; reduces atherogenic lipids; improves hepatic steatosis, inflammation, and fibrosis; and has no significant effect on THR-α. To view this Bench to Bedside, open or download the PDF.
Topics: Animals; Humans; Liver; Liver Cirrhosis; Mitochondria; Pyridazines; Uracil
PubMed: 38848671
DOI: 10.1016/j.cell.2024.05.009 -
Chemical Record (New York, N.Y.) Jun 2024In the last past twenty years, research on luminescent platinum (II) complexes has been intensively developed for useful application such as organic light emitting... (Review)
Review
In the last past twenty years, research on luminescent platinum (II) complexes has been intensively developed for useful application such as organic light emitting diodes (OLEDs). More recently, new photoluminescent complexes based on diazine ligands (pyrimidine, pyrazine, pyridazine, quinazoline and quinoxaline) have been developed in this context. This review will summarize the photophysical properties of most of the phosphorescent diazine Pt(II) complexes described in the literature and compare the results to pyridine analogues whenever possible. Based on the emission color, and the photoluminescence quantum yield (PLQY) values, the relationship between structure modification, and photophysical properties are highlighted. Tuning of emission color, quantum yields in solution and solid state and, for some complexes, aggregation induced emission (AIE) or thermally activated delayed fluorescence (TADF) properties are described. When emitting OLEDs have been built from diazine Pt(II) complexes, the external quantum efficiency (EQE) values and luminance for different emission wavelengths and in some cases, chromaticity coordinates obtained from devices, are given. Finally, this review highlights the growing interest in studies of new luminescent diazine Pt(II) complexes for OLED applications.
PubMed: 38847061
DOI: 10.1002/tcr.202300335 -
BMC Infectious Diseases Jun 2024The effectiveness of post-exposure prophylaxis (PEP) depends on participants adherence, making it crucial to assess and compare regimen options to enhance human...
BACKGROUND
The effectiveness of post-exposure prophylaxis (PEP) depends on participants adherence, making it crucial to assess and compare regimen options to enhance human immunodeficiency virus (HIV) prophylaxis strategies. However, no prospective study in China has shown that the completion rate and adherence of single-tablet regimens in HIV PEP are higher than those of multi-tablet preparations. Therefore, this study aimed to assess the completion rate and adherence of two HIV PEP regimens.
METHODS
In this single-center, prospective, open-label cohort study, we included 179 participants from May 2022 to March 2023 and analyzed the differences in the 28-day medication completion rate, adherence, safety, tolerance, and effectiveness of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and tenofovir disoproxil fumarate, emtricitabine, and dolutegravir (TDF/FTC + DTG).
RESULTS
The PEP completion rate and adherence were higher in the BIC/FTC/TAF group than in the TDF/FTC + DTG group (completion rate: 97.8% vs. 82.6%, P = 0.009; adherence: 99.6 ± 2.82% vs. 90.2 ± 25.29%, P = 0.003). The incidence of adverse reactions in the BIC/FTC/TAF and TDF/FTC + DTG groups was 15.2% and 10.3% (P = 0.33), respectively. In the TDF/FTC + DTG group, one participant stopped PEP owing to adverse reactions (1.1%). No other participants stopped PEP due to adverse events.
CONCLUSIONS
BIC/FTC/TAF and TDF/FTC + DTG have good safety and tolerance as PEP regimens. BIC/FTC/TAF has a higher completion rate and increased adherence, thus, is recommended as a PEP regimen. These findings emphasize the importance of regimen choice in optimizing PEP outcomes.
TRIAL REGISTRATION
The study was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2200059994(2022-05-14), https://www.chictr.org.cn/bin/project/edit?pid=167391 ).
Topics: Humans; HIV Infections; Prospective Studies; Male; Emtricitabine; Tenofovir; China; Adult; Female; Anti-HIV Agents; Pyridones; Amides; Heterocyclic Compounds, 3-Ring; Middle Aged; Post-Exposure Prophylaxis; Drug Combinations; Medication Adherence; Heterocyclic Compounds, 4 or More Rings; Alanine; Adenine; Young Adult; Piperazines
PubMed: 38844855
DOI: 10.1186/s12879-024-09407-9 -
Signal Transduction and Targeted Therapy Jun 2024Metastatic pancreatic cancer (mPC) has a dismal prognosis. Herein, we conducted a prospective, multicentre, single-arm, phase II trial evaluating the efficacy and safety...
First-line penpulimab (an anti-PD1 antibody) and anlotinib (an angiogenesis inhibitor) with nab-paclitaxel/gemcitabine (PAAG) in metastatic pancreatic cancer: a prospective, multicentre, biomolecular exploratory, phase II trial.
Metastatic pancreatic cancer (mPC) has a dismal prognosis. Herein, we conducted a prospective, multicentre, single-arm, phase II trial evaluating the efficacy and safety of penpulimab and anlotinib in combination with nab-paclitaxel/gemcitabine (PAAG) in patients with first-line mPC (NCT05493995). The primary endpoints included the objective response rate (ORR) and disease control rate (DCR), while secondary endpoints encompassed progression-free survival (PFS), overall survival (OS), and safety. In 66 patients analysed for efficacy, the best response, indicated by the ORR, was recorded at 50.0% (33/66) (95% CI, 37.4-62.6%), with 33 patients achieving partial response (PR). Notably, the DCR was 95.5% (63/66, 95% CI, 87.3-99.1%). The median PFS (mPFS) and OS (mOS) were 8.8 (95% CI, 8.1-11.6), and 13.7 (95% CI, 12.4 to not reached) months, respectively. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 39.4% of patients (26/66). In prespecified exploratory analysis, patients with altered SWI/SNF complex had a poorer PFS. Additionally, low serum CA724 level, high T-cell recruitment, low Th17 cell recruitment, and high NK CD56dim cell scores at baseline were potential predicative biomarkers for more favourable efficacy. In conclusion, PAAG as a first-line therapy demonstrated tolerability with promising clinical efficacy for mPC. The biomolecular findings identified in this study possess the potential to guide the precise clinical application of the triple-combo regimen.
Topics: Humans; Male; Pancreatic Neoplasms; Female; Paclitaxel; Middle Aged; Aged; Deoxycytidine; Gemcitabine; Indoles; Albumins; Quinolines; Antineoplastic Combined Chemotherapy Protocols; Prospective Studies; Adult; Neoplasm Metastasis; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Programmed Cell Death 1 Receptor
PubMed: 38844468
DOI: 10.1038/s41392-024-01857-6 -
PloS One 2024In randomized controlled trials, Nirmatrelvir/ritonavir (NMV/r) and Molnupiravir (MPV) reduced the risk of severe/fatal COVID-19 disease. Real-world data are limited,...
BACKGROUND
In randomized controlled trials, Nirmatrelvir/ritonavir (NMV/r) and Molnupiravir (MPV) reduced the risk of severe/fatal COVID-19 disease. Real-world data are limited, particularly studies directly comparing the two agents.
METHODS
Using the VA National COVID-19 database, we identified previously uninfected, non-hospitalized individuals with COVID-19 with ≥1 risk factor for disease progression who were prescribed either NMV/r or MPV within 3 days of a positive test. We used inverse probability of treatment weights (IPTW) to account for providers' preferences for a specific treatment. Absolute risk difference (ARD) with 95% confidence intervals were determined for those treated with NMV/r vs. MPV. The primary outcome was hospitalization or death within 30 days of treatment prescription using the IPTW approach. Analyses were repeated using propensity-score matched groups.
RESULTS
Between January 1 and November 30, 2022, 9,180 individuals were eligible for inclusion (6,592 prescribed NMV/r; 2,454 prescribed MPV). The ARD for hospitalization/death for NMV/r vs MPV was -0.25 (95% CI -0.79 to 0.28). There was no statistically significant difference in ARD among strata by age, race, comorbidities, or symptoms at baseline. Kaplan-Meier curves did not demonstrate a difference between the two groups (p-value = 0.6). Analysis of the propensity-score matched cohort yielded similar results (ARD for NMV/r vs. MPV -0.9, 95% CI -2.02 to 0.23). Additional analyses showed no difference for development of severe/critical/fatal disease by treatment group.
CONCLUSION
We found no significant difference in short term risk of hospitalization or death among at-risk individuals with COVID-19 treated with either NMV/r or MPV.
Topics: Humans; Male; Female; Ritonavir; Middle Aged; Hydroxylamines; Disease Progression; Cytidine; COVID-19; Antiviral Agents; Leucine; Aged; COVID-19 Drug Treatment; SARS-CoV-2; Hospitalization; Proline; Indoles; Adult; Pandemics; Risk Factors; Coronavirus Infections; Pneumonia, Viral; Betacoronavirus; Lactams; Nitriles
PubMed: 38843201
DOI: 10.1371/journal.pone.0298254 -
Clinical Drug Investigation Jun 2024Musculoskeletal disorders are an important cause of work absence. Clinical practice guidelines recommend nonsteroidal anti-inflammatory drugs (NSAIDs) for grade I-II... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Musculoskeletal disorders are an important cause of work absence. Clinical practice guidelines recommend nonsteroidal anti-inflammatory drugs (NSAIDs) for grade I-II cervical sprains. The combination of thiamine + pyridoxine + cyanocobalamin vitamins has been used, alone and in combination with NSAIDs, for pain and inflammation in musculoskeletal disorders.
OBJECTIVE
The objective of this study was to demonstrate the analgesic synergy of dexketoprofen, and the combination of vitamins thiamine + pyridoxine + cyanocobalamin in a fixed-dose combination (FDC) for the treatment of acute pain caused by grade I-II cervical sprains.
METHODS
We conducted a multicentre, prospective, randomized, double-blind, phase IIIb clinical study comparing two treatment groups: (1) dexketoprofen 25 mg/vitamin B (thiamine 100 mg, pyridoxine 50 mg and cyanocobalamin 0.50 mg) in an FDC (two or more active ingredients combined in a single dosage form) versus (2) dexketoprofen 25 mg monotherapy (single drug to treat a particular disease), one capsule or tablet orally, every 8 h for 7 days. Final mean, average change, and percentage change in pain perception (measured using a visual analogue scale [VAS]) were compared with baseline between groups. A p value < 0.05 was considered statistically significant. Analyses were conducted using SPSS software, v.29.0.
RESULTS
A statistically significant reduction in pain intensity was observed from the third day of treatment with the FDC compared with monotherapy (- 3.1 ± - 1.5 and - 2.6 ± - 1.1 cm, respectively) measured using the VAS (p = 0.011). Regarding the degree of disability, using the Northwick Park Neck Pain Questionnaire (NPQ), statistical difference was observed for the final measurement (7.5%, interquartile range [IQR] 2.5, 10.5; vs. 7.9%, IQR 5.0, 13.8; p = 0.028). A lower proportion of adverse events was reported when using the FDC.
CONCLUSIONS
The FDC of dexketoprofen/thiamine + pyridoxine + cyanocobalamin vitamins demonstrated superior efficacy and a better safety profile compared with dexketoprofen monotherapy for pain treatment in patients with grade I-II cervical sprains.
CLINICAL TRIALS REGISTRATION
NCT05001555, registered 29 July 2021 ( https://clinicaltrials.gov/study/NCT05001555 ).
Topics: Humans; Double-Blind Method; Thiamine; Ketoprofen; Female; Adult; Pyridoxine; Male; Anti-Inflammatory Agents, Non-Steroidal; Vitamin B 12; Middle Aged; Tromethamine; Drug Combinations; Prospective Studies; Vitamin B Complex; Pain Measurement; Young Adult
PubMed: 38842764
DOI: 10.1007/s40261-024-01370-2