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.
Exposure to fine particulate matter (PM2.5) is a major contributor to the global human disease burden. The indoor environment is of particular importance when considering the health effects ...associated with PM2.5 exposures because people spend the majority of their time indoors and PM2.5 exposures per unit mass emitted indoors are two to three orders of magnitude larger than exposures to outdoor emissions. Variability in indoor PM2.5 intake fraction (iFin,total), which is defined as the integrated cumulative intake of PM2.5 per unit of emission, is driven by a combination of building‐specific, human‐specific, and pollutant‐specific factors. Due to a limited availability of data characterizing these factors, however, indoor emissions and intake of PM2.5 are not commonly considered when evaluating the environmental performance of product life cycles. With the aim of addressing this barrier, a literature review was conducted and data characterizing factors influencing iFin,total were compiled. In addition to providing data for the calculation of iFin,total in various indoor environments and for a range of geographic regions, this paper discusses remaining limitations to the incorporation of PM2.5‐derived health impacts into life cycle assessments and makes recommendations regarding future research.
Prostate cancer is initially androgen-dependent but, over time, usually develops hormone- and chemo-resistance. The present study investigated a role for p21-activated kinase 4 (PAK4) in prostate ...cancer progression. PAK4 activation was markedly inhibited by H89, a specific protein kinase A (PKA) inhibitor, and PAK4 was activated by the elevation of cAMP. The catalytic subunit of PKA interacted with the regulatory domain of PAK4, and directly phosphorylated PAK4 at serine 474 (S474). Catalytically active PAK4 enhanced the transcriptional activity of CREB independent of S133 phosphorylation. Stable knockdown of PAK4 in PC-3 and DU145 prostate cancer cells inhibited tumor formation in nude mice. Decreased tumorigenicity correlated with decreased expression of CREB and its targets, including Bcl-2 and cyclin A1. Additionally, in androgen-dependent LNCap-FGC cells, PAK4 regulated cAMP-induced neuroendocrine differentiation, which is known to promote tumor progression. Finally, PAK4 enhanced survival and decreased apoptosis following chemotherapy. These results suggested that PAK4 regulates progression toward hormone- and chemo-resistance in prostate cancer, and this study identified both a novel activation mechanism and potential downstream effector pathways. Therefore, PAK4 may be a promising therapeutic target in prostate cancer.
Summary
Background
Little is known about factors affecting the quality of life (QoL) of patients with vitiligo, and previous studies have shown conflicting results.
Objectives
To explore the QoL of ...patients with vitiligo and to identify factors affecting QoL.
Methods
A nationwide questionnaire‐based study was conducted with 1123 patients with vitiligo recruited from 21 hospitals in Korea from July 2015 to June 2016. Data were collected using a structured questionnaire for demographic information and the Skindex‐29 instrument. Mild or severely impaired QoL in patients with vitiligo was assessed according to each domain (symptoms, functioning and emotions) of Skindex‐29. Multivariate logistic regression analyses were performed to determine the factors associated with QoL.
Results
Of the enrolled participants, 609 were male and 514 female, with a mean age of 49·8 years (range 20–84). The median duration of disease was 3·0 years (range 0–60). Using multivariate logistic regression modelling, the involvement of visible body parts and a larger affected body surface area were consistently associated with QoL impairment in all three domains of Skindex‐29. Additionally, the QoL of patients aged 20–59 years, who potentially had a more active social life than older patients, was associated with functional impairment. Furthermore, a higher educational background was associated with emotional impairment.
Conclusions
A multitude of factors significantly influence the QoL of patients with vitiligo. A better appreciation of these factors would help the management of these patients.
What's already known about this topic?
Quality of life is highly impaired in patients with vitiligo.
What does this study add?
The involvement of visible body parts and a larger affected body surface area were consistently associated with impaired symptoms, functioning and emotions.
Vitiligo with nonvisible lesions also considerably compromises quality of life; vitiligo should not be regarded as a cosmetic problem.
Patients aged 20–59 years experienced significant functional impairment, and those with a higher educational background had more impairment in their emotions.
Linked Comment: Ezzedine and Eleftheriadou. Br J Dermatol 2018; 178:28–29.
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We present new constraints on the dark matter-induced annual modulation signal using 1.7 years of COSINE-100 data with a total exposure of 97.7 kg yr. The COSINE-100 experiment, consisting of 106 kg ...of NaI(Tl) target material, is designed to carry out a model-independent test of DAMA/LIBRA's claim of WIMP discovery by searching for the same annual modulation signal using the same NaI(Tl) target. The crystal data show a 2.7 cpd/kg/keV background rate on average in the 2-6 keV energy region of interest. Using a χ-squared minimization method we observe best fit values for modulation amplitude and phase of 0.0092±0.0067 cpd/kg/keV and 127.2±45.9 d, respectively.
Objective
The autoimmune response in rheumatoid arthritis (RA) is marked by the presence of anti–citrullinated protein antibodies (ACPAs). A notable feature of IgG ACPA is the abundant expression of ...N‐linked glycans in the variable domain. However, the presence of ACPA variable domain glycosylation (VDG) across disease stages, and its response to therapy, are poorly described. To understand its dynamics, we investigated the abundance of IgG ACPA VDG in 1,498 samples from individuals in different clinical stages.
Methods
Using liquid chromatography, we analyzed IgG ACPA VDG profiles in 7 different cohorts from Japan, Canada, The Netherlands, and Sweden. We assessed 106 healthy individuals, 228 individuals with presymptomatic RA, 277 individuals with arthralgia, 307 patients with new‐onset/early RA, and 117 RA patients after prespecified treatment regimens. Additionally, we measured VDG in 234 samples from patients with RA who did or did not achieve long‐term drug‐free remission (DFR) during up to 16 years follow‐up.
Results
IgG ACPA VDG significantly increased (P < 0.0001) toward disease onset and was associated with ACPA levels and epitope spreading prior to diagnosis. A slight increase in VDG was observed in patients with established RA, with a moderate influence of treatment (P = 0.007). In patients in whom DFR was later achieved, IgG ACPA VDG was already reduced at the time of RA onset.
Conclusion
The abundance of IgG ACPA VDG increases toward RA onset and correlates with maturation of the ACPA response. While IgG ACPA VDG levels are fairly stable in established disease, a lower degree of VDG at RA onset correlates with DFR. Although the underlying biologic mechanisms remain elusive, our data support the concept that VDG relates to an expansion of the ACPA response in the pre‐disease phase and contributes to disease development.
The human impact on life on Earth has increased sharply since the 1970s, driven by the demands of a growing population with rising average per capita income. Nature is currently supplying more ...materials than ever before, but this has come at the high cost of unprecedented global declines in the extent and integrity of ecosystems, distinctness of local ecological communities, abundance and number of wild species, and the number of local domesticated varieties. Such changes reduce vital benefits that people receive from nature and threaten the quality of life of future generations. Both the benefits of an expanding economy and the costs of reducing nature's benefits are unequally distributed. The fabric of life on which we all depend-nature and its contributions to people-is unravelling rapidly. Despite the severity of the threats and lack of enough progress in tackling them to date, opportunities exist to change future trajectories through transformative action. Such action must begin immediately, however, and address the root economic, social, and technological causes of nature's deterioration.
This study was performed to evaluate the antioxidative potential and quality of the breast meat of broiler chickens fed a dietary medicinal herb extract mix (MHEM, consisting of mulberry leaf, ...Japanese honeysuckle, and goldthread at a ratio of 48.5:48.5:3.0). A total of 480 one-day-old male Cobb broiler chicks were randomly allotted to 12 pens, with 40 birds per pen (replicate), and reared for 35 d. Dietary treatments consisted of a corn-soybean meal basal diet (control); a basal diet with 0.3% MHEM (T1); and a basal diet with 1% (T2) MHEM. At the end of the feeding trial, breast meat samples were excised and stored in a refrigerator at 4°C to be analyzed at d 0, 3, and 7. The MHEM did not affect proximate composition of the breast meat. Total phenols content of the breast meats in the T1 and T2 diets was approximately 2 times greater than that of the control diet (P < 0.05). 1,1-Diphenyl-2-picrylhy-drazyl radical-scavenging activity and 2,2-azinobis-(3 ethylbenzothiazoline-6-sulfonic acid) cation-reduction activity were greater in the T2 diet at d 0 and in the T1 diet at d 3 compared with the control diet (P < 0.05). 2-Thiobarbituric acid-reactive substance values in the T1 and T2 diets were lower than in the control diet at d 3 and 7 and did not increase during storage, whereas the value in the control diet increased significantly. The pH of the T1 diet was significantly greater than that of the control diet at d 0 and 3. In a sensory test, panelists preferred the T1 breast meat throughout the 7-d storage period. This research indicates that dietary MHEM could increase the antioxidative potential and overall preference of breast meat during cold storage.
The Telescope Array (TA) observatory utilizes fluorescence detectors and surface detectors (SDs) to observe air showers produced by ultra high energy cosmic rays in Earth's atmosphere. Cosmic-ray ...events observed in this way are termed hybrid data. The depth of air shower maximum is related to the mass of the primary particle that generates the shower. This paper reports on shower maxima data collected over 8.5 yr using the Black Rock Mesa and Long Ridge fluorescence detectors in conjunction with the array of SDs. We compare the means and standard deviations of the observed X max distributions with Monte Carlo X max distributions of unmixed protons, helium, nitrogen, and iron, all generated using the QGSJet II-04 hadronic model. We also perform an unbinned maximum likelihood test of the observed data, which is subjected to variable systematic shifting of the data X max distributions to allow us to test the full distributions, and compare them to the Monte Carlo to see which elements are not compatible with the observed data. For all energy bins, QGSJet II-04 protons are found to be compatible with TA hybrid data at the 95% confidence level after some systematic X max shifting of the data. Three other QGSJet II-04 elements are found to be compatible using the same test procedure in an energy range limited to the highest energies where data statistics are sparse.
Although a possible mechanism for developing type 2 diabetes in relation to calcium intake has been suggested, there is currently little epidemiological evidence on the association between dietary ...calcium and type 2 diabetes (T2D). This study aimed to evaluate the prospective association between dietary calcium and T2D incidence among adults 40 years of age or over, from the Multi-rural Communities Cohort (MRCohort), South Korea.
In total, 8313 participants (3033 men and 5280 women) who did not have diabetes at baseline were recruited between 2005 and 2013. The incidence rate ratio (IRR) was estimated using a modified Poisson regression model with a robust error estimator. During follow-up (31,570 person-years), 322 T2D cases were newly diagnosed. Dietary calcium (total and vegetable calcium) were inversely associated with the risk of T2D incidence among women (IRR = 0.61, 95% CI = 0.43–0.86, P for trend = 0.007 in third tertile of baseline total calcium intake comparing to the first tertile; IRR = 0.57, 95% CI = 0.39–0.84, P for trend = 0.006 for baseline vegetable calcium intake), not for men. The tendency of those inverse associations remained in both the normal fasting blood glucose group and the impaired fasting blood glucose group and were independent of obesity, smoking, and magnesium intake.
Total and vegetable calcium may be inversely associated with T2D incidence among women, regardless of impaired fasting blood glucose group or normal group. The associations may be potentially dose-responsive. Moderate dietary calcium may be related to lower risk of T2D incidence comparing to low intake group among women.
•Dietary total and vegetable calcium without supplements may be associated with type 2 diabetes incidence.•Moderate dietary calcium may be potentially dose-responsive to the risk of type 2 diabetes incidence among women.•The association is noteworthy, because many populations have different calcium sources, such as plants, instead of milk.
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