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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 -
Microbiology Spectrum Jul 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.
Topics: Bangladesh; Humans; Antifungal Agents; Microbial Sensitivity Tests; Phylogeny; Candidiasis; Whole Genome Sequencing; Candida auris; Drug Resistance, Fungal; Genome, Fungal; Polymorphism, Single Nucleotide; Candida; Fluconazole; Female
PubMed: 38842332
DOI: 10.1128/spectrum.03540-23 -
Journal of the American Heart... Jun 2024We recently demonstrated that acute administration of ibrutinib, a Bruton's tyrosine kinase inhibitor used in chemotherapy for blood malignancies, increases ventricular...
Impaired Cardiac AMPK (5'-Adenosine Monophosphate-Activated Protein Kinase) and Ca-Handling, and Action Potential Duration Heterogeneity in Ibrutinib-Induced Ventricular Arrhythmia Vulnerability.
BACKGROUND
We recently demonstrated that acute administration of ibrutinib, a Bruton's tyrosine kinase inhibitor used in chemotherapy for blood malignancies, increases ventricular arrhythmia (VA) vulnerability. A pathway of ibrutinib-induced vulnerability to VA that can be modulated for cardioprotection remains unclear.
METHODS AND RESULTS
The effects of ibrutinib on cardiac electrical activity and Ca dynamics were investigated in Langendorff-perfused hearts using optical mapping. We also conducted Western blotting analysis to evaluate the impact of ibrutinib on various regulatory and Ca-handling proteins in rat cardiac tissues. Treatment with ibrutinib (10 mg/kg per day) for 4 weeks was associated with an increased VA inducibility (72.2%±6.3% versus 38.9±7.0% in controls, <0.002) and shorter action potential durations during pacing at various frequencies (<0.05). Ibrutinib also decreased heart rate thresholds for beat-to-beat duration alternans of the cardiac action potential (<0.05). Significant changes in myocardial Ca transients included lower amplitude alternans ratios (<0.05), longer times-to-peak (<0.05), and greater spontaneous intracellular Ca elevations (<0.01). We also found lower abundance and phosphorylation of myocardial AMPK (5'-adenosine monophosphate-activated protein kinase), indicating reduced AMPK activity in hearts after ibrutinib treatment. An acute treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside ameliorated abnormalities in action potential and Ca dynamics, and significantly reduced VA inducibility (37.1%±13.4% versus 72.2%±6.3% in the absence of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, <0.05) in hearts from ibrutinib-treated rats.
CONCLUSIONS
VA vulnerability inflicted by ibrutinib may be mediated in part by an impairment of myocardial AMPK activity. Pharmacological activation of AMPK may be a protective strategy against ibrutinib-induced cardiotoxicity.
Topics: Animals; Adenine; Piperidines; Action Potentials; Pyrimidines; AMP-Activated Protein Kinases; Pyrazoles; Male; Arrhythmias, Cardiac; Protein Kinase Inhibitors; Heart Rate; Isolated Heart Preparation; Calcium; Rats; Disease Models, Animal; Rats, Sprague-Dawley; Myocytes, Cardiac; Calcium Signaling; Time Factors
PubMed: 38842296
DOI: 10.1161/JAHA.123.032357 -
Archivos Espanoles de Urologia May 2024
Letter to the Editor Re: Treatment Progress of Compound Kushen Injection and Gemcitabine in Postoperative Patients with Bladder Cancer and Selection of Drug Delivery Mode.
Topics: Urinary Bladder Neoplasms; Humans; Gemcitabine; Deoxycytidine; Drug Delivery Systems; Antimetabolites, Antineoplastic
PubMed: 38840292
DOI: 10.56434/j.arch.esp.urol.20247704.63 -
Acta Pharmacologica Sinica Jul 2024Cardiac fibrosis is a pathological scarring process that impairs cardiac function. N-acetyltransferase 10 (Nat10) is recently identified as the key enzyme for the...
Cardiac fibrosis is a pathological scarring process that impairs cardiac function. N-acetyltransferase 10 (Nat10) is recently identified as the key enzyme for the N4-acetylcytidine (ac4C) modification of mRNAs. In this study, we investigated the role of Nat10 in cardiac fibrosis following myocardial infarction (MI) and the related mechanisms. MI was induced in mice by ligation of the left anterior descending coronary artery; cardiac function was assessed with echocardiography. We showed that both the mRNA and protein expression levels of Nat10 were significantly increased in the infarct zone and border zone 4 weeks post-MI, and the expression of Nat10 in cardiac fibroblasts was significantly higher compared with that in cardiomyocytes after MI. Fibroblast-specific overexpression of Nat10 promoted collagen deposition and induced cardiac systolic dysfunction post-MI in mice. Conversely, fibroblast-specific knockout of Nat10 markedly relieved cardiac function impairment and extracellular matrix remodeling following MI. We then conducted ac4C-RNA binding protein immunoprecipitation-sequencing (RIP-seq) in cardiac fibroblasts transfected with Nat10 siRNA, and revealed that angiomotin-like 1 (Amotl1), an upstream regulator of the Hippo signaling pathway, was the target gene of Nat10. We demonstrated that Nat10-mediated ac4C modification of Amotl1 increased its mRNA stability and translation in neonatal cardiac fibroblasts, thereby increasing the interaction of Amotl1 with yes-associated protein 1 (Yap) and facilitating Yap translocation into the nucleus. Intriguingly, silencing of Amotl1 or Yap, as well as treatment with verteporfin, a selective and potent Yap inhibitor, attenuated the Nat10 overexpression-induced proliferation of cardiac fibroblasts and prevented their differentiation into myofibroblasts in vitro. In conclusion, this study highlights Nat10 as a crucial regulator of myocardial fibrosis following MI injury through ac4C modification of upstream activators within the Hippo/Yap signaling pathway.
Topics: Animals; Myocardial Infarction; Fibrosis; Mice; Mice, Inbred C57BL; Male; YAP-Signaling Proteins; Fibroblasts; Cytidine; Mice, Knockout; Membrane Proteins; N-Terminal Acetyltransferase E; Hippo Signaling Pathway; Myocytes, Cardiac; Cells, Cultured; Signal Transduction; N-Terminal Acetyltransferases; Myocardium; Adaptor Proteins, Signal Transducing
PubMed: 38839936
DOI: 10.1038/s41401-024-01306-8 -
ESMO Open Jun 2024In most patients with advanced human epidermal growth factor receptor-2-positive (HER2+) breast cancer, anti-HER2 therapies fail due to the development of acquired...
BACKGROUND
In most patients with advanced human epidermal growth factor receptor-2-positive (HER2+) breast cancer, anti-HER2 therapies fail due to the development of acquired resistance, potentially mediated through phosphoinositide-3-kinase (PI3K) signaling. We investigated adding taselisib, an α-selective potent oral inhibitor of PI3K, to different HER2-directed regimens in order to improve disease control.
PATIENTS AND METHODS
Patients (n = 68) with advanced HER2+ breast cancer were enrolled to this open-label, dose-escalation phase Ib study. The primary endpoint was defining the maximal tolerated dose (MTD) for the various taselisib-containing combinations. The secondary endpoint was safety. Exploratory endpoints included circulating tumor DNA analysis. The study included four cohorts: (A) taselisib + trastuzumab emtansine (T-DM1), (C) taselisib + trastuzumab and pertuzumab (TP), (D) taselisib + TP + paclitaxel, and (E) taselisib + TP + fulvestrant.
RESULTS
Following dose escalation, the taselisib MTD was defined as 4 mg once daily. Treatment was associated with significant toxicities, as 34 out of 68 patients experienced grade ≥3 adverse events (AEs) attributed to taselisib, the most common all-grade AEs being diarrhea, fatigue, and oral mucositis. At a median follow-up of 43.8 months, median progression-free survival (PFS) for the MTD-treated population in cohorts A, C, and E was 6.3 [95% confidence interval (CI) 3.2-not applicable (NA)] months, 1.7 (95% CI 1.4-NA) months, and 10.6 (95% CI 8.3-NA) months, respectively. The median PFS for patients in cohort A with prior T-DM1 use was 10.4 (95% CI 2.7-NA) months.
CONCLUSIONS
PIK3CA targeting with taselisib in combination with HER2-targeted therapies was associated with both promising efficacy and substantial toxicities.
Topics: Humans; Female; Middle Aged; Breast Neoplasms; Receptor, ErbB-2; Aged; Adult; Antineoplastic Combined Chemotherapy Protocols; Maximum Tolerated Dose; Oxazoles; Quinazolines; Paclitaxel; Uracil; Ado-Trastuzumab Emtansine; Fulvestrant; Trastuzumab; Imidazoles; Oxazepines; Antibodies, Monoclonal, Humanized
PubMed: 38833970
DOI: 10.1016/j.esmoop.2024.103465 -
Analytical Chemistry Jun 2024Metal-organic frameworks (MOFs) show unique advantages in simulating the dynamics and fidelity of natural coordination. Inspired by zinc finger protein, a second linker...
Metal-organic frameworks (MOFs) show unique advantages in simulating the dynamics and fidelity of natural coordination. Inspired by zinc finger protein, a second linker was introduced to affect the homogeneous MOF system and thus facilitate the emergence of diverse functionalities. Under the systematic identification of 12 MOF species (i.e., metal ions, linkers) and 6 second linkers (trigger), a dissipative system consisting of Co-BDC-NO and -phenylenediamine (PD) was screened out, which can rapidly and in situ generate a high photothermal complex (η = 36.9%). Meanwhile, both the carboxylation of epigenetic modifications and metal ion (Fe, Ni, Cu, Zn, Co and Mn) screening were utilized to improve the local coordination environment so that the adaptable Co-MOF growth on the DNA strand was realized. Thus, epigenetic modification information on DNA was converted to an amplified metal ion signal, and then PD was further introduced to generate bimodal dissipative signals by which a simple, high-sensitivity detection strategy of 5-hydroxymethylcytosine (LOD = 0.02%) and 5-formylcytosine (LOD = 0.025‰) was developed. The strategy provides one low-cost method (< 0.01 $/sample) for quantifying global epigenetic modifications, which greatly promotes epigenetic modification-based early disease diagnosis. This work also proposes a general heterocoordination design concept for molecular recognition and signal transduction, opening a new MOF-based sensing paradigm.
Topics: Metal-Organic Frameworks; Cobalt; Epigenesis, Genetic; DNA; Phenylenediamines; 5-Methylcytosine; Cytosine; Limit of Detection
PubMed: 38833588
DOI: 10.1021/acs.analchem.4c01377 -
Scientific Reports Jun 2024The combination of trifluridine/tipiracil hydrochloride (FTD/TPI) plus ramucirumab has demonstrated clinical activity in patients with advanced gastric cancer (AGC). We... (Observational Study)
Observational Study Comparative Study
The combination of trifluridine/tipiracil hydrochloride (FTD/TPI) plus ramucirumab has demonstrated clinical activity in patients with advanced gastric cancer (AGC). We evaluated the efficacy and safety of this combination compared with those of FTD/TPI monotherapy in patients with AGC. We retrospectively reviewed data of patients with AGC who received FTD/TPI plus ramucirumab or FTD/TPI monotherapy as third- or later-line treatment. This study included 36 patients treated with FTD/TPI plus ramucirumab and 70 patients receiving FTD/TPI monotherapy. The objective response rate (ORR) and disease control rate (DCR) were 25.8% and 58.1%, respectively, in the FTD/TPI plus ramucirumab group and 5.0% and 38.3%, respectively, in the FTD/TPI group (ORR, P = 0.007; DCR, P = 0.081). The median progression-free survival (PFS) was significantly longer in the FTD/TPI plus ramucirumab group (median PFS, 2.9 vs. 1.8 months; hazard ratio [HR]: 0.52; P = 0.001). A numerical survival benefit was also observed (median overall survival, 7.9 months vs. 5.0 months; HR: 0.68, P = 0.089). In the multivariate analysis, PFS was significantly longer in the FTD/TPI plus ramucirumab group than in the FTD/TPI monotherapy group (HR: 0.61, P = 0.030). The incidence of febrile neutropenia was higher in the FTD/TPI plus ramucirumab group than in the FTD/TPI group (13.8% vs. 2.9%); however, no new safety signals were identified. Compared with FTD/TPI monotherapy, FTD/TPI plus ramucirumab offers clinical benefits with acceptable toxicity in heavily pretreated patients with AGC. Further investigation via randomized trials is warranted to confirm these findings.
Topics: Humans; Stomach Neoplasms; Ramucirumab; Male; Female; Thymine; Middle Aged; Aged; Trifluridine; Antibodies, Monoclonal, Humanized; Pyrrolidines; Antineoplastic Combined Chemotherapy Protocols; Retrospective Studies; Adult; Drug Combinations; Aged, 80 and over; Treatment Outcome; Uracil; Progression-Free Survival
PubMed: 38830895
DOI: 10.1038/s41598-024-61975-7