Systemic CD4 Immunity and PD-L1/PD-1 Blockade Immunotherapy

PD-L1/PD-1 blockade immunotherapy has changed the therapeutic approaches for the treatment of many cancers. Nevertheless, the mechanisms underlying its efficacy or treatment failure are still unclear. Proficient systemic immunity seems to be a prerequisite for efficacy, as recently shown in patients and in mouse models. It is widely accepted that expansion of anti-tumor CD8 T cell populations is principally responsible for anti-tumor responses. In contrast, the role of CD4 T cells has been less studied. Here we review and discuss the evidence supporting the contribution of CD4 T cells to anti-tumor immunity, especially recent advances linking CD4 T cell subsets to efficacious PD-L1/PD-1 blockade immunotherapy. We also discuss the role of CD4 T cell memory subsets present in peripheral blood before the start of immunotherapies, and their utility as predictors of response.     

The Crystal Structure of Mouse Ces2c,a Potential Ortholog of Human CES2, Shows Structural Similarities in Substrate Regulation and Product Release to Human CES1

Members of the carboxylesterase 2 (Ces2/CES2) family have been studied intensively with respect to their hydrolytic function on (pro)drugs, whereas their physiological role in lipid and energy metabolism has been realized only within the last few years. Humans have one CES2 gene which is highly expressed in liver, intestine, and kidney. Interestingly, eight homologous Ces2 (Ces2a to Ces2h) genes exist in mice and the individual roles of the corresponding proteins are incompletely understood. Mouse Ces2c (mCes2c) is suggested as potential ortholog of human CES2. Therefore, we aimed at its structural and biophysical characterization. Here, we present the first crystal structure of mCes2c to 2.12 Å resolution. The overall structure of mCes2c resembles that of the human CES1 (hCES1). The core domain adopts an α/β hydrolase-fold with S230, E347, and H459 forming a catalytic triad. Access to the active site is restricted by the cap, the flexible lid, and the regulatory domain. The conserved gate (M417) and switch (F418) residues might have a function in product release similar as suggested for hCES1. Biophysical characterization confirms that mCes2c is a monomer in solution. Thus, this study broadens our understanding of the mammalian carboxylesterase family and assists in delineating the similarities and differences of the different family members.     

Tunable Near UV Microcavity OLED Arrays: Characterization and Analytical Applications

A new approach is demonstrated to fabricate narrow‐band emission near‐UV microcavity OLEDs (μcOLEDs) with peak emission at ≈385 nm, in near‐perfect alignment with the narrow primary 385 nm absorption band of Pt octaethylporphyrin dye, using 4,4′‐bis(9‐carbazolyl)‐1,1′‐biphenyl (CBP) as the emissive layer. Although OLEDs have been extensively operated at optical wavelengths, only few have achieved near‐UV emission. Yet there is a growing need for portable compact narrow‐band near UV sources for many biomedical and forensic applications. A microcavity effect, due to metallic electrodes enclosing an optical cavity, is employed to achieve the desired narrow peak emission. An Al/Pd bi‐layer anode enables attaining a turn on voltage of 3.8 V and a 4,4′‐cyclohexylidenebis [N,N‐bis (4‐methylphenyl) benzenamine] (TAPC) layer improves electron‐hole recombination in the emissive layer. The fabricated μcOLED is efficiently used as the excitation source in a structurally integrated all‐organic oxygen sensor. Moreover, a CBP‐based combinatorial array of μcOLED pixels is fabricated by varying the thickness of the organic layers to obtain nine sharp, discrete emission peaks from 370 to 430 nm, employed in an all‐organic on‐chip spectrophotometer. The photodetectors are based on P3HT:PCBM (poly(3‐hexylthiophene):[6,6]‐phenyl‐C₆₀‐butyric acid methyl ester) or the more sensitive PTB7:PCBM (PTB7 is polythieno [3,4‐b]‐thiophene‐co‐benzodithiophene). Simulations of the OLEDs' emission are used for analysis of the experimental data, assisting in device fabrication.     

Determinants of hemodialysis‐induced segmental wall motion abnormalities

Patients who demonstrate worsening of cardiac wall motion (WM) during hemodialysis have higher 1‐year mortality. We sought to identify risk factors for dialysis‐induced WM abnormalities. Additionally, we examined the effects of hemodialysis on other parameters of cardiac function. Forty patients underwent echocardiography directly before dialysis and during the last hour of dialysis (79 dialysis sessions). Candidate predictors for intradialytic worsening of WM included age, a history of heart failure (HF) or coronary artery disease, changes in blood pressure or heart rate, high sensitivity cardiac troponin T and N‐terminal brain natriuretic peptide. Among 40 patients, WM worsened segmentally in eight patients (20%), worsened globally in one patient (3%), and improved segmentally in four patients (10%). Diastolic function worsened in 44% of patients, and left ventricular ejection fraction was largely unchanged during dialysis. The case of globally worsened WM occurred in the setting of intradialytic hypertension in a patient without HF. Surprisingly, history of coronary artery disease, hemodynamics, and serologic factors were not associated with worsened segmental WM during dialysis. After adjustment for history of coronary artery disease and other cardiac risk factors, patients with a history of HF had a threefold higher risk of worsening segmental WM during dialysis (RR 3.1, 95% CI [1.1, 9], p = 0.04). In conclusion, patients with a history of clinical HF were at higher risk of intradialytic worsening of segmental WM. Further studies are needed to determine the mechanism of this association and whether cardioprotective medications could ameliorate this adverse cardiac effect of hemodialysis.     

Tissue Engineering of Cartilage on Ground-Based Facilities

Investigations under simulated microgravity offer the opportunity for a better understanding of the influence of altered gravity on cells and the scaffold-free three-dimensional (3D) tissue formation. To investigate the short-term influence, human chondrocytes were cultivated for 2 h, 4 h, 16 h, and 24 h on a 2D Fast-Rotating Clinostat (FRC) in DMEM/F-12 medium supplemented with 10 % FCS. We detected holes in the vimentin network, perinuclear accumulations of vimentin after 2 h, and changes in the chondrocytes shape visualised by F-actin staining after 4 h of FRC-exposure. Scaffold-free cultivation of chondrocytes for 7 d on the Random Positioning Machine (RPM), the FRC and the Rotating Wall Vessel (RWV) resulted in spheroid formation, a phenomenon already known from spaceflight experiments with chondrocytes (MIR Space Station) and thyroid cancer cells (SimBox/Shenzhou-8 space mission). The experiments enabled by the ESA-CORA-GBF programme gave us an optimal opportunity to study gravity-related cellular processes, validate ground-based facilities for our chosen cell system, and prepare long-term experiments under real microgravity conditions in space