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Investigations for programmed cell death-1 (PD-1) blockade-induced hyperprogressive disease (HPD) have not been stringently conducted in patients with advanced gastric cancer (AGC). We explored the occurrence of HPD and its clinical implications in patients with AGC and treated with PD-1 inhibitors.We enrolled 169 patients with AGC and treated with either the PD-1 blockade (nivolumab or pembrolizumab; N = 112) or irinotecan monotherapy (N = 57) as a single agent. Tumour growth dynamics based on tumour growth kinetics and tumour growth rate (TGR) and time to treatment failure were analysed to define HPD. The incidence, clinical consequences and predictive markers of HPD were investigated.The optimal criteria for HPD were 4-fold increases in both tumour growth kinetics and TGR ratios and a 40% increase in TGR based on the analysis for patients treated with irinotecan. In total, 10.7% (12/112) of patients experienced HPD after PD-1 inhibitor treatment. Patients with HPD had both shorter progression-free survival (hazard ratio: 2.318; 95% confidence interval: 1.205-4.460) and overall survival (hazard ratio: 2.542; 95% confidence interval: 1.314-4.918) than patients with progressive disease without HPD, losing opportunities for subsequent systemic treatments. Although other variables including PD-L1 expression were not associated with the occurrence of HPD, hypoalbuminemia (lt;3.25 mg/dL) at baseline was significantly associated with the occurrence of HPD (P lt; 0.001) and inferior survival outcomes.HPD occurs in a proportion of patients with AGC and treated with PD-1 inhibitors. PD-1 inhibitor-induced HPD is associated with worse outcome, loss of eligibility for subsequent treatment and hypoalbuminemia, warranting further investigation.

Background The predictive value of immune monitoring with circulating CD8+ T lymphocytes for treatment response to programmed cell death protein 1 (PD-1) inhibitors has not been explored in non-small-cell lung cancer (NSCLC), prompting us to investigate whether dynamic changes in PD-1+CD8+ T lymphocytes have predictive value for durable clinical benefit (DCB) and survival after PD-1 blockade. Methods Patients with recurrent and/or metastatic NSCLC treated with PD-1 inhibitors were enrolled (discovery cohort; n = 94). Peripheral blood was obtained immediately before and after one cycle of treatment with PD-1 blockade. Phenotyping of circulating CD8+ T lymphocytes was conducted using multi-colour flow cytometry. Predictive values of dynamic changes in circulating PD-1+CD8+ T lymphocytes during the first cycle were validated in an independent cohort (validation cohort; n = 54) of a prospective trial with a PD-1 inhibitor (NCT03486119). Results Circulating PD-1+CD8+ T lymphocytes were enriched with effector/memory populations with elevated expression of activation- and exhaustion-related markers. Reduction in the frequency of PD-1+ cells among CD8+ T lymphocytes after one cycle of treatment was associated with a higher probability of DCB and superior survival outcomes in the discovery cohort. Similar results were obtained in the analysis of tumour antigen NY-ESO-1-specific CD8+ T lymphocytes and the validation cohort. Mechanistically, PD-1 molecule expression on CD8+ T lymphocytes suppresses the effector functions of tumour antigen-specific CD8+ T lymphocytes. Conclusions Dynamic changes in circulating PD-1+CD8+ T lymphocytes predict clinical, and survival benefit from PD-1 blockade treatment in NSCLC, providing a useful tool to identify patient subgroups who will optimally benefit from PD-1 inhibitors.

Background & Aims Human liver CD69+CD8+ T cells are ~95% CD103- and ~5% CD103+. Although CD69+CD103+CD8+ T cells show tissue residency and robustly respond to antigens, CD69+CD103-CD8+ T cells are not yet well understood. Methods Liver perfusate and paired peripheral blood were collected from healthy living donors and recipients with cirrhosis during liver transplantation. Liver tissues were obtained from patients with acute hepatitis A. Phenotypic and functional analyses were performed by flow cytometry. Gene expression profiles were determined by microarray and quantitative reverse transcription PCR. PT-2385 was used to inhibit hypoxia-inducible factor (HIF)-2α. Results Human liver CD69+CD103-CD8+ T cells exhibited HIF-2α upregulation with a phenotype of tissue residency and terminal differentiation. CD103- cells comprised non-hepatotropic virus-specific T cells as well as hepatotropic virus-specific T cells, but CD103+ cells exhibited only hepatotropic virus specificity. Although CD103- cells were weaker effectors on a per cell basis than CD103+ cells, following T cell receptor or interleukin-15 stimulation, they remained the major CD69+CD8+ effector population in the liver, surviving with less cell death. An HIF-2α inhibitor suppressed the effector functions and survival of CD69+CD103-CD8+ T cells. In addition, HIF-2α expression in liver CD69+CD103-CD8+ T cells was significantly increased in patients with acute hepatitis A or cirrhosis. Conclusions Liver CD69+CD103-CD8+ T cells are tissue resident and terminally differentiated, and their effector functions depend on HIF-2α. Furthermore, activation of liver CD69+CD103-CD8+ T cells with HIF-2α upregulation is observed during liver pathology. Lay summary The immunologic characteristics and the role of CD69+CD103-CD8+ T cells, which are a major population of human liver CD8+ T cells, remain unknown. Our study shows that these T cells have a terminally differentiated tissue-resident phenotype, and their effector functions depend on a transcription factor, HIF-2α. Furthermore, these T cells were activated and expressed higher levels of HIF-2α in liver pathologies, suggesting that they play an important role in immune responses in liver tissues and the pathogenesis of human liver disease.

With the advent of electrically driven mechanical man ipulators, multidisciplinary mechatronic engineering and the requirement of information acquisition has increased. The systems removed elements of human mechanical effort from the welding operation, improve consistency and got rid of the operator from the welding hazards. However, the system can only be applied to small- lot assembly and to the production of a single part until now. Therefore, an intelligent model that predicts bead geometry and accomplishes the desired mechanical properties of the weldment in the automated GMA(Gas Metal Arc) welding should be required. In this study, an intelligent model which employed the neural network, one of AI (Artificial Intelligence) technolo gies has been developed to study the effects of welding parameters on the bead penetration area and predict bead penetration area for Lap-joint in the automated GMA welding process. BP (Back Propagation) and LM (Levenberg-Marquardt) neural network algorithm have been employed for developing the intelligent model. Not only the fitting of these models have been checked and compared by using the variance test, but also the prediction on a bead penetration area using the developed models have been verified.

This paper proposes a simple, eco-friendly and economical fluid-based triboelectric nanogenerator (Flu-TENG), which is based on polyvinylidene fluoride (PVDF) between elastomeric tubes (P-TENG) and biaxially oriented polypropylene (BOPP) between elastomeric tubes (B-TENG). We examined the interactions based on the relation between the hydrodynamics of pipe flow and electrostatic induction at the electrical double layer (EDL). This is the first study to focus on the hydrodynamics of the unsteady pipe flow. From the experimental results, it was verified that the peak to peak current from unsteady flow is 70 times higher than that of steady flow. We also investigated the effect of triboelectric series to generate higher output. When the PVDF and Ground/PVDF/BOPP are connected respectively, it is called as P-TENG/PP-TENG/PB-TENG. The measured short circuit current at 15.9 Hz for P-TENG/PP-TENG/PB-TENG are 0.29 μA, 1.59 μA and 2.40 μA, respectively. And the measured open circuit voltage of P-TENG/PP-TENG/PB-TENG are 3.71 V, 14.6 V and 29.7 V, respectively. Finally, we verified the maximum power reaches 11.5 μW in the case of PB-TENG. This provides a new approach for improving the output power of the FluTENG for special applications.

During the biosynthetic processing of 2-keto- l -gulonic acid (2-KLG) from 2,5-diketo- d -gluconic acid (2,5-DKG) by Corynebacterium sp., 2-keto- d -glutonic acid (2-KDG) is produced as a byproduct. These organic acids have been analyzed by high-performance liquid chromatography (HPLC) on an Aminex HPX-87H column, but the resolution was not good enough for quantitative analysis. We investigated the quantitation of 2-KLG, 2-KDG and 2,5-DKG using capillary electrophoresis (CE) and the results were compared with those of HPLC. With CE, in contrast to HPLC, good resolution, efficiency and rapid analysis were demonstrated as well as low consumption of solvent and samples. The CE system was applied at 15 kV with UV detection at 195 nm using 100 mM sodium borate (pH 8.4) as an electrolyte. The results were shown within 5 min with efficiency approaching 100 000 theoretical plates. The relative standard deviations of migration time and peak area were less than 0.9% and 1.6%, respectively. The detection limits for quantitative determination were 0.5–1.3 μM level. The above compounds, in fermentation broth, were analyzed under the optimum conditions. Considering the results of our study, the CE method should be highly suitable for the separation of 2-KLG, 2-KDG and 2,5-DKG in the fermentation broth.