Elevated calcitonin precursor levels are related to mortality in an animal model of sepsis

BACKGROUND: Increased serum levels of procalcitonin (ProCT) and its component peptides have been reported in humans with sepsis. Using a hamster model of bacterial peritonitis, we investigated whether serum ProCT levels are elevated and correlate with mortality and hypocalcemia. RESULTS: Incremental increases in doses of bacteria resulted in proportional increases in 72h mortality rates (0, 20, 70, and 100%) as well as increases in serum total immunoreactive calcitonin (iCT) levels at 12 h (250, 380, 1960, and 4020 pg/ml, respectively, vs control levels of 21 pg/ml). Gel filtration studies revealed that ProCT was the predominant (> 90%) molecular form of serum iCT secreted. In the metabolic experiments, total iCT peaked at 12 h concurrent with the maximal decrease in serum calcium. CONCLUSIONS: In this animal model, hyper-procalcitoninemia was an early systemic marker of sepsis which correlated closely with mortality and had an inverse correlation with serum calcium levels

Synthetic DNA immunotherapy in biochemically relapsed prostate cancer

Background: INO-5150 (PSA and PSMA) +/- INO-9012 (IL-12), a synthetic DNA immunotherapy, was assessed for safety, immunogenicity and efficacy in biochemically recurrent prostate cancer patients (pts). Methods: Phase I, open-label, multi-center study in the US included pts with rising PSA after surgery and/or RT, PSA doubling time (PSADT) \u3e3 months (mos), testosterone \u3e150 ng/dL and no concurrent ADT. Safety, immunogenicity and efficacy (PSA kinetics, PFS) were evaluated in 4 treatment arms of 15 pts each. Arms A: 2mg INO-5150, B: 8.5 mg INO-5150, C: 2mg INO-5150 + 1mg INO-9012 and D: 8.5mg INO-5150 + 1mg INO-9012. Pts received 4 IM doses of vaccine followed by electroporation on day 0, wks 3, 12 and 24 and were followed for 72 wks. Results: 50/61 (82%) pts completed all visits and treatments were well tolerated with no safety concerns. Median PFS for overall population [N = 61, baseline (D0) PSADT range (mos) 1.5-217.1, median 9.8] and for a subset of pts with D0 PSADT ≤12mos (N = 36) has not yet been reached (FU 3-19 mos). 86% of pts with D0 PSADT ≤12 mos were progression free through 19mos FU. 27 out of 36 (75%) pts with D0 PSADT≤ 12 mos had disease stabilization at wks 27 evidenced by significant improvement in log2PSA change over time (slope) and PSADT from D0 (Slope=0.19 declined to 0.1, PSADT=5.3 improved to 10.1 mos, p = \u3c0.0001). This effect was maintained at wk 72 (Slope=0.09, PSADT=10.6, p = \u3c0.0001). Immunogenicity was observed in 77% (47/61) of pts by multiple immunologic assessments. Patient immunogenicity to INO-5150 as determined by CD38 and Perforin + CD8 T cell immune reactivity correlated with attenuated % PSA rise compared to pts without reactivity (p = 0.05, n = 50). Conclusions: INO-5150 +/- INO-9012 was safe, well tolerated and immunogenic. Clinical efficacy was observed in the patients with D0 PSADT≤ 12 mos as evidenced by a significant dampening of log2PSA change over time and increased PSADT up to 72 weeks FU. Additional genomic analyses are ongoing to further elucidate the correlation of immunologic efficacy and clinical benefit. (NCT02514213)

An exploratory study of how a Korean chaebol’s learning culture facilitates customer service

This paper explains how the organizational learning concept is used by managers in a global Korean company to promote group work, information sharing and an open communication style in order to produce a high level of customer service. Previously collected data from a set of in-depth personal interviews undertaken with three senior managers in a Korean electronics company were analyzed and interpreted using the grounded theory approach, and a number of propositions are put forward. The research findings show that managers in a chaebol deploy organizational learning to identify skilled and knowledgeable staff, and improve the organization’s capability by placing emphasis on developing harmonious, mutually oriented relationships that permeate throughout the organization. Top management demand that staff identify with government economic objectives and align the organization’s strategy accordingly so that the products produced are marketable. To achieve this, the organization fosters continual interaction among managers throughout the organization’s hierarchy. The chaebol’s organizational learning model encapsulates a “corollary” (continual communication) and “tools” (cultural influence and relationship management), and manifests in a unique strategy that allows management systems to evolve naturally

Robust detection of communities with multi-semantics in large attributed networks

© 2018, Springer Nature Switzerland AG. In this paper, we are interested in how to explore and utilize the relationship between network communities and semantic topics in order to find the strong explanatory communities robustly. First, the relationship between communities and topics displays different situations. For example, from the viewpoint of semantic mapping, their relationship can be one-to-one, one-to-many or many-to-one. But from the standpoint of underlying community structures, the relationship can be consistent, partially consistent or completely inconsistent. Second, it will be helpful to not only find communities more precise but also reveal the communities’ semantics that shows the relationship between communities and topics. To better describe this relationship, we introduce the transition probability which is an important concept in Markov chain into a well-designed nonnegative matrix factorization framework. This new transition probability matrix with a suitable prior which plays the role of depicting the relationship between communities and topics can perform well in this task. To illustrate the effectiveness of the proposed new approach, we conduct some experiments on both synthetic and real networks. The results show that our new method is superior to baselines in accuracy. We finally conduct a case study analysis to validate the new method’s strong interpretability to detected communities

Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases

Activation of androgen receptor (AR) may play a role in the development of castration resistant prostate cancer. Two intracellular tyrosine kinases, Ack1 (activated cdc42-associated kinase) and Src, phosphorylate and enhance AR activity and promote prostate xenograft tumor growth in castrated animals. However, the upstream signals that activate these kinases and lead to AR activation are incompletely characterized. In this study, we investigated AR phosphorylation in response to non-androgen ligand stimulation using phospho-specific antibodies. Treatment of LNCaP and LAPC-4 cells with epidermal growth factor (EGF), heregulin, Gas6 (ligand binding to Mer receptor tyrosine kinase and activating Ack1 downstream), interleukin (IL)-6 or bombesin stimulated cell proliferation in the absence of androgen. Treatment of LNCaP and LAPC-4 cells with EGF, heregulin, or Gas6 induced AR phosphorylation at Tyr-267; IL-6 or bombesin treatment did not. AR phosphorylation at Tyr-534 was induced by treatment with EGF, IL-6 or bombesin, but not by heregulin or Gas6. siRNA-mediated knockdown of Ack1 or Src showed that Ack1 mediates heregulin- and Gas6-induced AR Tyr-267 phosphorylation whereas Src mediates Tyr-534 phosphorylation induced by EGF, IL-6, and bombesin. Dasatinib, a Src inhibitor, blocked EGF-induced Tyr-534 phosphorylation. In addition, we show dasatinib also inhibited Ack1 kinase. Dasatinib inhibited heregulin-induced Ack1 kinase activity and AR Tyr-267 phosphorylation. Dasatinib inhibited heregulin-induced AR-dependent reporter activity. Dasatinib also inhibited heregulin-induced expression of endogenous AR target genes. Dasatinib inhibited Ack1-dependent colony formation and prostate xenograft tumor growth in castrated mice. Interestingly, Ack1 or Src knockdown or dasatinib did not inhibit EGF-induced AR Tyr-267 phosphorylation or EGF-stimulated AR activity, suggesting the existence of an additional tyrosine kinase that phosphorylates AR at Tyr-267. These data suggest that specific tyrosine kinases phosphorylate AR at distinct sites and that dasatinib may exert anti-tumor activity in prostate cancer through inhibition of Ack1