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Cancer Medicine Jun 2024Pancreatic cancer is one of the most lethal malignancies, partly due to resistance to conventional chemotherapy. The chemoresistance of malignant tumors is associated...
BACKGROUND AND AIMS
Pancreatic cancer is one of the most lethal malignancies, partly due to resistance to conventional chemotherapy. The chemoresistance of malignant tumors is associated with epithelial-mesenchymal transition (EMT) and the stemness of cancer cells. The aim of this study is to investigate the availability and functional mechanisms of trefoil factor family 1 (TFF1), a tumor-suppressive protein in pancreatic carcinogenesis, to treat pancreatic cancer.
METHODS
To investigate the role of endogenous TFF1 in human and mice, specimens of human pancreatic cancer and genetically engineered mouse model of pancreatic cancer (KPC/TFF1KO; Pdx1-Cre/LSL-KRAS/LSL-p53/TFF1) were analyzed by immunohistochemistry (IHC). To explore the efficacy of extracellular administration of TFF1, recombinant and chemically synthesized TFF1 were administered to pancreatic cancer cell lines, a xenograft mouse model and a transgenic mouse model.
RESULTS
The deficiency of TFF1 was associated with increased EMT of cancer cells in mouse models of pancreatic cancer, KPC. The expression of TFF1 in cancer cells was associated with better survival rate of the patients who underwent chemotherapy, and loss of TFF1 deteriorated the benefit of gemcitabine in KPC mice. Extracellular administration of TFF1 inhibited gemcitabine-induced EMT, Wnt pathway activation and cancer stemness, eventually increased apoptosis of pancreatic cancer cells in vitro. In vivo, combined treatment of gemcitabine and subcutaneous administration of TFF1 arrested tumor growth in xenograft mouse model and resulted in the better survival of KPC mice by inhibiting EMT and cancer stemness.
CONCLUSION
These results indicate that TFF1 can contribute to establishing a novel strategy to treat pancreatic cancer patients by enhancing chemosensitivity.
Topics: Animals; Pancreatic Neoplasms; Trefoil Factor-1; Humans; Mice; Epithelial-Mesenchymal Transition; Neoplastic Stem Cells; Drug Resistance, Neoplasm; Cell Line, Tumor; Tumor Suppressor Proteins; Xenograft Model Antitumor Assays; Gemcitabine; Mice, Transgenic; Female; Male; Cell Proliferation; Deoxycytidine; Apoptosis; Gene Expression Regulation, Neoplastic
PubMed: 38872370
DOI: 10.1002/cam4.7395 -
Journal of Infection in Developing... May 2024The coronavirus disease 2019 (COVID-19) pandemic started in March 2020. Since then, there has been an urgent need for effective therapeutic methods to manage the... (Observational Study)
Observational Study
INTRODUCTION
The coronavirus disease 2019 (COVID-19) pandemic started in March 2020. Since then, there has been an urgent need for effective therapeutic methods to manage the disease. We aimed to assess the effectiveness of molnupiravir in reducing the need for hospitalization in at-risk, non-hospitalized COVID-19 patients.
METHODOLOGY
This was a single-center, non-randomized, observational retrospective study of non-hospitalized patients with confirmed COVID-19, treated at the Clinic for Infectious and Tropical Diseases, University Clinical Center in Belgrade, Serbia.
RESULTS
The study was conducted between 15 December 2021 and 15 February 2022 and included 320 patients. Of these, 165 (51.6%) received treatment with molnupiravir. The study and control groups were similar in gender and age distribution. The study group had a higher proportion of vaccination (75.2% vs. 51%, p < 0.001). There was no statistically significant difference in presence of comorbidity within the groups. Majority of the patients who received molnupiravir did not require hospitalization; and this was statistically significant in comparison to control group (92.7 vs. 24.5%, p < 0.001). Oxygen supplementation was less frequently required in the study group compared to the control group (0.6% vs. 31%, p < 0.001). During the follow-up period of 12.12 ± 3.5 days, significantly less patients from the study group were admitted to the intensive care unit (p < 0.001). Molnupiravir significantly reduced the risk of hospitalization by 97.9% (HR 0.021; 95% CI 0.005-0.089; p < 0.001).
CONCLUSIONS
Molnupiravir is an effective therapy in preventing the development of severe forms of COVID-19 and hospitalization.
Topics: Humans; Male; Female; Retrospective Studies; COVID-19 Drug Treatment; Middle Aged; Antiviral Agents; Hospitalization; Hydroxylamines; Cytidine; Adult; SARS-CoV-2; Aged; COVID-19; Serbia; Leucine; Treatment Outcome; Outpatients
PubMed: 38865400
DOI: 10.3855/jidc.18802 -
Open Biology Jun 2024Nanopore sequencing platforms combined with supervised machine learning (ML) have been effective at detecting base modifications in DNA such as 5-methylcytosine (5mC)...
Nanopore sequencing platforms combined with supervised machine learning (ML) have been effective at detecting base modifications in DNA such as 5-methylcytosine (5mC) and N6-methyladenine (6mA). These ML-based nanopore callers have typically been trained on data that span all modifications on all possible DNA [Formula: see text]-mer backgrounds-a training dataset. However, as nanopore technology is pushed to more and more epigenetic modifications, such complete training data will not be feasible to obtain. Nanopore calling has historically been performed with hidden Markov models (HMMs) that cannot make successful calls for [Formula: see text]-mer contexts not seen during training because of their independent emission distributions. However, deep neural networks (DNNs), which share parameters across contexts, are increasingly being used as callers, often outperforming their HMM cousins. It stands to reason that a DNN approach should be able to better generalize to unseen [Formula: see text]-mer contexts. Indeed, herein we demonstrate that a common DNN approach (DeepSignal) outperforms a common HMM approach (Nanopolish) in the incomplete data setting. Furthermore, we propose a novel hybrid HMM-DNN approach, amortized-HMM, that outperforms both the pure HMM and DNN approaches on 5mC calling when the training data are incomplete. This type of approach is expected to be useful for calling other base modifications such as 5-hydroxymethylcytosine and for the simultaneous calling of different modifications, settings in which complete training data are not likely to be available.
Topics: Epigenesis, Genetic; 5-Methylcytosine; DNA Methylation; Neural Networks, Computer; Nanopore Sequencing; Nanopores; Humans; Markov Chains; DNA
PubMed: 38862018
DOI: 10.1098/rsob.230449 -
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 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 -
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 -
Microbiology Spectrum Jun 2024, initially identified in 2009, has rapidly become a critical concern due to its antifungal resistance and significant mortality rates in healthcare-associated...
, initially identified in 2009, has rapidly become a critical concern due to its antifungal resistance and significant mortality rates in healthcare-associated outbreaks. To date, whole-genome sequencing (WGS) has identified five unique clades of , with some strains displaying resistance to all primary antifungal drug classes. In this study, we presented the first WGS analysis of from Bangladesh, describing its origins, transmission dynamics, and antifungal susceptibility testing (AFST) profile. Ten isolates collected from hospital settings in Bangladesh were initially identified by CHROMagar Candida Plus, followed by VITEK2 system, and later sequenced using Illumina NextSeq 550 system. Reference-based phylogenetic analysis and variant calling pipelines were used to classify the isolates in different clades. All isolates aligned ~90% with the Clade I B11205 reference genome. Of the 10 isolates, 8 were clustered with Clade I isolates, highlighting a South Asian lineage prevalent in Bangladesh. Remarkably, the remaining two isolates formed a distinct cluster, exhibiting >42,447 single-nucleotide polymorphism differences compared to their closest Clade IV counterparts. This significant variation corroborates the emergence of a sixth clade (Clade VI) of in Bangladesh, with potential for international transmission. AFST results showed that 80% of the isolates were resistant to fluconazole and voriconazole, whereas Clade VI isolates were susceptible to azoles, echinocandins, and pyrimidine analogue. Genomic sequencing revealed _Y132F mutation conferring azole resistance while _S70R mutation found inconsequential in describing 5-flucytosine resistance. Our study underscores the pressing need for comprehensive genomic surveillance in Bangladesh to better understand the emergence, transmission dynamics, and resistance profiles of infections. Unveiling the discovery of a sixth clade (Clade VI) accentuates the indispensable role of advanced sequencing methodologies.IMPORTANCE is a nosocomial fungal pathogen that is commonly misidentified as other species. Since its emergence in 2009, this multidrug-resistant fungus has become one of the five urgent antimicrobial threats by 2019. Whole-genome sequencing (WGS) has proven to be the most accurate identification technique of which also played a crucial role in the initial discovery of this pathogen. WGS analysis of has revealed five distinct clades where isolates of each clade differ among themselves based on pathogenicity, colonization, infection mechanism, as well as other phenotypic characteristics. In Bangladesh, was first reported in 2019 from clinical samples of a large hospital in Dhaka city. To understand the origin, transmission dynamics, and antifungal-resistance profile of isolates circulating in Bangladesh, we conducted a WGS-based surveillance study on two of the largest hospital settings in Dhaka, Bangladesh.
PubMed: 38842332
DOI: 10.1128/spectrum.03540-23