PD-L1 immunohistochemistry (IHC) testing is usually carried out on tissue blocks from core needle biopsy or surgical resections. In this study, we assessed the feasibility of using cytology cell ...blocks for PD-L1 IHC assay.
A total of 1419 consecutive cases of non-small-cell lung cancer (NSCLC), including 371 cytology cell blocks, 809 small biopsies, and 239 surgical specimens, were included in the study. The cytology cell blocks were prepared with formalin only, methanol/alcohol only or both. PD-L1 expression was examined by staining with Dako PD-L1 IHC 22C3 pharmDx kit. A Tumor Proportion Score (TPS) was categorized as <1%, 1%–49% and ≥50% tumor cells. A total of 100 viable tumor cells were required for adequacy.
Of the cytology cell blocks, 92% of the specimens had an adequate number of tumor cells, not significantly different from small biopsies. The rate of TPS ≥50% differed between sample types and was observed in 42% of cytology cell blocks versus 36% of small biopsies (P = 0.04), and 29% of surgical resections (P = 0.001). The fixative methods did not affect the immunostaining, with overall PD-L1 high expression (TPS ≥50%) rates of 42% in formalin-fixed specimens versus 40% in specimens with combined fixation by methanol/alcohol and formalin (NS). The PD-L1 high expression rate was not associated with EGFR, ALK or KRAS molecular alterations. Higher stage (IV) was associated with higher PD-L1 TPS (P= 0.001).
Our results show that when the TPS ≥50% is used as the end point, PD-L1 IHC performs well with cytology cell blocks. Cell blocks should be considered as a valuable resource for PD-L1 testing in advanced NSCLC. The clinical significance of higher PD-L1 IHC scores in cytology specimens needs to be evaluated prospectively.
During the last decades, much effort has been devoted to explain the discrepancy between the amount of intracluster medium (ICM) estimated from stellar evolution theories and that emerging from ...observations in globular clusters (GCs). One possible scenario is the accretion of this medium by an intermediate-mass black hole (IMBH) at the centre of the cluster. In this work, we aim at modelling the cluster colour-excess profile as a tracer of the ICM density, both with and without an IMBH. Comparing the profiles with observations allows us to test the existence of IMBHs and their possible role in the cleansing of the ICM. We derive the intracluster density profiles from hydrodynamical models of accretion on to a central IMBH in a GC and we determine the corresponding dust density. This model is applied to a list of 25 Galactic GCs. We find that central IMBHs decrease the ICM by several orders of magnitude. In a subset of nine clusters, the absence of the black hole combined with a low-ICM temperature would be at odds with present gas mass content estimations. As a result, we conclude that IMBHs are an effective cleansing mechanism of the ICM of GCs. We construct synthetic extinction maps for M 62 and ωCen, two clusters in the small subset of nine with observed 2D extinction maps. We find that under reasonable assumptions regarding the model parameters, if the gas temperature in M 62 is close to 8000 K, an IMBH needs to be invoked. Further ICM observations regarding both the gas and dust in GCs could help to settle this issue.
Transition-edge sensors (TES) are outstanding calorimeters based on the steep superconductive transition of a metallic film. Among other photon detectors, they are renowned for the fine energy ...resolution, the photon-number resolving (PNR) capability and an extremely low dark count rate. Due to the broad detection spectrum, from gamma-ray to visible and submillimetre wavelengths, TESs are highly sought-after in a great variety of fields, such as X-ray detection and quantum technologies. Each of these fields demands a step forward in TESs performance with regards to the recovery time and energy resolution. Here we present a program, primarily capable of predicting the performance of TESs. Using established theoretical and empirical methods we developed a software that allows the users to choose active area, thickness, and material composition of a TES and to calculate its performance. Furthermore, the software can simulate TES properties at different working points. The aim of the software is to minimize the production cost and speed up the overall process for the creation of new devices with improved performance.
The existence of intermediate-mass (∼103 M) black holes (IMBHs) in the centre of globular clusters has been suggested by different observations. The X-ray sources observed in NGC 6388 and in G1 in ...M31 could be interpreted as being powered by the accretion of matter on to such objects. In this work, we explore a scenario in which the black hole accretes from the cluster interstellar medium, which is generated by the mass-loss of the red giants in the cluster. We estimate the accretion rate on to the black hole and compare it to the values obtained via the traditional Bondi-Hoyle model. Our results show that the accretion rate is no longer solely defined by the black hole mass and the ambient parameters but also by the host cluster itself. Furthermore, we find that the more massive globular clusters with large stellar velocity dispersion are the best candidates in which accretion on to IMBHs could be detected.
cP450aromatase deficiency provides clues for the understanding of the role of aromatase in prepubertal and pubertal human health and disease. Placental aromatization of androgens protects the female ...fetus against the virilizing action of fetal androgens. After birth, the dual effect of aromatase deficiency, excessive androgens, and insufficient estrogens is responsible for a variable clinical picture. Nineteen cases of aromatase gene (CYP19) deficiency have been reported.
Phenotype is dependent on sex and age. In newborns, aromatase deficiency should be considered in the etiology of 46,XX DSD, after ruling out congenital adrenal hyperplasia. In prepubertal aromatase deficient girls, high levels of ovarian androgens and gonadotropins facilitate the formation of ovarian cysts. Bone mineralization can be affected and bone aging is delayed. In pubertal girls, there is poor sexual development and abnormal virilization. The phenotype may be variable according to enzyme activity level. Insulin sensitivity may be abnormal in both men and women. Finally, aromatase might also play a role in the regulation of testicular cell mass in the newborn testis.
Adequate interpretation of clinical data should lead to the analysis of the CYP19 gene for diagnostic confirmation and implementation of appropriate management.
The critical temperature ( T c ) of superconducting Ti/Au bilayer films is crucial for the performance of transition-edge sensors. We use a co-sputtering technique to insert a Ti-Au mixture layer as ...an artificial diffusion layer between a superconducting Ti film and a normal Au bilayer. The Ti-Au mixture layers have different thicknesses and component ratios. The cross-section and element information of thin films was characterized by a high-resolution transmission electron microscopy (HRTEM) and energy dispersive X-ray spectroscopy (EDS). The variation of T c is measured for a series of Ti/Ti-Au/Au films. T c is related to both the thickness and Ti-Au ratio in the mixture layer. We attempt to model the T c variation based on the Usadel theory with an equivalent thickness ratio.
•The PD-L1 expression similar in NSCLC from distant metastatic sites.•Samples from any accessible distant metastatic sites can be used for PD-L1 testing.•The discrepancy of PD-L1 between two ...metastatic sites likely due to heterogeneity.
PD-L1 expression by immunohistochemistry (IHC) testing with Tumor Proportion Score (TPS) ≥50% and ≥1% is required to be eligible for first- and second-line Pembrolizumab treatment for metastatic non-small cell lung cancer (NSCLC) respectively. Stage IV NSCLC often presents with metastasis to multiple distant sites which are easily accessible for biopsy. Knowing whether PD-L1 IHC TPS can be indifferently measured from different metastatic site is therefore an important clinical question. In this study, we evaluated PD-L1 expression in NSCLC from varied distant metastatic sites.
A total of 580 NSCLC specimens of distant metastases were retrieved for study, including 35 paired samples from two different metastatic sites. The metastatic sites included brain, bone, remote lymph nodes, serous membranes (pleura, pericardium and peritoneum), extra-thoracic solid organs and skin/soft tissues. The samples were cytology cell blocks, small biopsies or surgical resections. IHC was performed using Dako PD-L1 IHC 22C3 pharmDx. A total of 100 viable tumor cells was required for adequacy. TPS ≥ 50% and 1–49% were defined as high and low PD-L1 expression respectively.
PD-L1 TPS scores were not significantly different across a range of distant metastatic sites nor between metastases in paired samples.
Our results suggest that the PD-L1 TPS scoring is similar across different metastatic sites and any site biopsied will yield necessary information for guiding clinical management.
Polychlorinated biphenyls (PCBs) exist as 209 congeners, consisting of biphenyl molecules, where the number and substitution positions of halogen atoms are known to affect industrial uses, ...environmental transport mechanisms, distribution, fate, and toxicity. The complexity of the problem requires accurate physicochemical studies of an increasing number of congeners in order to understand the environmental and biological processes at play. This work presents a systematic study on the thermodynamic and kinetic properties of PCBs by quadrupole ion trap mass spectrometry. A clear relationship between structure and behavior of PCBs in mass spectrometry experiments has been observed. Overall data demonstrate that di‐ortho congeners show lower thermodynamic stability and higher fragmentation rate than non/mono‐ortho. Congeners follow different fragmentation mechanisms according to the number of chlorine atoms in ortho position of the biphenyl system. Experimental kinetic curves of mono/non‐ortho and di‐ortho congeners show a strong similarity with classical first‐order kinetics curves; in particular, di‐ortho congeners follow a first‐order consecutive reaction, while mono/non‐ortho follow a first‐order parallel reaction. For each studied congener, the kinetic constant of reaction (fragmentation) has been determined. Data support environmental levels and biochemical transformations described in literature. The general picture of the PCB behavior inside a quadrupole ion trap provides the basis for the development of reliable and cost‐effective analytical methods to the determination of ultra‐low level trace of PCB congeners.
A retrospective cohort study considered patients 18 or more years of age diagnosed between January 2007 and May 2018 with unresectable stage iii non-small-cell lung cancer (nsclc) who received ...combined chemoradiation (crt). Survival was analyzed using the Kaplan-Meier method to determine median overall (os) and progression-free survival (pfs) and the associated 95% confidence intervals (cis). Cox regression analysis was performed to identify factors prognostic for survival, including age, sex, smoking status, Eastern Cooperative Oncology Group performance status (ecog ps), histology, treatment type, tumour size, and nodal status.
Of 226 patients diagnosed with unresectable stage iii disease, 134 (59%) received combined crt. Mean age was 63 years; most patients were white, were current smokers, had an ecog ps of 0 or 1, and had nonsquamous histology. Median pfs was 7.03 months (95% ci: 5.6 months to 8.5 months), and os for the cohort was 18.7 months (95% ci: 12.4 months to 24.8 months). Of those patients, 78% would have been eligible for durvalumab consolidation therapy. Univariate analysis demonstrated a significant os benefit (
= 0.010) for concurrent crt (ccrt) compared with sequential crt (scrt). Disease-specific survival remained significantly better in the ccrt group (
= 0.004). No difference in pfs was found between the ccrt and scrt groups. In addition, tumour size and nodal involvement were significant discriminating factors for survival (
< 0.05). In this patient cohort, 64% of patients progressed and received subsequent therapy. Based on multivariate analysis, tumour size and nodal station were the only factors predictive of survival in patients with unresectable stage iii nsclc treated with crt.
Combined crt has been the standard treatment for unresectable stage iii nsclc. In our study, a trend of better survival was seen for ccrt compared with scrt. Factors predictive of survival in patients with stage iii disease treated with crt were tumour size and nodal station. Most patients with stage iii disease would potentially be eligible for durvalumab maintenance therapy based on the eligibility criteria from the pacific trial. The use and effectiveness of novel treatments will have to be further studied in our real-world patient population and similar populations elsewhere.
In this paper an Advanced Process Control system aimed at controlling and optimizing a pusher type reheating furnace located in an Italian steel plant is proposed. The designed controller replaced ...the previous control system, based on PID controllers manually conducted by process operators. A two-layer Model Predictive Control architecture has been adopted that, exploiting a chemical, physical and economic modelling of the process, overcomes the limitations of plant operators' mental model and knowledge. In addition, an ad hoc decoupling strategy has been implemented, allowing the selection of the manipulated variables to be used for the control of each single process variable. Finally, in order to improve the system flexibility and resilience, the controller has been equipped with a supervision module. A profitable trade-off between conflicting specifications, e.g. safety, quality and production constraints, energy saving and pollution impact, has been guaranteed. Simulation tests and real plant results demonstrated the soundness and the reliability of the proposed system.
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