Endocrine immune-related adverse events in patients with metastatic renal and urothelial cancer treated with immune checkpoint-inhibitors

Purpose To evaluate the incidence, diagnosis and treatment of immune-related adverse events (e-irAE) of checkpoint inhibition (ICI) in metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma (mRCC). Methods A retrospective, single-center study was conducted to identify a cohort that received ICI for mUC or mRCC. e-irAE were classified according to the CTCAE V.5.0. Patients received ICI for mUC or mCC between 01/2017 and 03/2021. A retrospective chart review was performed. T-Test, the chi-squared test, and Fisher's exact test were performed. Results 102 Patients received ICI [mUC: 40 (39%), mRCC: 62 (61%)]. 64 (63%) received an ICI monotherapy, 27 (27%) a dual ICI therapy, 11 (11%) a combination with VEGFi. e-irAE occurred in 19 (19%) patients [grade 1–2: 17 (84%), grade 3: 3 (16%)]. The median time until e-irAE was 42 days (range 11–211 days). 14 Patients developed thyroidism (14%), 4 (4%) a hypophysitis, 1 (1%) an adrenal insufficiency (AI). 7 patients (7%) had to discontinue ICI therapy [hypophysitis (100%), AI (100%), thyroidism (14%)]. 6 (86%) received cortisone. After a median range of 34 days 5 patients (71%) restarted ICI therapy. All patients (n = 4) with hypophysitis continued ICI [4 (100%) prednisone, 3 (75%) levothyroxine]. 11 (79%) presented with hyperthyroidism. 4 (37%) needed therapy (1 (7%) prednisone, 3 (21%) thiamazole, 2 (14%) beta blocker). The 9 (64%) patients with hypothyroidism received levothyroxine. Hypophysitis appears only on dual ICI (CTLA-4/PD-1) inhibition (p 0.007). Conclusion This study shows the importance of adequate diagnosis and therapy of e-irAEs

Development of CVD diamond radiation detectors

Diamond is a nearly ideal material for detecting ionizing radiation. Its outstanding radiation hardness, fast charge collection and low leakage current allow a diamond detector to be used in high ra diation, high temperature and in aggressive chemical media. We have constructed charged particle detectors using high quality CVD diamond. Characterization of the diamond samples and various detect ors are presented in terms of collection distance, $d=\mu E \tau$, the average distance electron-hole pairs move apart under the influence of an electric field, where $\mu$ is the sum of carrier mo bilities, $E$ is the applied electric field, and $\tau$ is the mobility weighted carrier lifetime. Over the last two years the collection distance increased from $\sim$ 75 $\mu$m to over 200 $\mu$ m. With this high quality CVD diamond a series of micro-strip and pixel particle detectors have been constructed. These devices were tested to determine their position resolution and signal to n oise performance. Diamond detectors were exposed to large fluences of pions, protons and neutrons to establish their radiation hardness properties. The results of these tests and their correlati on with the characterization studies are presented

Micro-strip sensors based on CVD Diamond

In this article we present the performance of recent chemical vapour deposition (CVD) diamond micro-strip sensors in beam tests. In addition we present the first comparison of a CVD diamond micro-strip sensor before and after proton irradiation

Performance of irradiated CVD diamond micro-strip sensors

CVD diamond detectors are of interest for charged particle detection and tracking due to their high radiation tolerance. In this article we present, for the first time, beam test results from recently manufactured CVD diamond strip detectors and their behavior under low doses of electrons from a $\beta$-source and the performance before and after intense ($>10^{15}/{\rm cm^2}$) proton- and pion-irradiations. We find that low dose irradiations increase the signal-to-noise ratio (pumping of the signal) and slightly deteriorate the spatial resolution. Intense irradiations with protons ($2.2\times 10^{15}~p/{\rm cm^2}$) lowers the signal-to-noise ratio slightly. Intense irradiation with pions ($2.9\times 10^{15}~\pi/{\rm cm^2}$) lowers the signal-to-noise ratio more. The spatial resolution of the diamond sensors improves after irradiations

Proton Irradiation of CVD Diamond Detectors for High Luminosity Experiments at the LHC

CVD diamond shows promising properties for use as a position sensitive detector for experiments in the highest radiation areas at the Large Hadron Collider. In order to study the radiation hardn ess of diamond we exposed CVD diamond detector samples to 24~GeV/$c$ and 500~MeV protons up to a fluence of $5\times 10^{15}~p/{\rm cm^2}$. We measured the charge collection distance, the ave rage distance electron hole pairs move apart in an external electric field, and leakage currents before, during, and after irradiation. The charge collection distance remains unchanged up to $1\ times 10^{15}~p/{\rm cm^2}$ and decreases by $\approx$40~\% at $5\times 10^{15}~p/{\rm cm^2}$. Leakage currents of diamond samples were below 1~pA before and after irradiation. The particle indu ced currents during irradiation correlate well with the proton flux. In contrast to diamond, a silicon diode, which was irradiated for comparison, shows the known large increase in leakage curren t. We conclude that CVD diamond detectors are radiation hard to 24~GeV/$c$ and 500~MeV protons up to at least $1\times 10^{15}~p/{\rm cm^2}$ without signal loss

Identification of novel small-molecule histone deacetylase inhibitors by medium-throughput screening using a fluorigenic assay

International audienceHistone deacetylases (HDACs) are considered to be among the most important enzymes regulating gene expression in eukaryotic cells. In general, increased levels of histone acetylation are associated with increased transcriptional activity, whereas decreased levels are linked to repression of gene expression. HDACs associate with a number of cellular oncogenes and tumor-suppressor genes leading to an aberrant recruitment of HDAC activity, which results in changes of gene expression, impaired differentiation and excessive proliferation of tumor cells. Therefore, HDAC-inhibitors are efficient anti-proliferative agents in both in vitro and in vivo preclinical models of cancer making them promising anti-cancer therapeutics. Here, we present the results of a medium-throughput screening program aiming at the identification of novel HDAC-inhibitors using histone deacetylase-like amidohydrolase from strain FB188 (FB188 HDAH) as model enzyme. Within a library of 3719 compounds, several new classes of HDAC-inhibitors were identified. Among these hit compounds, there were also potent inhibitors of eukaryotic HDACs, as demonstrated by an increase in histone H4 acetylation accompanied by a decrease in tumor cell metabolism in both SHEP neuroblastoma and T24 bladder carcinoma cells. In conclusion, screening of a compound library using FB188 HDAH as model enzyme identified several promising new lead structures for further development