Studying deformation mechanisms of nanocrystalline nickel by thermal activation analysis at subambient temperatures and high strain rates

Electrodeposition and magnetron sputtering are promising methods for depositing thin films with nanocrystalline (nc) microstructures. Nc metals are attractive materials, as they show considerably higher mechanical strength compared to their poly- or monocrystalline counterparts. However, they also feature pronounced time- and rate-dependent inelastic behavior and their microstructure may change drastically when exposed to elevated temperatures or ion irradiation. Therefore, in order to assess the mechanical behavior and deformation mechanisms of these materials under controlled conditions and at a constant microstructure, it is desirable to perform thermal activation analysis at subambient temperatures and high strain rates on pristine samples. Large arrays of micropillars were fabricated by electrodeposition of nc Ni into lithography molds by LIGA leading to non-tapered, damage-free microspecimens. X-ray diffraction (XRD) measurements and transmission electron microscopy (TEM) imaging revealed a grain size of approximately 28nm. EDX analysis showed a homogeneous elemental composition and no concentration of impurities at the grain boundaries. A micromechanical testing device was developed that allows performing nanomechanical experiments at sub-ambient temperatures down to 120K in a large range of strain rates between 10-4 and 103s-1. Please click Additional Files below to see the full abstract

Proteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis

Myelofibrosis is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. Myelofibrosis patients frequently carry driver mutations in either JAK2 or Calreticulin (CALR) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across myelofibrosis patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three targetable vulnerabilities. First, CALR mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous CALR mutations result in high endoplasmic reticulum (ER) stress, responding to ER stressors and unfolded protein response inhibition. Overall, our integrated analyses provide a molecularly motivated roadmap for individualized myelofibrosis patient treatment

Targeting CD47 in Anaplastic Thyroid Carcinoma Enhances Tumor Phagocytosis by Macrophages and Is a Promising Therapeutic Strategy.

Background: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human cancers, with a median survival of only three to six months. Standard treatment options and even targeted therapies have so far failed to improve long-term overall survival. Thus, novel treatment modalities for ATC, such as immunotherapy, are urgently needed. CD47 is a "don't eat me" signal, which prevents cancer cells from phagocytosis by binding to signal regulatory protein alpha on macrophages. So far, the role of macrophages and the CD47-signal regulatory protein alpha signaling axis in ATC is not well understood. Methods: This study analyzed 19 primary human ATCs for macrophage markers, CD47 expression, and immune checkpoints by immunohistochemistry. ATC cell lines and a fresh ATC sample were assessed by flow cytometry for CD47 expression and macrophage infiltration, respectively. CD47 was blocked in phagocytosis assays of co-cultured macrophages and ATC cell lines. Anti-CD47 antibody treatment was administered to ATC cell line xenotransplanted immunocompromised mice, as well as to tamoxifen-induced ATC double-transgenic mice. Results: Human ATC samples were heavily infiltrated by CD68- and CD163-expressing tumor-associated macrophages (TAMs), and expressed CD47 and calreticulin, the dominant pro-phagocytic molecule. In addition, ATC tissues expressed the immune checkpoint molecules programmed cell death 1 and programmed death ligand 1. Blocking CD47 promoted the phagocytosis of ATC cell lines by macrophages in vitro. Anti-CD47 antibody treatment of ATC xenotransplanted mice increased the frequency of TAMs, enhanced the expression of macrophage activation markers, augmented tumor cell phagocytosis, and suppressed tumor growth. In double-transgenic ATC mice, CD47 was expressed on tumor cells, and blocking CD47 increased TAM frequencies. Conclusions: Targeting CD47 or CD47 in combination with programmed cell death 1 may potentially improve the outcomes of ATC patients and may represent a valuable addition to the current standard of care

Evaluation of N-acetyltaurine as an ethanol marker in human blood.

To investigate the potential of N-acetyltaurine (NAcT) in blood as a biomarker for alcohol uptake, a previously published LC-MS/MS method for urine was modified to simultaneously detect NAcT and ethyl glucuronide (EtG). The method was applied in a drinking study and by analyzing 147 forensic case samples. In the drinking study, contrary to EtG, NAcT proved to be an endogenous substance, which was present at 22 ± 7 ng/mL (13-31 ng/mL) in the blood after 2 weeks of abstinence. A moderate increase in NAcT to 40 ± 10 ng/mL (27-57 ng/mL) was observed after drinking. Within 24 h, the NAcT concentrations declined to starting concentrations in seven out of eight subjects. Peak EtG concentrations (c¯max) of 445 ± 101 ng/mL (278-662 ng/mL) were reached. While EtG in blood can be used to detect alcohol consumption even if ethanol is already eliminated, some of the maximum NAcT concentrations after a single ethanol dose were in the range of endogenous levels detected prior to the start of drinking in other subjects. In the 147 blood samples, the following concentrations were found: blood alcohol concentration (BAC): 1.22 ± 0.95 g/kg (0-3.46 g/kg); NAcT: 37.8 ± 18.4 ng/mL (12.1-109 ng/mL); EtG: 1149 ± 1121 ng/mL (0-5950 ng/mL). ROC curve analysis for BAC thresholds at 0.8 and 1.6 g/kg were performed for EtG and NAcT. Due to the presence of endogenous NAcT levels resulting in a lower sensitivity and selectivity when compared to EtG, and due to a minor increase in concentration after alcohol uptake, the usefulness of NAcT as an alcohol biomarker in blood is very limited