This phase I study evaluated the safety, pharmacokinetics and pharmacodynamics of OPB-51602, a novel oral small-molecule STAT3 inhibitor, in patients with advanced solid tumors. A tolerable dose was ...established; gastrointestinal toxicities and peripheral neuropathy were dose-limiting. Responses observed in EGFR TKI-resistant NSCLC patients suggest anti-tumor activity, warranting further studies.
The aim of this study was to determine the maximum-tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of OPB-51602, an oral, direct signal transduction activator of transcription 3 (STAT3) inhibitor, in patients with refractory solid tumors.
Three cohorts were studied: cohort A, a sequential dose escalation of OPB-51602 administered intermittently (days 1–14 every 21 days); cohort B, an expansion cohort evaluating the dose lower than the MTD; cohort C, evaluating continuous daily dosing.
Fifty-one patients were studied at 2, 4, and 5 mg per day dosing. The MTD was 5 mg; first-cycle dose-limiting toxicities (DLTs) were grade 3 hyponatremia in one patient, and grade 3 dehydration in another. Intermittent dosing of both 2 and 4 mg doses were tolerable, and the recommended phase II dose was 4 mg. Cohort B investigated 4 mg intermittently, whereas cohort C investigated 4 mg continuously. Common toxicities included fatigue, nausea/vomiting, diarrhea, anorexia, and early-onset peripheral neuropathy. Drug-induced pneumonitis occurred in two patients in cohort C. Continuous dosing was associated with a higher incidence of peripheral neuropathy and a lower mean relative dose intensity, compared with intermittent dosing. Steady-state pharmacokinetics was characterized by high oral clearance, mean elimination half-life ranging from 44 to 61 h, and a large terminal-phase volume of distribution. An active metabolite, OPB-51822, accumulated to a greater extent than OPB-51602. Flow cytometry of peripheral blood mononuclear cells demonstrated pSTAT3 (Tyr705) inhibition following exposure. Two patients achieved partial responses at 5 mg intermittently and 4 mg continuously; both had epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor exposure.
OPB-51602 demonstrates promising antitumor activity, particularly in NSCLC. Its long half-life and poorer tolerability of continuous dosing, compared with intermittent dosing, suggest that less frequent dosing should be explored.
NCT01184807.
Targeted therapies have transformed clinical management of advanced biliary tract cancer (BTC). Cell-free DNA (cfDNA) analysis is an attractive approach for cancer genomic profiling that overcomes ...many limitations of traditional tissue-based analysis. We examined cfDNA as a tool to inform clinical management of patients with advanced BTC and generate novel insights into BTC tumor biology.
We analyzed next-generation sequencing data of 2068 cfDNA samples from 1671 patients with advanced BTC generated with Guardant360. We carried out clinical annotation on a multi-institutional subset (n = 225) to assess intra-patient cfDNA–tumor concordance and the association of cfDNA variant allele fraction (VAF) with clinical outcomes.
Genetic alterations were detected in cfDNA in 84% of patients, with targetable alterations detected in 44% of patients. Fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, and BRAF V600E were clonal in the majority of cases, affirming these targetable alterations as early driver events in BTC. Concordance between cfDNA and tissue for mutation detection was high for IDH1 mutations (87%) and BRAF V600E (100%), and low for FGFR2 fusions (18%). cfDNA analysis uncovered novel putative mechanisms of resistance to targeted therapies, including mutation of the cysteine residue (FGFR2 C492F) to which covalent FGFR inhibitors bind. High pre-treatment cfDNA VAF was associated with poor prognosis and shorter response to chemotherapy and targeted therapy. Finally, we report the frequency of promising targets in advanced BTC currently under investigation in other advanced solid tumors, including KRAS G12C (1.0%), KRAS G12D (5.1%), PIK3CA mutations (6.8%), and ERBB2 amplifications (4.9%).
These findings from the largest and most comprehensive study to date of cfDNA from patients with advanced BTC highlight the utility of cfDNA analysis in current management of this disease. Characterization of oncogenic drivers and mechanisms of therapeutic resistance in this study will inform drug development efforts to reduce mortality for patients with BTC.
•Targetable genetic alterations were detected in cfDNA in 44% of patients with advanced BTC.•cfDNA analysis detected IDH1 mutations and BRAF V600E at similar rates to tissue biopsies, but only 18% of FGFR2 fusions.•cfDNA analysis uncovered novel putative mechanisms of resistance to targeted therapies in advanced BTC.•High pre-treatment cfDNA VAF was associated with poor prognosis and shorter response to chemotherapy and targeted therapy.•We provide the frequencies of a compendium of promising targets present in cfDNA in BTC that are under investigation in other solid tumors.
Mortality rates from chronic kidney disease (CKD) have increased in the last decade. In this pre-specified analysis of the DAPA-CKD trial, we determined the effects of dapagliflozin on cardiovascular ...and non-cardiovascular causes of death.
DAPA-CKD was an international, randomized, placebo-controlled trial with a median of 2.4 years of follow-up. Eligible participants were adult patients with CKD, defined as a urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g and an estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2. All-cause mortality was a key secondary endpoint. Cardiovascular and non-cardiovascular death was adjudicated by an independent clinical events committee. The DAPA-CKD trial randomized participants to dapagliflozin 10 mg/day (n = 2152) or placebo (n = 2152). The mean age was 62 years, 33% were women, the mean eGFR was 43.1 mL/min/1.73 m2, and the median UACR was 949 mg/g. During follow-up, 247 (5.7%) patients died, of whom 91 (36.8%) died due to cardiovascular causes, 102 (41.3%) due to non-cardiovascular causes, and in 54 (21.9%) patients, the cause of death was undetermined. The relative risk reduction for all-cause mortality with dapagliflozin (31%, hazard ratio HR 95% confidence interval (CI) 0.69 0.53, 0.88; P = 0.003) was consistent across pre-specified subgroups. The effect on all-cause mortality was driven largely by a 46% relative risk reduction of non-cardiovascular death (HR 95% CI 0.54 0.36, 0.82). Deaths due to infections and malignancies were the most frequently occurring causes of non-cardiovascular deaths and were reduced with dapagliflozin vs. placebo.
In patients with CKD, dapagliflozin prolonged survival irrespective of baseline patient characteristics. The benefits were driven largely by reductions in non-cardiovascular death.
Internal hospital crises and disasters (IHCDs) are events that disrupt the routine functioning of a hospital while threatening the well-being of patients and staff. IHCDs may cause hospital closure, ...evacuations of patients and loss of healthcare capacity. The consequences may be ruinous for local communities. Although IHCDs occur with regularity, information on the frequency and types of these events is scarcely published in the medical literature. However, gray literature and popular media reports are widely available. We therefore conducted a scoping review of these literature sources to identify and characterize the IHCDs that occurred in Dutch hospitals from 2000 to 2020. The aim is to develop a systematic understanding of the frequency of the various types of IHCDs occurring in a prosperous nation such as the Netherlands.
A systematic scoping review of news articles retrieved from the LexisNexis database, Google, Google News, PubMed and EMBASE between 2000 and 2020. All articles mentioning the closure of a hospital department in the Netherlands were analyzed.
A total of 134 IHCDs were identified in a 20-year time period. Of these IHCDs, there were 96 (71.6%) emergency department closures, 76 (56.7%) operation room closures, 56 (41.8%) evacuations, 26 (17.9%) reports of injured persons, and 2 (1.5%) reported casualties. Cascading events of multiple failures transpired in 39 (29.1%) IHCDs. The primary causes of IHCDs (as reported) were information and communication technology (ICT) failures, technical failures, fires, power failures, and hazardous material warnings. An average of 6.7 IHCDs occurred per year. From 2000-2009 there were 32 IHCDs, of which one concerned a primary ICT failure. Of the 102 IHCDs between 2010-2019, 32 were primary ICT failures.
IHCDs occur with some regularity in the Netherlands and have marked effects on hospital critical care departments, particularly emergency departments. Cascading events of multiple failures transpire nearly a third of the time, limiting the ability of a hospital to stave off closure due to failure. Emergency managers should therefore prioritize the risk of ICT failures and cascading events and train hospital staff accordingly.
ObjectiveTo identify the prevalence of stage B heart failure (SBHF) in patients with type 2 diabetes mellitus (T2DM) with no history of cardiovascular disease (CVD).DesignObservational study.SettingA ...single-centre study in which eligible patients were recruited from T2DM clinic. Following consent, patients completed a questionnaire and underwent physical examinations. Patients had blood drawn for laboratory investigations and had a transthoracic echocardiography.ParticipantsA total of 305 patients who were not known to have CVD were recruited. Patients with deranged liver function tests and end stage renal failure were excluded.Main outcome measuresEchocardiographic parameters such as left ventricular ejection fraction, left ventricular mass index (LVMI), left ventricular hypertrophy, left atrial enlargement and diastolic function were examined.ResultsA total of 305 patients predominantly females (65%), with mean body mass index of 27.5 kg/m2 participated in this study. None of them had either a history or signs and symptoms of CVD. Seventy-seven percent of patients had a history of hypertension and 83% of this study population had T2DM for more than 10 years. Mean HbA1c of 8.3% was recorded. Almost all patients were taking metformin. Approximately, 40% of patients were on newer anti-T2DM agents such as sodium-glucose cotransporter-2 and dipeptidyl peptidase 4 inhibitors. Fifty-seven percent (n=174) of the study population had SBHF at the time of study: diastolic dysfunction, increased LVMI and increased left atrial volume index (LAVI) were noted in 51 patients (17%), 128 patients (42%) and 98 patients (32%), respectively. Thirty-seven patients (12%) had both increase LVMI and LAVI.ConclusionOur study has revealed a high prevalence of SBHF in T2DM patients without overt cardiac disease in Malaysia that has one of the highest prevalence of TDM in the world.
Summary
Background
Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps (NPs). One of the features of NPs is ...excessive fibrin deposition, which is associated with down‐regulation of tissue plasminogen activator (t‐PA) in NPs. As t‐PA is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t‐PA would be a potential new strategy for the treatment of NPs.
Objective
The objective of this study was to determine whether short‐chain fatty acids (SCFAs) can induce t‐PA in airway epithelial cells via their known receptors GPR41 and GPR43.
Methods
We performed immunohistochemistry (IHC) to determine whether receptors for SCFAs, known as G protein‐coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3) and GPR43/FFAR2, are expressed in nasal tissue. Primary normal human bronchial epithelial (NHBE) cells were stimulated with different concentrations of SCFAs to test induction of t‐PA, which was analysed by expression of mRNA and protein. Mediation of responses by SCFA receptors was evaluated by specific receptor gene silencing with siRNA.
Results
Immunohistochemistry study revealed that airway epithelial cells expressed GPR41 and GPR43. Acetic acid, propionic acid, butyric acid and valeric acid significantly induced t‐PA expression from two‐ to tenfolds. The strongest inducer of t‐PA from NHBE cells was propionic acid; cells stimulated with propionic acid released t‐PA into the supernatant in its active form. Gene silencing of GPR41 and GPR43 revealed that induction of t‐PA by SCFAs was dependent upon both GPR41 and GPR43.
Conclusions and Clinical Relevance
Short‐chain fatty acids were shown to induce airway epithelial cell expression of t‐PA via GPR41 and GPR43. Topical delivery of potent compounds that activate these receptors may have value by reducing fibrin deposition and shrinking nasal polyp growth.
We present the detection of three exoplanets orbiting the early M dwarf TOI-663 (TIC 54962195; V = 13.7 mag, J = 10.4 mag, R ★ = 0.512 ± 0.015 R ⊙ , M ★ = 0.514 ± 0.012 M ⊙ , d = 64 pc). TOI-663 b, ...c, and d, with respective radii of 2.27 ± 0.10 R ⊕ , 2.26 ± 0.10 R ⊕ , and 1.92 ± 0.13 R ⊕ and masses of 4.45 ± 0.65 M ⊕ , 3.65 ± 0.97 M ⊕ , and <5.2 M ⊕ at 99%, are located just above the radius valley that separates rocky and volatile-rich exoplanets. The planet candidates are identified in two TESS sectors and are validated with ground-based photometric follow-up, precise radial-velocity measurements, and high-resolution imaging. We used the software package juliet to jointly model the photometric and radial-velocity datasets, with Gaussian processes applied to correct for systematics. The three planets discovered in the TOI-663 system are low-mass mini-Neptunes with radii significantly larger than those of rocky analogs, implying that volatiles, such as water, must predominate. In addition to this internal structure analysis, we also performed a dynamical analysis that confirmed the stability of the system. The three exoplanets in the TOI-663 system, similarly to other sub-Neptunes orbiting M dwarfs, have been found to have lower densities than planets of similar sizes orbiting stars of different spectral types.
Plastic pellets represent a significant component of microplastic (< 5 mm) pollution. Impacts caused by plastic pellets involve physical harm and toxicity related to ingestion and non-ingestion (such ...as the release of chemicals in leachates). The latter is the main route of exposure for invertebrate macrobenthic populations. This study aimed to compare the toxicity of plastic pellets in distinct marine macrobenthic populations, considering the influence of sediment characteristics (organic matter and grain size) and quality (contamination by hydrophobic chemicals) on ecotoxicological effects, as well as the influence of color on the toxicity of beach-stranded plastic pellets. We performed three experiments on plastic pellet exposure using Excirolana armata from beaches with high and low pellet density. When exposed to pellets, populations that inhabit beaches without pellets demonstrate higher mortality than those inhabiting beaches with high pellet densities. The mortality of E. armata to pellets was higher when the exposure occurred in sediment with high organic matter (OM), suggesting that chemicals were transferred from pellets to OM. Yellowish beach-stranded pellets induced higher mortality of E. armata than the white tones did. We also observed lethargic (near-dead) and dead individuals being preyed upon by healthy individuals, a cannibalistic behavior that raises an ecological concern regarding the negative effects of this exposure on intraspecific interactions in marine macrobenthic populations.
ABSTRACT
We report the discovery in TESS Sectors 3 and 4 of a compact triply eclipsing triple star system. TIC 209409435 is a previously unknown eclipsing binary with a period of 5.717 d, and the ...presence of a third star in an outer eccentric orbit of 121.872-d period was found from two sets of third-body eclipses and from eclipse timing variations. The latter exhibits signatures of strong third-body perturbations. After the discovery, we obtained follow-up ground-based photometric observations of several binary eclipses as well as another of the third-body eclipses. We carried out comprehensive analyses, including the simultaneous photodynamical modelling of TESS and ground-based light curves (including both archival WASP data, and our own follow-up measurements), as well as eclipse timing variation curves. Also, we have included in the simultaneous fits multiple star spectral energy distribution data and theoretical PARSEC stellar isochrones. We find that the inner binary consists of near twin stars of mass 0.90 M⊙ and radius 0.88 R⊙. The third star is just 9 per cent more massive and 18 per cent larger in radius. The inner binary has a rather small eccentricity, while the outer orbit has e = 0.40. The inner binary and outer orbit have inclination angles within 0.1° and 0.2° of 90°, respectively. The mutual inclination angle is ≲1/4°. All of these results were obtained without radial velocity observations.
Based on TiO2 nanorod arrays@PDA/Ag (TNRs@PDA/Ag), a better surface-enhanced Raman scattering (SERS) sensor with effective enrichment and enhancement was investigated for duplex SERS detection of ...illicit food dyes. Biomimetic PDA functions as binary mediators by utilizing the structural characteristics of polydopamine (PDA), which include the conjugated structure and abundant hydrophilic groups. One PDA functioned as an electron transfer mediator to enhance the efficiency of electron transfer, and the other as an enrichment mediator to effectively enrich rhodamine B (RhB) and crystal violet (CV) through hydrogen bonding, π-π stacking, and electrostatic interactions. Individual and duplex detection of illicit food dyes (RhB and CV) was performed using TNRs@PDA/Ag to estimate SERS applications. Their linear equations and limits of detection of 1 nM for RhB and 5 nM for CV were derived. Individual and duplex food colour detection was successfully accomplished even in genuine chili meal with good results. The bifunctional TNRs@PDA/Ag-based highly sensitive and duplex SERS dye detection will have enormous potential for food safety monitoring.
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