Characteristics of tumor-infiltrating lymphocytes prior to and during immune checkpoint inhibitor therapy

The tumor immune contexture plays a major role for the clinical outcome of patients. High densities of CD45RO + T helper 1 cells and CD8 + T cells are associated with improved survival of patients with various cancer entities. In contrast, a higher frequency of tumor-infiltrating M2 macrophages is correlated with poor prognosis. Recent studies provide evidence that the tumor immune architecture also essentially contributes to the clinical efficacy of immune checkpoint inhibitor (CPI) therapy in patients. Pretreatment melanoma samples from patients who experienced a clinical response to anti-programmed cell death protein 1 (PD-1) treatment show higher densities of infiltrating CD8 + T cells compared to samples from patients that progressed during therapy. Anti-PD-1 therapy results in an increased density of tumor-infiltrating T lymphocytes in treatment responders. In addition, elevated frequencies of melanoma-infiltrating TCF7 + CD8 + T cells are correlated with beneficial clinical outcome of anti-PD-1-treated patients. In contrast, a high density of tumor-infiltrating, dysfunctional PD-1 + CD38 hi CD8 + cells in melanoma patients is associated with anti-PD-1 resistance. Such findings indicate that comprehensive tumor immune contexture profiling prior to and during CPI therapy may lead to the identification of underlying mechanisms for treatment response or resistance, and the design of improved immunotherapeutic strategies. Here, we focus on studies exploring the impact of intratumoral T and B cells at baseline on the clinical outcome of CPI-treated cancer patients. In addition, recent findings demonstrating the influence of CPIs on tumor-infiltrating lymphocytes are summarized

Ipigrix (ipidacrin) in the complex treatment of patients with idiopathic axonal polyneuropathy

Department of Neurology, Institute of Neurology and Neurosurgery, Nicolae Testemitsanu State University of Medicine and Pharmacy, Chisinau, the Republic of MoldovaBackground: Peripheral neuropathy is a frequent nosologic unit, its prevalence being estimated as 2-8% of the population. Polyneuropathy treatment is especially difficult in the axonal forms cases. To study the effectiveness of the medicines acting on the pathogenetic evolution of the polyneuropathy is very important. The objectives of the study have been to assess the efficiency of ipigrix (ipidacrin) with regard to the clinical state of the patients with idiopathic axonal polyneuropathy (IAP) and to determine its influence on electromyographic indices. Material and methods: 2 groups of 30 patients with IAP have been examined in an open controlled trial. In the complex treatment of the patients of group A ipigrix (ipidacrin) has been added – 15 mg (1.5% solution – 1.0 ml) intramuscularly for 20 days. The patients of group B have received a standard treatment. Results: After the course of the treatment in the both studied groups the improvement has been recorded both in clinic and electromyographic indices. But the statistically significant changes have been observed only in group A – in the patients who have additionally received ipidacrin. These changes have been related to the significant increase of the nerve conduction velocity in motor and sensory fibers of peripheral nerves. Conclusions: ipigrix (ipidacrin) positively influences and improves the clinical outcomes and electromyographic indices in the patients with IAP. It can be successfully used in the complex treatment of axonal polyneuropathies of other determined etiologies (diabetic, alcoholic, uremic, etc.)

Glucocortiocoid Treatment of MCMV Infected Newborn Mice Attenuates CNS Inflammation and Limits Deficits in Cerebellar Development

Infection of the developing fetus with human cytomegalovirus (HCMV) is a major cause of central nervous system disease in infants and children; however, mechanism(s) of disease associated with this intrauterine infection remain poorly understood. Utilizing a mouse model of HCMV infection of the developing CNS, we have shown that peripheral inoculation of newborn mice with murine CMV (MCMV) results in CNS infection and developmental abnormalities that recapitulate key features of the human infection. In this model, animals exhibit decreased granule neuron precursor cell (GNPC) proliferation and altered morphogenesis of the cerebellar cortex. Deficits in cerebellar cortical development are symmetric and global even though infection of the CNS results in a non-necrotizing encephalitis characterized by widely scattered foci of virus-infected cells with mononuclear cell infiltrates. These findings suggested that inflammation induced by MCMV infection could underlie deficits in CNS development. We investigated the contribution of host inflammatory responses to abnormal cerebellar development by modulating inflammatory responses in infected mice with glucocorticoids. Treatment of infected animals with glucocorticoids decreased activation of CNS mononuclear cells and expression of inflammatory cytokines (TNF-α, IFN-β and IFNγ) in the CNS while minimally impacting CNS virus replication. Glucocorticoid treatment also limited morphogenic abnormalities and normalized the expression of developmentally regulated genes within the cerebellum. Importantly, GNPC proliferation deficits were normalized in MCMV infected mice following glucocorticoid treatment. Our findings argue that host inflammatory responses to MCMV infection contribute to deficits in CNS development in MCMV infected mice and suggest that similar mechanisms of disease could be responsible for the abnormal CNS development in human infants infected in-utero with HCMV

The fast response of the tropical circulation to CO 2 forcing

Atmosphere-only CMIP5 idealized climate experiments with quadrupling of atmospheric CO 2 are analyzed to understand the fast response of the tropical overturning circulation to this forcing and the main mechanism of this response. A new metric for the circulation, based on pressure velocity in the subsidence regions, is defined, taking advantage of the dynamical stability of these regions and their reduced sensitivity to the GCM’s cloud and precipitation parameterization schemes. This definition permits us to decompose the circulation change into a sum of relative changes in subsidence area, static stability, and heating rate. A comparative analysis of aqua- and Earth-like planet experiments reveals the effect of the land-sea contrast on the total change in circulation. On average, under the influence of CO 2 increase without surface warming, the atmosphere radiatively cools less, and this drives the 3%-4% slowdown of the tropical circulation. Even in an Earth-like planet setup, the circulation weakening is dominated by the radiatively driven changes in the subsidence regions over the oceans. However, the land-sea differential heating contributes to the vertical pattern of the circulation weakening by driving the vertical expansion of the tropics. It is further found that the surface warming would, independently of the CO 2 effect, lead to up to a 12% slowdown in circulation, dominated by the enhancement of the static stability in the upper troposphere. The two mechanisms identified above combine in the coupled experiment with abrupt quadrupling, causing a circulation slowdown (focused in the upper troposphere) of up to 18%. Here, the independent effect of CO 2 has a considerable impact only at time scales less than one year, being overtaken quickly by the impact of surface warming. © 2018 American Meteorological Society

How Robust Is the Weakening of the Pacific Walker Circulation in CMIP5 Idealized Transient Climate Simulations?

The tropical overturning circulations are likely weakening under increased CO2 forcing. However, insufficient understanding of the circulations’ dynamics diminishes the full confidence in such a response. Based on a CMIP5 idealized climate experiment, this study investigates the changes in the Pacific Walker circulation under anthropogenic forcing and the sensitivity of its weakening response to internal variability, general circulation model (GCM) configuration, and indexing method. The sensitivity to internal variability is analyzed by using a 68-member ensemble of the MPI-ESM-LR model, and the influence of model physics is analyzed by using the 28-member CMIP5 ensemble. Three simple circulation indices—based on mean sea level pressure, 500-hPa vertical velocity, and 200-hPa velocity potential—are computed for each member of the two ensembles. The study uses the output of the CMIP5 idealized transient climate simulations with 1% yr−1 CO2 increase from preindustrial level, and investigates the detected circulation response until the moment of CO2 doubling (70 yr). Depending on the indexing method, it is found that 50%–93% of the MPI-ESM-LR and 54%–75% of the CMIP5 ensemble members project significant negative trends in the circulation’s intensity. This large spread in the ensembles reduces the confidence that a weakening circulation is a robust feature of climate change. Furthermore, the similar magnitude of the spread in both ensembles shows that the Walker circulation response is strongly influenced by natural variability, even over a 70-yr period