The Prognostic Value of a Single, Randomly Timed Circulating Tumor DNA Measurement in Patients with Metastatic Melanoma

Simple Summary In this study, we investigated the associations of circulating tumor DNA (ctDNA), measured at a random time point during the patient’s treatment, with tumor progression and routine blood markers (protein S100, lactate dehydrogenase (LDH), and C-reactive protein (CRP)) in a cohort of patients with metastatic melanoma. Detectable ctDNA was associated with the presence of extracerebral disease, tumor progression, and poorer overall survival (OS). Elevated S100 and CRP was correlated with detectable ctDNA, whereas LDH was not. Our results further support the use of ctDNA in the clinical management of patients with metastatic melanoma. Abstract Melanoma currently lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy. Circulating tumor DNA (ctDNA), originating from tumor cells and detectable in plasma, has emerged as a possible biomarker in patients with metastatic melanoma. In this retrospective, single-center study, we collected 129 plasma samples from 79 patients with stage IIIB–IV melanoma as determined by the American Joint Committee on Cancer (AJCC, 8th edition). For the determination of ctDNA levels, we used eight different assays of droplet digital polymerase chain reaction (ddPCR) to detect the most common hotspot mutations in the BRAF and NRAS genes. The aim of the study was to investigate the association of the detectability of ctDNA at a non-prespecified time point in a patient’s treatment with tumor progression, and to correlate ctDNA with commonly used biomarkers (protein S100, LDH, and CRP). Patients with detectable ctDNA progressed more frequently in PET-CT within 12 months than those without detectable ctDNA. Detectability of ctDNA was associated with shorter OS in univariate and multivariate analyses. ctDNA was detectable in a statistically significantly larger proportion of patients with distant metastases (79%) than in patients with no distant metastases or only intracranial metastases (32%). Elevated protein S100 and CRP correlated better with detectable ctDNA than LDH. This study supports the potential of ctDNA as a prognostic biomarker in patients with metastatic melanoma. However, additional prospective longitudinal studies with quantitative assessments of ctDNA are necessary to investigate the limitations and strengths of ctDNA as a biomarker. Keywords: ctDNA; melanoma; tumor progression; PET-CT; S100; biomarke

The reaction Δ+N→N+N+ϕ\Delta+N\to N+N+\phi in ion-ion collisions

We study the threshold $\phi$-meson production in the process $\Delta+N\to N+N+\phi$, which appears as a possible important mechanism in high energy nuclei-nuclei collisions. The isotopic invariance of the strong interaction and the selection rules due to P-parity and total angular momentum result in a general and model independent parametrization of the spin structure of the matrix element in terms of three partial amplitudes. In the framework of one-pion exchange model these amplitudes can be derived in terms of the two threshold partial amplitudes for the process $\pi+N\to N+\phi$. We predict the ratio of cross sections for $\phi-$meson production in $pp$- and $\Delta N$-collisions and the polarization properties of the $\phi$-meson, in $\Delta+N\to N+N+\phi$, as a function of a single parameter, which characterizes the relative role of transversal and longitudinal $\phi$-meson polarizations in the process $\pi+N\to N+\phi$.Comment: 10 pages 3 figure

Pennsylvania Folklife Vol. 18, No. 4

• Discord in the Garden • The Folk Festival Seminars: Crafts and Customs of the Year • What to Read on the Amish • Soup\u27s On! • Festival Highlights • Folk Festival Program • Folk Festival Geisinger • Four Interviews with Powwowers • The First Historian of the Pennsylvania Germans • The Public Sale Sixty Years Ago • The Long Shingle • Quilts and Quilting: Folk-Cultural Questionnaire No. 12https://digitalcommons.ursinus.edu/pafolklifemag/1036/thumbnail.jp

GPR182 is a broadly scavenging atypical chemokine receptor influencing T-independent immunity.

Immune responses highly depend on the effective trafficking of immune cells into and within secondary lymphoid organs (SLOs). Atypical chemokine receptors (ACKRs) scavenge chemokines to eliminate them from the extracellular space, thereby generating gradients that guide leukocytes. In contrast to canonical chemokine receptors, ACKRs do not induce classical intracellular signaling that results in cell migration. Recently, the closest relative of ACKR3, GPR182, has been partially deorphanized as a potential novel ACKR. We confirm and extend previous studies by identifying further ligands that classify GPR182 as a broadly scavenging chemokine receptor. We validate the "atypical" nature of the receptor, wherein canonical G-protein-dependent intracellular signaling is not activated following ligand stimulation. However, β-arrestins are required for ligand-independent internalization and chemokine scavenging whereas the C-terminus is in part dispensable. In the absence of GPR182 in vivo, we observed elevated chemokine levels in the serum but also in SLO interstitium. We also reveal that CXCL13 and CCL28, which do not bind any other ACKR, are bound and efficiently scavenged by GPR182. Moreover, we found a cooperative relationship between GPR182 and ACKR3 in regulating serum CXCL12 levels, and between GPR182 and ACKR4 in controlling CCL20 levels. Furthermore, we unveil a new phenotype in GPR182-KO mice, in which we observed a reduced marginal zone (MZ), both in size and in cellularity, and thus in the T-independent antibody response. Taken together, we and others have unveiled a novel, broadly scavenging chemokine receptor, which we propose should be named ACKR5

Considerations on rescattering effects for threshold photo- and electro-production of π0\pi^0 on deuteron

We show that for the S-state $\pi^0$-production in processes $\gamma+d\to d+\pi^0$ and $e^-+d\to e^-+d+\pi^0$ the rescattering effects due to the transition: $\gamma+d\to p+p+\pi^-$ (or $n+n+\pi^+)\to d+\pi^0$ are cancelled out due to the Pauli principle. The large values for these effects predicted in the past may result from the fact that the spin structure of the corresponding matrix element and the necessary antisymmetrization induced by the presence of identical protons (or neutrons) in the intermediate state was not taken into account accurately. One of the important consequences of these considerations is that $\pi^0$ photo- and electro-production on deuteron near threshold can bring direct information about elementary neutron amplitudes.Comment: Add a new sectio

No association between islet cell antibodies and coxsackie B, mumps, rubella and cytomegalovirus antibodies in non-diabetic individuals aged 7–19 years

Viral antibodies were tested in a cohort of 44 isletcell antibody-positive individuals age 7–19 years, and 44 of their islet cell antibody-negative age and sex-matched classmates selected from a population study of 4208 pupils who had been screened for islet cell antibodies. Anti-coxsackie B1-5 IgM responses were detected in 14 of 44 (32%) of the islet cell antibody-positive subjects and in 7 of 44 (16%) control subjects. This difference did not reach the level of statistical significance. None of the islet cell antibody-positive subjects had specific IgM antibodies to mumps, rubella, or cytomegalovirus. There was also no increase in the prevalence or the mean titres of anti-mumps-IgG or IgA and anti-cytomegalovirus-IgG in islet cell antibody-positive subjects compared to control subjects. These results do not suggest any association between islet cell antibodies, and possibly insulitis, with recent mumps, rubella or cytomegalo virus infection. Further studies are required to clarify the relationship between islet cell antibodies and coxsackie B virus infections

Heterologous effects of infant BCG vaccination: potential mechanisms of immunity

The current antituberculosis vaccine, BCG, was derived in the 1920s, yet the mechanisms of BCG-induced protective immunity and the variability of protective efficacy among populations are still not fully understood. BCG challenges the concept of vaccine specificity, as there is evidence that BCG may protect immunized infants from pathogens other than Mycobacterium tuberculosis – resulting in heterologous or nonspecific protection. This review summarizes the up-to-date evidence for this phenomenon, potential immunological mechanisms and implications for improved childhood vaccine design. BCG induces functional changes in infant innate and adaptive immune compartments, encouraging their collaboration in the first year of life. Understanding biological mechanisms beyond heterologous BCG effects is crucial to improve infant protection from infectious diseases.MRC; IMmunising PRegnant women and INfants neTwork (IMPRINT); GCRF Networks in Vaccines Research and Development; BBSRC; the National Vaccine Program Office (NVPO); Bill & Melinda Gates Foundation; Novavax, GSK; Janssen; European Commission; Horizon2020 TBVAC2020 (Grant No. H2020 PHC-643381); GCRF Networks in Vaccines Research and Development VALIDATE Network which was co-funded by the MRC and BBSRC (Grant No. MR/R005850/1)

The X-ray Telescope of CAST

The Cern Axion Solar Telescope (CAST) is in operation and taking data since 2003. The main objective of the CAST experiment is to search for a hypothetical pseudoscalar boson, the axion, which might be produced in the core of the sun. The basic physics process CAST is based on is the time inverted Primakoff effect, by which an axion can be converted into a detectable photon in an external electromagnetic field. The resulting X-ray photons are expected to be thermally distributed between 1 and 7 keV. The most sensitive detector system of CAST is a pn-CCD detector combined with a Wolter I type X-ray mirror system. With the X-ray telescope of CAST a background reduction of more than 2 orders off magnitude is achieved, such that for the first time the axion photon coupling constant g_agg can be probed beyond the best astrophysical constraints g_agg < 1 x 10^-10 GeV^-1.Comment: 19 pages, 25 figures and images, replaced by the revised version accepted for publication in New Journal of Physic

Metastatic acral lentiginous melanoma in a tertiary referral center in Switzerland: a systematic analysis

Acral lentiginous melanoma (ALM) is a unique histopathological subtype of melanoma with a poorer prognosis than other cutaneous melanomas. This study aims to evaluate the clinicopathological characteristics, metastatic pattern, prognostic factors, response to systemic therapy, and overall survival (OS) of ALM in a White population. This is a retrospective study of patients who were diagnosed and/or treated for ALM at the Department of Dermatology of the University Hospital Zurich, Switzerland, from January 2005 to December 2015. Overall, 172 patients with histologically confirmed ALM were included in the study. In univariate Cox regression, Breslow thickness (P<0.001), age (P=0.003), status of sentinel lymph node (P=0.005), and ulceration (P=0.008) were identified as significant prognostic factors for OS in ALM. In multivariate analysis, only Breslow thickness (P=0.0003) showed statistical significance. The median OS (mOS) was 155.7 months in the entire cohort (n=172) and 11.2 months for stage IV patients (n=36), irrespective of treatment. When first treatment was considered (n=35), mOS for stage IV patients was 8.9, 16.6, 21.7, and 3.7 months, for patients who had received chemotherapy (ChT) (n=17), immunotherapy (n=9), targeted therapy (TT) (n=3), and no therapy (n=6), respectively. The overall response rate was 44% (7/16 patients) to ChT, 100% to TT (3/3), and 25% to ipilimumab (2/8). In our study, Breslow thickness represents the best prognostic factor for OS. In stage IV ALM patients treated with either immunotherapy or TT, there is a trend for extended mOS compared with ChT

Gating of Long-Term Potentiation by Nicotinic Acetylcholine Receptors at the Cerebellum Input Stage

The brain needs mechanisms able to correlate plastic changes with local circuit activity and internal functional states. At the cerebellum input stage, uncontrolled induction of long-term potentiation or depression (LTP or LTD) between mossy fibres and granule cells can saturate synaptic capacity and impair cerebellar functioning, which suggests that neuromodulators are required to gate plasticity processes. Cholinergic systems innervating the cerebellum are thought to enhance procedural learning and memory. Here we show that a specific subtype of acetylcholine receptors, the α7-nAChRs, are distributed both in cerebellar mossy fibre terminals and granule cell dendrites and contribute substantially to synaptic regulation. Selective α7-nAChR activation enhances the postsynaptic calcium increase, allowing weak mossy fibre bursts, which would otherwise cause LTD, to generate robust LTP. The local microperfusion of α7-nAChR agonists could also lead to in vivo switching of LTD to LTP following sensory stimulation of the whisker pad. In the cerebellar flocculus, α7-nAChR pharmacological activation impaired vestibulo-ocular-reflex adaptation, probably because LTP was saturated, preventing the fine adjustment of synaptic weights. These results show that gating mechanisms mediated by specific subtypes of nicotinic receptors are required to control the LTD/LTP balance at the mossy fibre-granule cell relay in order to regulate cerebellar plasticity and behavioural adaptation