Combination immunotherapy with anti-PD-L1 antibody and depletion of regulatory T cells during acute viral infections results in improved virus control but lethal immunopathology

Combination immunotherapy (CIT) is currently applied as a treatment for different cancers and is proposed as a cure strategy for chronic viral infections. Whether such therapies are efficient during an acute infection remains elusive. To address this, inhibitory receptors were blocked and regulatory T cells depleted in acutely Friend retrovirus-infected mice. CIT resulted in a dramatic expansion of cytotoxic CD4+ and CD8+ T cells and a subsequent reduction in viral loads. Despite limited viral replication, mice developed fatal immunopathology after CIT. The pathology was most severe in the gastrointestinal tract and was mediated by granzyme B producing CD4+ and CD8+ T cells. A similar post-CIT pathology during acute Influenza virus infection of mice was observed, which could be prevented by vaccination. Melanoma patients who developed immune-related adverse events under immune checkpoint CIT also presented with expanded granzyme-expressing CD4+ and CD8+ T cell populations. Our data suggest that acute infections may induce immunopathology in patients treated with CIT, and that effective measures for infection prevention should be applied

Photocarcinogenesis – Molecular Mechanisms

The carcinogenicity (photocarcinogenicity) of sunlight to human skin has been recognized more than a century ago. Last decades numerous experimental studies show that UV rays damage DNA, cause gene mutations leading to the development of malignant tumors such basal cell carcinomas, squamous cell carcinomas and melanomas. The tumors occur most frequently in fair skinned people, and the mutations typically are found at dipyrimidine sites with C-T or / and CC-TT tandem double mutations. The authors briefly summarize their investigation of the p53 suppressor gene, and expose their hypothesis of hTERT involvement in cancerogenesis. Also their underline the importance of UV induced immunosuppression in photocarcinogenesis. Psoriatic patients are exposed to numerous cancerogens in their treatment. A better understanding of the mechanisms of photocarcinogenesis could provide new ways in the treatment of skin tumors

Uncertainty-aware data pipeline of calibrated MEMS sensors used for machine learning

Sensors are a key element of recent Industry 4.0 developments and currently further sophisticated functionality is embedded into them, leading to smart sensors. In a typical “Factory of the Future” (FoF) scenario, several smart sensors and different data acquisition units (DAQs) will be used to monitor the same process, e.g. the wear of a critical component, in this paper an electromechanical cylinder (EMC). If the use of machine learning (ML) applications is of interest, data of all sensors and DAQs need to be brought together in a consistent way. To enable quality information of the obtained ML results, decisions should also take the measurement uncertainty into account. This contribution shows an ML pipeline for time series data of calibrated Micro-Electro-Mechanical Systems (MEMS) sensors. Data from a lifetime test of an EMC from multiple DAQs is integrated by alignment, (different schemes of) interpolation and careful handling of data defects to feed an automated ML toolbox. In addition, uncertainty of the raw data is obtained from calibration information and is evaluated in all steps of the data processing pipeline. The results for the lifetime prognosis of the EMC are evaluated in the light of “fitness for purpose”.EMPIR Met4Fo

Evaluations of affective stimuli modulated by another person's presence and affiliative touch

Affiliative touch carries affective meaning and affects the receiver. Although research demonstrates that receiving touch modulates the neural processing of emotions, its effects on evaluations of affective stimuli remain unexplored. The current research examined the effects of affiliative touch on the evaluation of affective images across 3 studies and aimed to disentangle the effect of another person’s mere presence from the addition of affiliative touch. Participants thus underwent experimental conditions of social manipulation (presence, alone) and touch manipulations (receiving, self-providing, providing to experimenter) while viewing affective images (negative, neutral, and positive valence) and evaluated their valence. Study 1 included hand-squeezing (N = 39), and Study 2 included forearm-stroking (N = 40) in a within-subjects design. Study 3 included hand-squeezing (N = 109) in a between-subjects design. Across both studies, the results suggested that the receiving condition decreased the negativity of negative images, and the providing condition reduced the positivity of positive images. Furthermore, the other presence condition increased the positivity of positive images compared with the alone condition in Study 1 and to the receiving condition in Study 2. Hand-squeezing and forearm-stroking had differential effects on affective image evaluations depending on the image valence and who provided the touch. Overall, receiving touch seems to attenuate negative evaluations in negative contexts and the presence of others amplifies positive evaluations in positive situations. Discussion highlights the importance of affiliative touch within social interactions

Photocarcinogenesis – Molecular Mechanisms

The carcinogenicity (photocarcinogenicity) of sunlight to human skin has been recognized more than a century ago. Last decades numerous experimental studies show that UV rays damage DNA, cause gene mutations leading to the development of malignant tumors such basal cell carcinomas, squamous cell carcinomas and melanomas. The tumors occur most frequently in fair skinned people, and the mutations typically are found at dipyrimidine sites with C-T or / and CC-TT tandem double mutations. The authors briefly summarize their investigation of the p53 suppressor gene, and expose their hypothesis of hTERT involvement in cancerogenesis. Also their underline the importance of UV induced immunosuppression in photocarcinogenesis. Psoriatic patients are exposed to numerous cancerogens in their treatment. A better understanding of the mechanisms of photocarcinogenesis could provide new ways in the treatment of skin tumors

Photocarcinogenesis – Molecular Mechanisms

The carcinogenicity (photocarcinogenicity) of sunlight to human skin has been recognized more than a century ago. Last decades numerous experimental studies show that UV rays damage DNA, cause gene mutations leading to the development of malignant tumors such basal cell carcinomas, squamous cell carcinomas and melanomas. The tumors occur most frequently in fair skinned people, and the mutations typically are found at dipyrimidine sites with C-T or / and CC-TT tandem double mutations. The authors briefly summarize their investigation of the p53 suppressor gene, and expose their hypothesis of hTERT involvement in cancerogenesis. Also their underline the importance of UV induced immunosuppression in photocarcinogenesis. Psoriatic patients are exposed to numerous cancerogens in their treatment. A better understanding of the mechanisms of photocarcinogenesis could provide new ways in the treatment of skin tumors

A High-Throughput Screen Indicates Gemcitabine and JAK Inhibitors May be Useful for Treating Pediatric AML

Improvement in survival has been achieved for children and adolescents with AML but is largely attributed to enhanced supportive care as opposed to the development of better treatment regimens. High risk subtypes continue to have poor outcomes with event free survival rates \u3c 40% despite the use of high intensity chemotherapy in combination with hematopoietic stem cell transplant. Here we combine high-throughput screening, intracellular accumulation assays, and in vivo efficacy studies to identify therapeutic strategies for pediatric AML. We report therapeutics not currently used to treat AML, gemcitabine and cabazitaxel, have broad anti-leukemic activity across subtypes and are more effective relative to the AML standard of care, cytarabine, both in vitro and in vivo. JAK inhibitors are selective for acute megakaryoblastic leukemia and significantly prolong survival in multiple preclinical models. Our approach provides advances in the development of treatment strategies for pediatric AML

Inhibition of rainbow trout acetylcholinesterase by aqueous and suspended particle-associated organophosphorous insecticides

Spraydrift and edge-of-field runoff are important routes of pesticide entry into streams. Pesticide contamination originating from spraydrift usually resides in the water phase, while pesticides in contaminated runoff are to a large extent associated with suspended particles (SPs). The effects of two organophosphorous insecticides (OPs), chloropyrifos (CPF) and azinphos-methyl (AZP), on acetylcholinesterase (AChE) activity in rainbow trout were compared between two exposure scenarios, simulating spraydrift- and runoff-borne contamination events in the Lourens River (LR), Western Cape, South Africa. NOECs of brain AChE inhibition, determined after 1 h of exposure followed by 24 h of recovery, were 0.33 μg l−1 for aqueous CPF, 200 mg kg−1 for SP-associated CPF and 20 mg kg−1 for SP-associated AZP (at 0.5 g l−1 SP). The highest aqueous AZP concentration tested (3.3 μg l−1) was without significant effects. Previously reported peak levels of aqueous CPF in the LR (not, vert, similar0.2 μg l−1) are close to its NOEC (this study), suggesting a significant toxicological risk to fish in the LR. By contrast, reported levels of SP-associated OPs in the LR are 20–200-fold lower than their NOECs (this study). In a comparative in situ study, trout were exposed for seven days at agricultural (LR2, LR3) and upstream reference (LR1) sites. No runoff occurred during the study. Brain AChE was significantly inhibited at LR3. However, OP levels at LR3 (CPF 0.01 μg l−1; AZP 0.14 μg l−1) were minor compared to concentrations having effects in the laboratory (see above). Additionally, muscle AChE activity was significantly higher in caged trout from LR1 than in animals maintained in laboratory tanks

Prognostic impact of t(16;21)(p11;q22) and t(16;21)(q24;q22) in pediatric AML: A retrospective study by the I-BFM study group

To study the prognostic relevance of rare genetic aberrations in acute myeloid leukemia (AML), such as t(16:21), international collaboration is required. Two different types of t(16:21) translocations can be distinguished: t(16:21)(p11;q22), resulting in the FUS-ERG fusion gene; and t(16:21)(q24;q22), resulting in RUNX1-core binding factor (CBFA2T3). We collected data on clinical and biological characteristics of 54 pediatric AML cases with t(16:21) rearrangements from 14 international collaborative study groups participating in the international Berlin-Frankfurt-Miinster (I-BFM) AML study group. The AML-BFM cohort diagnosed between 1997 and 2013 was used as a reference cohort. RUNX1-CBFA2T3 (n = 23) had significantly lower median white blood cell count (12.5 x 10(9)/L, P = .03) compared with the reference cohort. FUS-ERG rearranged AML (n = 31) had no predominant French-American-British (FAB) type, whereas 76% of RUNX1-CBFA2T3 had an M1/M2 FAB type (M1, M2), significantly different from the reference cohort (P = .004). Four-year event-free survival (EFS) of patients with FUS-ERG was 7% (standard error [SE] = 5%), significantly lower compared with the reference cohort (51%, SE = 1%, P < .001). Four-year EFS of RUNX1-CBFA2T3 was 77% (SE = 8%, P = .06), significantly higher compared with the reference cohort. Cumulative incidence of relapse was 74% (SE = 8%) in FUS-ERG, 0% (SE = 0%) in RUNX1-CBFA2T3, compared with 32% (SE = 1%) in the reference cohort (P < .001). Multivariate analysis identified both FUS-ERG and RUNX1-CBFA2T3 as independent risk factors with hazard ratios of 1.9 (P < .0001) and 0.3 (P = .025), respectively. These results describe 2 clinically relevant distinct subtypes of pediatric AML. Similarly to other core-binding factor AMLs, patients with RUNX1-CBFA2T3 rearranged AML may benefit from stratification in the standard risk treatment, whereas patients with FUS-ERG rearranged AML should be considered high-risk