Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with ...non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade.
We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD.
A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868–7.440 and overall survival (HR, 5.079; 95% CI, 3.136–8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7−CD45RA− T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate.
HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.
We present results from an analysis of all data taken by the BICEP2, Keck Array, and BICEP3 CMB polarization experiments up to and including the 2018 observing season. We add additional Keck Array ...observations at 220 GHz and BICEP3 observations at 95 GHz to the previous 95 / 150 / 220 GHz dataset. The Q / U maps now reach depths of 2.8, 2.8, and 8.8 μ KCMB arcmin at 95, 150, and 220 GHz, respectively, over an effective area of ≈ 600 square degrees at 95 GHz and ≈ 400 square degrees at 150 and 220 GHz. The 220 GHz maps now achieve a signal-to-noise ratio on polarized dust emission exceeding that of Planck at 353 GHz. We take auto- and cross-spectra between these maps and publicly available WMAP and Planck maps at frequencies from 23 to 353 GHz and evaluate the joint likelihood of the spectra versus a multicomponent model of lensed Λ CDM + r + dust + synchrotron + noise . The foreground model has seven parameters, and no longer requires a prior on the frequency spectral index of the dust emission taken from measurements on other regions of the sky. This model is an adequate description of the data at the current noise levels. The likelihood analysis yields the constraint r0.05 < 0.036 at 95% confidence. Running maximum likelihood search on simulations we obtain unbiased results and find that σ ( r ) = 0.009 . These are the strongest constraints to date on primordial gravitational waves.
ABO incompatibility is no longer considered a contraindication for adult living donor liver transplantation (ALDLT) due to various strategies to overcome the ABO blood group barrier. We report the ...largest single‐center experience of ABO‐incompatible (ABOi) ALDLT in 235 adult patients. The desensitization protocol included a single dose of rituximab and total plasma exchange. In addition, local graft infusion therapy, cyclophosphamide, or splenectomy was used for a certain time period, but these treatments were eventually discontinued due to adverse events. There were three cases (1.3%) of in‐hospital mortality. The cumulative 3‐year graft and patient survival rates were 89.2% and 92.3%, respectively, and were comparable to those of the ABO‐compatible group (n = 1301). Despite promising survival outcomes, 17 patients (7.2%) experienced antibody‐mediated rejection that manifested as diffuse intrahepatic biliary stricture; six cases required retransplantation, and three patients died. ABOi ALDLT is a feasible method for expanding a living liver donor pool, but the efficacy of the desensitization protocol in targeting B cell immunity should be optimized.
This article presents the clinical results of ABO‐incompatible adult living donor liver transplantation in a single institution.
The large volume of adult living donor liver transplantations (ALDLTs) at our center affords a unique opportunity to examine the impact of acute‐on‐chronic liver failure (ACLF) among high–Model for ...End‐Stage Liver Disease MELD score patients. From February 1998 to March 2010, 1958 cirrhotic recipients were analyzed to study the relationship between MELD scores and ALDLT outcomes. A total of 327 high‐MELD score recipients were categorized into ACLF and non‐ACLF groups, and their outcomes were compared. The 5‐year graft and patient survival in the high‐MELD group were 75.2% and 76.4%, respectively, which were significantly worse than the low and intermediate MELD groups. The presence of ACLF associated with higher MELD scores appeared to be the dominant factor responsible for the inferior results of patients with MELD score of 30–34 points. The 5‐year graft survivals in the ACLF group was 70.5% and in the non‐ACLF group it was 81.0% (p = 0.035). Therefore, ALDLT should be performed as soon as possible in high‐MELD score patients prior to ACLF development. Moreover, ACLF patients should be separately categorized when analyzing the outcomes of ALDLT. ALDLT for ACLF patients should not be discouraged because favorable outcomes can be expected through timely ALDLT and comprehensive management.
While adult living donor liver transplantation should be performed as soon as possible before acute‐on‐chronic liver failure develops, it should not be discouraged for patients with acute‐on‐chronic liver failure since timely transplantation and comprehensive management can bring a favorable outcome.
Aims: An investigation was carried out on an oxidative and SDS‐stable alkaline protease secreted by Bacillus clausii of industrial significance.
Methods and Results: Maximum enzyme activity was ...produced when the bacterium was grown in the medium containing (g l−1): soyabean meal, 15; wheat flour, 10; liquid maltose, 25; K2HPO4, 4; Na2HPO4, 1; MgSO4·7H2O, 0·1; Na2CO3, 6. The enzyme has an optimum pH of around 11 and optimum temperature of 60°C. The alkaline protease showed extreme stability towards SDS and oxidizing agents, which retained its activity above 75 and 110% on treatment for 72 h with 5% SDS and 10% H2O2, respectively. Inhibition profile exhibited by phenylmethylsulphonyl fluoride suggested that the protease from B. clausii belongs to the family of serine proteases.
Conclusions: Bacillus clausii produced high levels of an extracellular protease having high stability towards SDS and H2O2.
Significance and Impact of the Study: The alkaline protease from B. clausii I‐52 is significant for an industrial perspective because of its ability to function in broad pH and temperature ranges in addition to its tolerance and stability in presence of an anionic surfactant, like SDS and oxidants like peroxides and perborates. The enzymatic properties of the protease also suggest its suitable application as additive in detergent formulations.
Abstract Purpose Combined hepatocellular carcinoma (HCC) and cholangiocellular carcinoma (CCC) is a rare pair of intrahepatic malignancies. Differential diagnosis among combined HCC-CCC, HCC, or CCC ...can be difficult; thus malignancies other than ordinary HCC are occasionally encountered unexpectedly in explanted liver specimens. The present study analyzed the long-term outcomes of liver transplantation (OLT) among patients with HCC-CCC. Methods Between January 1999 and December 2009, we performed 2137 adult OLT at our institution including 15 cases of pathologically confirmed HCC-CCC, who all underwent OLT with a pretransplant diagnosis of HCC. We reviewed retrospectively the medical records of these 15 patients. Results Their mean age was 58.9 ± 7.2 years. The median preoperative alpha-fetoprotein level was 32.6 ng/mL. Fourteen patients underwent living donor and one deceased donor OLT. The Milan criteria were met in 12 cases. A single tumor was identified in 8 and multiple lesions in 7 patients. The maximal tumor diameter was 2.9 ± 1.7 cm. Seven patients experienced tumor recurrences: including 6 within the first 12 months. All of the patients who experienced recurrences died at a median 4 months after that diagnosis. The overall patient survival rates were 66.7% at 1 year and 60.0% at 3 and 5 years. Disease-free patient survival rates were 60.0% at 1 year and 53.3% at 3 and 5 years. Conclusions Patients with combined HCC-CCC showed a high rate of early recurrences, particularly within the first year.
A recent observation points to an excess in the expected 21-cm brightness temperature from cosmic dawn. In this paper, we present an alternative explanation of this phenomenon, an interaction in the ...dark sector. Interacting dark energy models have been extensively studied recently and there is a whole variety of such in the literature. Here we particularize to a specific model in order to make explicit the effect of an interaction.
Manipulating structure, defects and composition of a material at the atomic scale for enhancing its physical or mechanical properties is referred to as nanostructuring. Here, by combining advanced ...microscopy techniques, we unveil how formation of highly regular nano-arrays of nanoparticles doubles the strength of an Fe-based alloy, doped with Ti, Mo, and V, from 500 MPa to 1 GPa, upon prolonged heat treatment. The nanoparticles form at moving heterophase interfaces during cooling from the high-temperature face-centered cubic austenite to the body-centered cubic ferrite phase. We observe MoC and TiC nanoparticles at early precipitation stages as well as core-shell nanoparticles with a Ti-C rich core and a Mo-V rich shell at later precipitation stages. The core-shell structure hampers particle coarsening, enhancing the material's strength. Designing such highly organized metallic core-shell nanoparticle arrays provides a new pathway for developing a wide range of stable nano-architectured engineering metallic alloys with drastically enhanced properties.
TDCOSMO Birrer, S.; Shajib, A. J.; Galan, A. ...
Astronomy and astrophysics (Berlin),
11/2020, Letnik:
643
Journal Article, Web Resource
Recenzirano
Odprti dostop
The H0LiCOW collaboration inferred via strong gravitational lensing time delays a Hubble constant value of
H
0
= 73.3
−1.8
+1.7
km s
−1
Mpc
−1
, describing deflector mass density profiles by either a ...power-law or stars (constant mass-to-light ratio) plus standard dark matter halos. The mass-sheet transform (MST) that leaves the lensing observables unchanged is considered the dominant source of residual uncertainty in
H
0
. We quantify any potential effect of the MST with a flexible family of mass models, which directly encodes it, and they are hence maximally degenerate with
H
0
. Our calculation is based on a new hierarchical Bayesian approach in which the MST is only constrained by stellar kinematics. The approach is validated on mock lenses, which are generated from hydrodynamic simulations. We first applied the inference to the TDCOSMO sample of seven lenses, six of which are from H0LiCOW, and measured
H
0
= 74.5
−6.1
+5.6
km s
−1
Mpc
−1
. Secondly, in order to further constrain the deflector mass density profiles, we added imaging and spectroscopy for a set of 33 strong gravitational lenses from the Sloan Lens ACS (SLACS) sample. For nine of the 33 SLAC lenses, we used resolved kinematics to constrain the stellar anisotropy. From the joint hierarchical analysis of the TDCOSMO+SLACS sample, we measured
H
0
= 67.4
−3.2
+4.1
km s
−1
Mpc
−1
. This measurement assumes that the TDCOSMO and SLACS galaxies are drawn from the same parent population. The blind H0LiCOW, TDCOSMO-only and TDCOSMO+SLACS analyses are in mutual statistical agreement. The TDCOSMO+SLACS analysis prefers marginally shallower mass profiles than H0LiCOW or TDCOSMO-only. Without relying on the form of the mass density profile used by H0LiCOW, we achieve a ∼5% measurement of
H
0
. While our new hierarchical analysis does not statistically invalidate the mass profile assumptions by H0LiCOW – and thus the
H
0
measurement relying on them – it demonstrates the importance of understanding the mass density profile of elliptical galaxies. The uncertainties on
H
0
derived in this paper can be reduced by physical or observational priors on the form of the mass profile, or by additional data.
In this work, we present measurements of the E-mode (EE) polarization power spectrum and temperature-E-mode (TE) cross-power spectrum of the cosmic microwave background using data collected by ...SPT-3G, the latest instrument installed on the South Pole Telescope. This analysis uses observations of a 1500 deg2 region at 95, 150, and 220 GHz taken over a four-month period in 2018. We report binned values of the EE and TE power spectra over the angular multipole range 300≤ℓ<3000, using the multifrequency data to construct six semi-independent estimates of each power spectrum and their minimum-variance combination. These measurements improve upon the previous results of SPTpol across the multipole ranges 300 ≤ ℓ ≤ 1400 for EE and 300 ≤ ℓ ≤ 1700 for TE, resulting in constraints on cosmological parameters comparable to those from other current leading ground-based experiments. We find that the SPT-3G data set is well fit by a ΛCDM cosmological model with parameter constraints consistent with those from Planck and SPTpol data. From SPT-3G data alone, we find H0=68.8±1.5 km s-1 Mpc-1 and σ8=0.789±0.016, with a gravitational lensing amplitude consistent with the ΛCDM prediction (AL=0.98±0.12). We combine the SPT-3G and the Planck data sets and obtain joint constraints on the ΛCDM model. The volume of the 68% confidence region in six-dimensional ΛCDM parameter space is reduced by a factor of 1.5 compared to Planck-only constraints, with no significant shifts in central values. We note that the results presented here are obtained from data collected during just half of a typical observing season with only part of the focal plane operable, and that the active detector count has since nearly doubled for observations made with SPT-3G after 2018.
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