Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype

Immune checkpoint inhibitor treatment has the potential to prolong survival in non-small cell lung cancer (NSCLC), however, some of the patients develop resistance following initial response. Here, we analyze the immune phenotype of matching tumor samples from a cohort of NSCLC patients showing good initial response to immune checkpoint inhibitors, followed by acquired resistance at later time points. By using imaging mass cytometry and whole exome and RNA sequencing, we detect two patterns of resistance¨: One group of patients is characterized by reduced numbers of tumor-infiltrating CD8$^{+}$ T cells and reduced expression of PD-L1 after development of resistance, whereas the other group shows high CD8$^{+}$ T cell infiltration and high expression of PD-L1 in addition to markedly elevated expression of other immune-inhibitory molecules. In two cases, we detect downregulation of type I and II IFN pathways following progression to resistance, which could lead to an impaired anti-tumor immune response. This study thus captures the development of immune checkpoint inhibitor resistance as it progresses and deepens our mechanistic understanding of immunotherapy response in NSCLC

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

This is the three year update of a randomised phase III trial in patients with locally advanced inoperable stage III or stage IV melanoma. 1296 patients were radomised to receive either ipilimumab (Ipi), nivolumab (Nivo) or both antibodies (Ipi+Nivo). Complete responses were seen in 5, 16 & 19% of patients in the Ipi, Nivo and Ipi+Nivo groups respectively. Partial responses were seen in 14, 28 & 29% of patients respectively. With a minimum follow up of 28 months 3 year overall survivals were 32, 52 & 58% in the Ipi, Nivo & Ipi+Nivo respectively. In patients with braf mutations the three year survivals were 37, 56 & 68% in the three groups. This compares with a three year survival of 44% in the dabrafenib plus trametinib arm of the COMBI-D trial (J. Clin. Oncol. 2017 Dob: 10.1200/JCO.2017.74.1025). These data represent practice changing data for oncologist who treat melanoma and life changing treatment for patients with metastatic melanoma

Measurement Invariance of the Intelligence and Development Scales–2 Across Language Versions, Gender, and Age

Supplemental material to "Measurement Invariance of the Intelligence and Development Scales–2 Across Language Versions, Gender, and Age

Sex differences in the effects of MDMA (ecstasy) on plasma copeptin in healthy subjects

BACKGROUND:3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) misuse is associated with hyponatremia particularly in women. Hyponatremia is possibly due to inappropriate secretion of plasma arginine vasopressin (AVP). OBJECTIVE: To assess whether MDMA increases plasma AVP and copeptin in healthy male and female subjects and whether effects depend on MDMA-induced release of serotonin and norepinephrine. Copeptin, the C-terminal part of the AVP precursor preprovasopressin, is cosecreted with AVP and can be determined more reliably. METHODS: We used a randomized placebo-controlled crossover design. Plasma and urine osmolalities as well as AVP and copeptin levels were measured in 16 healthy subjects (eight female, eight male) at baseline and after MDMA (125 mg) administration. In addition, we tested whether effects of MDMA on AVP and copeptin secretion can be prevented by pretreatment with the serotonin and norepinephrine transporter inhibitor duloxetine (120 mg), which blocks MDMA-induced transporter-mediated release of serotonin and norepinephrine. RESULTS: MDMA significantly elevated plasma copeptin levels at 60 min and at 120 min compared with placebo in women but not in men. The copeptin response to MDMA in women was prevented by duloxetine. MDMA also nonsignificantly increased plasma AVP levels in women, and the effect was prevented by duloxetine. Although subjects drank more water after MDMA compared with placebo administration, MDMA tended to increase urine sodium levels and urine osmolality compared with placebo, indicating increased renal water retention. CONCLUSION: MDMA increased plasma copeptin, a marker for AVP secretion, in women but not in men. This sex difference in MDMA-induced AVP secretion may explain why hyponatremia is typically reported in female ecstasy users. The copeptin response to MDMA is likely mediated via MDMA-induced release of serotonin and/or norepinephrine because it was prevented by duloxetine, which blocks the interaction of MDMA with the serotonergic and noradrenergic system

The polarized Sun and sky radiometer SSARA: design, calibration, and application for ground-based aerosol remote sensing

Recently, polarimetry has been used to enhance classical photometry to infer aerosol optical properties, as polarized radiation contains additional information about the particles. Therefore, we have equipped the Sun-sky automatic radiometer (SSARA) with polarizer filters to measure linearly polarized light at 501.5 nm. We describe an improved radiometric and polarimetric calibration method, which allows us to simultaneously determine the linear polarizers' diattenuation and relative orientation with high accuracy (0.002 and 0.1 degrees, respectively). Furthermore, we employed a new calibration method for the alt-azimuthal mount capable of correcting the instrument's pointing to within 32 arcmin. So far, this is limited by the accuracy of the Sun tracker. Both these methods are applicable to other Sun and sky radiometers, such as the Cimel CE318-DP instruments used in the AErosol RObotic NETwork (AERONET). During the A-LIFE (Absorbing aerosol layers in a changing climate: aging, LIFEtime and dynamics) field campaign in April 2017, SSARA collected 22 d of data. Here, we present two case studies. The first demonstrates the performance of an aerosol retrieval from SSARA observations under partially cloudy conditions. In the other case, a high aerosol load due to a Saharan dust layer was present during otherwise clear-sky conditions