Strangeness Production close to Threshold in Proton-Nucleus and Heavy-Ion Collisions

We discuss strangeness production close to threshold in p+A and A+A collision. Comparing the body of available K+, K0, K-, and Lambda data with the IQMD transport code and for some key observables as well with the HSD transport code, we find good agreement for the large majority of the observables. The investigation of the reaction with help of these codes reveals the complicated interaction of the strange particles with hadronic matter which makes strangeness production in heavy-ion collisions very different from that in elementary interactions. We show how different strange particle observables can be used to study the different facets of this interaction (production, rescattering and potential interaction) which finally merge into a comprehensive understanding of these interactions. We identify those observables which allow for studying (almost) exclusively one of these processes to show how future high precision experiments can improve our quantitative understanding. Finally, we discuss how the K+ multiplicity can be used to study the hadronic equation of state.Comment: 134 pages, pdf 3.3MB, version to be published in Physics Report

The BAF complex inhibitor pyrimethamine reverses HIV-1 latency in people with HIV-1 on antiretroviral therapy

Reactivation of the latent HIV-1 reservoir is a first step toward triggering reservoir decay. Here, we investigated the impact of the BAF complex inhibitor pyrimethamine on the reservoir of people living with HIV-1 (PLWH). Twenty-eight PLWH on suppressive antiretroviral therapy were randomized (1:1:1:1 ratio) to receive pyrimethamine, valproic acid, both, or no intervention for 14 days. The primary end point was change in cell-associated unspliced (CA US) HIV-1 RNA at days 0 and 14. We observed a rapid, modest, and significant increase in (CA US) HIV-1 RNA in response to pyrimethamine exposure, which persisted throughout treatment and follow-up. Valproic acid treatment alone did not increase (CA US) HIV-1 RNA or augment the effect of pyrimethamine. Pyrimethamine treatment did not result in a reduction in the size of the inducible reservoir. These data demonstrate that the licensed drug pyrimethamine can be repurposed as a BAF complex inhibitor to reverse HIV-1 latency in vivo in PLWH, substantiating its potential advancement in clinical studies.</p

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Characterization of circulating breast cancer cells with tumorigenic and metastatic capacity

Functional studies giving insight into the biology of circulating tumor cells (CTCs) remain scarce due to the low frequency ofCTCs and lack of appropriate models. Here, we describe the characterization of a novelCTC-derived breast cancer cell line, designatedCTC-ITB-01, established from a patient with metastatic estrogen receptor-positive (ER+) breast cancer, resistant to endocrine therapy.CTC-ITB-01 remainedER(+)in culture, and copy number alteration (CNA) profiling showed high concordance betweenCTC-ITB-01 andCTCs originally present in the patient with cancer at the time point of blood draw.RNA-sequencing data indicate thatCTC-ITB-01 has a predominantly epithelial expression signature. Primary tumor and metastasis formation in an intraductalPDXmouse model mirrored the clinical progression ofER(+)breast cancer. DownstreamERsignaling was constitutively active inCTC-ITB-01 independent of ligand availability, and theCDK4/6 inhibitor Palbociclib strongly inhibitedCTC-ITB-01 growth. Thus, we established a functional model that opens a new avenue to studyCTCbiology

Characterization of circulating breast cancer cells with tumorigenic and metastatic capacity

Functional studies giving insight into the biology of circulating tumor cells (CTCs) remain scarce due to the low frequency ofCTCs and lack of appropriate models. Here, we describe the characterization of a novelCTC-derived breast cancer cell line, designatedCTC-ITB-01, established from a patient with metastatic estrogen receptor-positive (ER+) breast cancer, resistant to endocrine therapy.CTC-ITB-01 remainedER(+)in culture, and copy number alteration (CNA) profiling showed high concordance betweenCTC-ITB-01 andCTCs originally present in the patient with cancer at the time point of blood draw.RNA-sequencing data indicate thatCTC-ITB-01 has a predominantly epithelial expression signature. Primary tumor and metastasis formation in an intraductalPDXmouse model mirrored the clinical progression ofER(+)breast cancer. DownstreamERsignaling was constitutively active inCTC-ITB-01 independent of ligand availability, and theCDK4/6 inhibitor Palbociclib strongly inhibitedCTC-ITB-01 growth. Thus, we established a functional model that opens a new avenue to studyCTCbiology