Frequency feedback for two-photon interference from separate quantum dots

We employ active feedback to stabilize the frequency of single photons emitted by two separate quantum dots to an atomic standard. The transmission of a rubidium-based Faraday filter serves as the error signal for frequency stabilization. We achieve a residual frequency deviation of <30 MHz, which is less than 1.5% of the quantum dot linewidth. Long-term stability is demonstrated by Hong-Ou-Mandel interference between photons from the two quantum dots. Their internal dephasing limits the expected visibility to V = 40%. We observe V_lock = (41 ± 5)% for frequency-stabilized dots as opposed to Vfree = (31 ± 7)% for free-running emission. Our technique reaches the maximally expected visibility for the given system and therefore facilitates quantum networks with indistinguishable photons from distributed sources. ©2018 American Physical Societ

GTPase domain of the 54-kD subunit of the mammalian signal recognition particle is required for protein translocation but not for signal sequence binding

Abstract. The 54-kD subunit of the signal recognition particle (SRP54) binds to signal sequences of nascent secretory and transmembrane proteins. SRP54 consists of two separable domains, a 33-kD amino-terminal domain that contains a GTP-binding site (SRP54G) and a 22-kD carboxy-terminal domain (SRP54M) containing binding sites for both the signal sequence and SRP RNA. To examine the function of the two domains in more detail, we have purified SRP54M and used it to assemble a partial SRP that lacks the amino-terminal domain of SRP54 [SRP(-54G)]. This particle recognized signal sequences in two independent assays, albeit less efficiently than intact SRP. Analysis of the signal sequence binding activity of free SRP54 and SRP54M supports the conclusion that SRP54M bind

Additional file 2: Figure S1. of Antitumor activity of the multikinase inhibitor regorafenib in patient-derived xenograft models of gastric cancer

Dose-dependent effects of regorafenib 5, 10, and 15 mg/kg/day on tumor growth inhibition (A), tumor weight (B), and bodyweight (C) in xenograft model GC28-1107. (PDF 143 kb

Additional file 1: Table S1. of Antitumor activity of the multikinase inhibitor regorafenib in patient-derived xenograft models of gastric cancer

Tumor xenograft model histology and mutation status. (PDF 11 kb

Additional file 4: Figure S3. of Antitumor activity of the multikinase inhibitor regorafenib in patient-derived xenograft models of gastric cancer

Effects of regorafenib on TIE2 expression in gastric cancer xenograft model GC05-0208B. (PDF 94 kb

Effects of regorafenib on the mononuclear/phagocyte system and how these contribute to the inhibition of colorectal tumors in mice

Abstract Background Regorafenib was previously shown to reduce tumor-associated macrophages and potently inhibit colony-stimulating factor 1 receptor (CSF1R), also known as CD115, in biochemical assays. The CSF1R signaling pathway is essential in the biology of the mononuclear/phagocyte system, which can promote the development of cancer. Methods A deeper investigation of regorafenib’s effects on CSF1R signaling was performed using preclinical in vitro and in vivo studies with syngeneic CT26 and MC38 mouse models of colorectal cancer. Peripheral blood and tumor tissue were analyzed mechanistically by flow cytometry using antibodies against CD115/CSF1R and F4/80 and by ELISA for chemokine (C–C motif) ligand 2 (CCL2) levels. These read-outs were correlated with drug levels for the detection of pharmacokinetic/pharmacodynamic relationships. Results Potent inhibition of CSF1R by regorafenib and its metabolites M-2, M-4, and M-5 was confirmed in vitro in RAW264.7 macrophages. The dose-dependent growth inhibition of subcutaneous CT26 tumors by regorafenib was associated with a significant reduction in both the number of CD115hi monocytes in peripheral blood and the number of selective subpopulations of intratumoral F4/80hi tumor-associated macrophages. CCL2 levels were not affected by regorafenib in blood but increased in tumor tissue, which may contribute to drug resistance and prevent complete tumor remission. An inverse relationship between regorafenib concentration and the number of CD115hi monocytes and CCL2 levels was observed in peripheral blood, supporting the mechanistic involvement of regorafenib. Conclusions These findings may be clinically useful in optimizing drug dosing using blood-based pharmacodynamic markers and in identifying resistance mechanisms and ways to overcome them by appropriate drug combinations

Predictive Factors of Mortality After PEG Insertion: Guidance for Clinical Practice

Background: Percutaneous endoscopic gastrostomy (PEG) is considered the preferred route for long-term enteral feeding. The aim of this study was to determine predictors of an increased mortality risk after PEG insertion. Methods: A retrospective study was conducted during a 13-year period in the gastroenterology department of Erlangen University Hospital. The authors completed a questionnaire with details of demographic data, diagnosis, indication for PEG, type of tube, and cause of death. Patients were contacted regularly at scheduled appointments. Results: In total, 787 patients (574 male [72.9%]) underwent PEG placement by the pull technique. The main underlying disease was malignant (75.6%). By the end of the study period, 614 patients had died. The average survival time was 720 days. The 30-, 60-, 90-day and 1-, 3-, and 5-year mortality rates amounted to 6.5%, 9.8%, 13%, 32.1%, 59.3%, and 69.8%, respectively. Predictive factors of increased 30-day mortality were higher age, lower body mass index (BMI), and the presence of diabetes mellitus. The presence of all 3 variables served as an indicator to detect high-risk patients, with a sensitivity of 0.80 and a specificity of 0.64. Conclusion: Mortality predictors for patients after PEG insertion are higher age, lower BMI, and the presence of diabetes mellitus. To avoid unnecessary and dangerous examinations in high-risk patients, the above-mentioned predictive factors of mortality should be checked before PEG placement

Regorafenib enhances anti-PD1 immunotherapy efficacy in murine colorectal cancers and their combination prevents tumor regrowth

Background!#!Patients with advanced colorectal cancer (CRC) have a poor prognosis. Combinations of immunotherapies and anti-angiogenic agents are currently being evaluated in clinical trials. In this study, the multikinase inhibitor regorafenib (REG) was combined with an anti-programmed cell death protein 1 (aPD1) antibody in syngeneic murine microsatellite-stable (MSS) CT26 and hypermutated MC38 colon cancer models to gain mechanistic insights into potential drug synergism.!##!Methods!#!Growth and progression of orthotopic CT26 and subcutaneous MC38 colon cancers were studied under treatment with varying doses of REG and aPD1 alone or in combination. Sustained effects were studied after treatment discontinuation. Changes in the tumor microenvironment were assessed by dynamic contrast-enhanced MRI, and histological and molecular analyses.!##!Results!#!In both models, REG and aPD1 combination therapy significantly improved anti-tumor activity compared with single agents. However, in the CT26 model, the additive benefit of aPD1 only became apparent after treatment cessation. The combination treatment efficiently prevented tumor regrowth and completely suppressed liver metastasis, whereas the anti-tumorigenic effects of REG alone were abrogated soon after drug discontinuation. During treatment, REG significantly reduced the infiltration of immunosuppressive macrophages and regulatory T (Treg) cells into the tumor microenvironment. aPD1 significantly enhanced intratumoral IFNγ levels. The drugs synergized to induce sustained M1 polarization and durable reduction of Treg cells, which can explain the sustained tumor suppression.!##!Conclusions!#!This study highlights the synergistic immunomodulatory effects of REG and aPD1 combination therapy in mediating a sustained inhibition of colon cancer regrowth, strongly warranting clinical evaluation in CRC, including MSS tumors