The PD-L1/PD-1 pathway is a critical component of the immunosuppressive tumor microenvironment in acute myeloid leukemia (AML), but little is known about its regulation. We investigated the role of ...the MUC1 oncoprotein in modulating PD-L1 expression in AML. Silencing of MUC1 in AML cell lines suppressed PD-L1 expression without a decrease in PD-L1 mRNA levels, suggesting a post-transcriptional mechanism of regulation. We identified the microRNAs miR-200c and miR-34a as key regulators of PD-L1 expression in AML. Silencing of MUC1 in AML cells led to a marked increase in miR-200c and miR-34a levels, without changes in precursor microRNA, suggesting that MUC1 might regulate microRNA-processing. MUC1 signaling decreased the expression of the microRNA-processing protein DICER, via the suppression of c-Jun activity. NanoString (Seattle, WA, USA) array of MUC1-silenced AML cells demonstrated an increase in the majority of probed microRNAs. In an immunocompetent murine AML model, targeting of MUC1 led to a significant increase in leukemia-specific T cells. In concert, targeting MUC1 signaling in human AML cells resulted in enhanced sensitivity to T-cell-mediated lysis. These findings suggest MUC1 is a critical regulator of PD-L1 expression via its effects on microRNA levels and represents a potential therapeutic target to enhance anti-tumor immunity.
Abstract Understanding how galaxies quench their star formation is crucial for studies of galaxy evolution. Quenching is related to a decrease of cold gas. In the first paper we showed that the dust ...removal timescale in early-type galaxies (ETGs) is about 2.5 Gyr. Here we present carbon monoxide and 21 cm hydrogen line observations of these galaxies and measure the timescale of removal of the cold interstellar medium (ISM). We find that all the cold ISM components (dust and molecular and atomic gas) decline at similar rates. This allows us to rule out a wide range of potential ISM-removal mechanisms (including starburst-driven outflows, astration, or a decline in the number of asymptotic giant branch stars), and artificial effects like the stellar mass–age correlation, environmental influence, mergers, and selection bias, leaving ionization by evolved low-mass stars and ionization/outflows by Type Ia supernovae or active galactic nuclei as viable mechanisms. We also provide evidence for an internal origin of the detected ISMs. Moreover, we find that the quenching of star formation in these galaxies cannot be explained by a reduction in the gas amount alone, because the star formation rates (SFRs) decrease faster (on a timescale of about 1.8 Gyr) than the amount of cold gas. Furthermore, the star formation efficiency (SFE) of the ETGs ( SFE ≡ SFR / M H 2 ) is lower than that of star-forming galaxies, whereas their gas mass fractions ( f H 2 ≡ M H 2 / M * ) are normal. This may be explained by the stabilization of gas against fragmentation, for example due to morphological quenching, turbulence, or magnetic fields.
ABSTRACT
Blazar S5 0716+714 is well-known for its short-term variability, down to intraday time-scales. We here present the 2-min cadence optical light curve obtained by the TESS space telescope in ...2019 December–2020 January and analyse the object fast variability with unprecedented sampling. Supporting observations by the Whole Earth Blazar Telescope Collaboration in B, V, R, and I bands allow us to investigate the spectral variability during the TESS pointing. The spectral analysis is further extended in frequency to the UV and X-ray bands with data from the Neil Gehrels Swift Observatory. We develop a new method to unveil the shortest optical variability time-scales. This is based on progressive de-trending of the TESS light curve by means of cubic spline interpolations through the binned fluxes, with decreasing time bins. The de-trended light curves are then analysed with classical tools for time-series analysis (periodogram, autocorrelation, and structure functions). The results show that below 3 d there are significant characteristic variability time-scales of about 1.7, 0.5, and 0.2 d. Variability on time-scales $\lesssim 0.2$ d is strongly chromatic and must be ascribed to intrinsic energetic processes involving emitting regions, likely jet substructures, with dimension less than about 10−3 pc. In contrast, flux changes on time-scales $\gtrsim 0.5$ d are quasi-achromatic and are probably due to Doppler factor changes of geometric origin.
The 3-30-300 rule offers benchmarks for cities to promote equitable nature access. It dictates that individuals should see three trees from their dwelling, have 30 % tree canopy in their ...neighborhood, and live within 300 m of a high-quality green space. Implementing this demands thorough measurement, monitoring, and evaluation methods, yet little guidance is currently available to pursue these actions. To overcome this gap, we employed an expert-based consensus approach to review the available ways to measure 3-30-300 as well as each measure's strengths and weaknesses. We described seven relevant data and processes: vegetation indices, street level analyses, tree inventories, questionnaires, window view analyses, land cover maps, and green space maps. Based on the reviewed strengths and weaknesses of each measure, we presented a suitability matrix to link recommended measures with each component of the rule. These recommendations included surveys and window-view analyses for the '3 component', high-resolution land cover maps for the '30 component', and green space maps with network analyses for the '300 component'. These methods, responsive to local situations and resources, not only implement the 3-30-300 rule but foster broader dialogue on local desires and requirements. Consequently, these techniques can guide strategic investments in urban greening for health, equity, biodiversity, and climate adaptation.
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•Vesatolimod was safe and well-tolerated in patients with chronic HBV infection.•Dose-dependent pharmacodynamic induction of ISGs was demonstrated with vesatolimod.•No significant ...HBsAg declines were observed with vesatolimod treatment.
Vesatolimod (GS-9620) is an oral agonist of toll-like receptor 7, an activator of innate and adaptive immune responses. Herein the safety and efficacy of vesatolimod is assessed after once-weekly treatment in patients with chronic hepatitis B (CHB) infection suppressed on oral antiviral treatment.
In a phase II, double-blind, randomized, placebo (PBO)-controlled study, 162 patients stratified by hepatitis B surface antigen (HBsAg) levels and serum hepatitis B e antigen (HBeAg) status were randomized 1:3:3:3 to once-weekly oral PBO or vesatolimod (1-, 2-, or 4-mg doses) for 4, 8 or 12 weeks per cohort. Efficacy was assessed by change in baseline HBsAg (log10 IU/ml) at the primary endpoint (Week 24). Safety assessments included adverse events (AE) and laboratory abnormality monitoring. Pharmacodynamic assessments included peripheral cytokine level quantification and interferon-stimulated gene (ISG) mRNA expression evaluation.
The majority of patients were male (76%) and HBeAg-negative (79%) at baseline. Most (41–80%) experienced ≥1 AE during the study with the majority of AEs mild or moderate in severity. No significant declines in HBsAg were observed at the primary (Week 24) or secondary endpoints (Weeks 4, 8, 12, and 48). ISG15 induction was dose-dependent and consistent after repeat dosing, returning closer to baseline by one week after treatment at all dose levels; no patient demonstrated significant serum interferon alpha (IFNα) expression at any timepoint evaluated. Multivariate analyses showed that ≥2-fold ISG15 induction is associated with 2- or 4-mg vesatolimod dose and female sex.
Vesatolimod was safe and well-tolerated in patients with CHB, demonstrating consistent dose-dependent pharmacodynamic induction of ISG15 without significant systemic induction of IFNα expression or related symptoms. However, no significant HBsAg declines were observed.
In a phase II study, vesatolimod, an oral, once-weekly, experimental immune-activating drug for the treatment of hepatitis B virus (HBV), is safe and well-tolerated in chronic HBV patients who are virally suppressed on oral antiviral treatment. Despite demonstrating on-target biomarker responses in patients, no significant declines in hepatitis B surface antigen were observed.
Clinical Trial Number: GS-US-283-1059; NCT 02166047.
The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate ...linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician’s choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes.
Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline.
Of 468 assessable patients, 290 had Trop-2 expression data 64% (n = 151 SG) versus 60% (n = 139 TPC) and 292 had known BRCA1/2 mutation status 63% (n = 149 SG) versus 61% (n = 143 TPC). Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations.
SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup.
•The majority of patients (80%) with mTNBC in the ASCENT study with available data had high/medium tumor Trop-2 expression.•Survival outcomes and ORRs were numerically higher in SG- versus TPC-treated patients with high/medium Trop-2 expression.•Benefit of SG in patients with high/medium Trop-2 expression was similar to that of overall primary efficacy population.•The small number of patients with low Trop-2 expression prevents definitive conclusions on benefit of SG in this subgroup.•Benefit of SG over TPC was also similar regardless of germline BRCA1/2 mutation status.
We investigated the properties of a sample of red Quasi-stellar Objects (QSOs) using optical, radio, and infrared data. These QSOs were selected from the Sloan Digital Sky Survey Data Release 7 ...quasar catalog. We only selected sources with sky coverage in the Very Large Array Faint Images of the Radio Sky at Twenty-centimeters survey, and searched for sources with Wide-field Infrared Survey Explorer counterparts. We defined the spectral color of the QSOs based on the flux ratio of the rest-frame 4000 to 3000 continuum emission to select red QSOs and typical QSOs. In accordance with this criterion, only QSOs with redshifts between 0.3 and 1.2 could be selected. We found that red QSOs have stronger infrared emission than typical QSOs. We noted that the number ratios of red QSOs to typical QSOs decrease with increasing redshifts, although the number of typical QSOs increase with redshifts. Furthermore, at high redshifts, the luminosity distributions of typical QSOs and red QSOs seem to have similar peaks; however, at low redshifts, the luminosities of red QSOs seem to be lower than those of typical QSOs. These findings suggest that there might be at least two types of red QSOs in our QSO samples.
Context.
An important aspect of quenching star formation is the removal of the cold interstellar medium (ISM; non-ionised gas and dust) from a galaxy. In addition, dust grains can be destroyed in a ...hot or turbulent medium. The adopted timescale of dust removal usually relies on uncertain theoretical estimates. It is tricky to track dust removal because the dust is constantly being replenished by consecutive generations of stars.
Aims.
Our objective is to carry out an observational measurement of the timescale of dust removal.
Methods.
We explored an approach to select galaxies that demonstrate detectable amounts of dust and cold ISM coupled with a low current dust production rate. Any decrease of the dust and gas content as a function of the age of such galaxies must, therefore, be attributed to processes governing ISM removal. We used a sample of the galaxies detected by
Herschel
in the far-infrared with visually assigned early-type morphology or spirals with red colours. We also obtained JCMT/SCUBA-2 observations for five of these galaxies.
Results.
We discovered an exponential decline of the dust-to-stellar mass ratio with age, which we interpret as an evolutionary trend for the dust removal of these galaxies. For the first time, we have directly measured the dust removal timescale for such galaxies, with a result of
τ
= (2.5 ± 0.4) Gyr (the corresponding half-life time is (1.75 ± 0.25) Gyr). This quantity may be applied to models in which it must be assumed a priori and cannot be derived.
Conclusions.
Any process which removes dust in these galaxies, such as dust grain destruction, cannot happen on shorter timescales. The timescale is comparable to the quenching timescales found in simulations for galaxies with similar stellar masses. The dust is likely of internal, not external origin. It was either formed in the past directly by supernovae (SNe) or from seeds produced by SNe, and with grain growth in the ISM contributing substantially to the dust mass accumulation.
Nonalcoholic steatohepatitis (NASH), a chronic liver disease without an approved therapy, is associated with lipotoxicity and insulin resistance and is a major cause of cirrhosis and hepatocellular ...carcinoma. Aramchol, a partial inhibitor of hepatic stearoyl-CoA desaturase (SCD1) improved steatohepatitis and fibrosis in rodents and reduced steatosis in an early clinical trial. ARREST, a 52-week, double-blind, placebo-controlled, phase 2b trial randomized 247 patients with NASH (n = 101, n = 98 and n = 48 in the Aramchol 400 mg, 600 mg and placebo arms, respectively; NCT02279524 ). The primary end point was a decrease in hepatic triglycerides by magnetic resonance spectroscopy at 52 weeks with a dose of 600 mg of Aramchol. Key secondary end points included liver histology and alanine aminotransferase (ALT). Aramchol 600 mg produced a placebo-corrected decrease in liver triglycerides without meeting the prespecified significance (-3.1, 95% confidence interval (CI) -6.4 to 0.2, P = 0.066), precluding further formal statistical analysis. NASH resolution without worsening fibrosis was achieved in 16.7% (13 out of 78) of Aramchol 600 mg versus 5% (2 out of 40) of the placebo arm (odds ratio (OR) = 4.74, 95% CI = 0.99 to 22.7) and fibrosis improvement by ≥1 stage without worsening NASH in 29.5% versus 17.5% (OR = 1.88, 95% CI = 0.7 to 5.0), respectively. The placebo-corrected decrease in ALT for 600 mg was -29.1 IU l
(95% CI = -41.6 to -16.5). Early termination due to adverse events (AEs) was <5%, and Aramchol 600 and 400 mg were safe, well tolerated and without imbalance in serious or severe AEs between arms. Although the primary end point of a reduction in liver fat did not meet the prespecified significance level with Aramchol 600 mg, the observed safety and changes in liver histology and enzymes provide a rationale for SCD1 modulation as a promising therapy for NASH and fibrosis and are being evaluated in an ongoing phase 3 program.
Cardiovascular risk attributable to bevacizumab (Avastin®, BEV) for treatment of metastatic colorectal cancer (CRC) remains unclear. We conducted a population-based cohort study to assess the safety ...of BEV use among patients aged ≥65.
We identified CRC patients diagnosed from 2005 to 2007 who received chemotherapy and were followed until 31 December 2009. Outcomes were 3-year risk of arterial thromboembolic events (ATEs), cardiomyopathy or congestive heart failure (CM/CHF), and cardiac death (CD) after chemotherapy initiation. We fitted Cox-proportional hazards (PHs) models with inverse-probability-of-treatment-weights and calculated hazard ratios (HRs) for the risk of adverse events.
We identified 6803 CRC patients (median age: 73 years). Those with cardiac comorbidity were less likely to receive BEV (P < 0.0001). BEV is associated with an elevated risk of ATEs (HR = 1.82, 95% CI = 1.20–2.76, P < 0.001; rate difference: 3.5 additional cases/1000 person-years). We observed no association between BEV and CD or CM/CHF.
In general practice, the cardiovascular risk of BEV in elderly CRC is modest. The observed ATEs risk is lower than reported in clinical trials, which may be due to careful patient selection. Our findings may facilitate clinical decision-making of BEV use in elderly patients.
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