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Background: Supportive care interventions used to manage chemotherapy‐induced myelosuppression (CIM), including granulocyte colony‐stimulating factors (G‐CSFs), erythropoiesis‐stimulating agents (ESAs), and red blood cell (RBC) transfusions, are burdensome to patients and associated with greater costs to health care systems. We evaluated the utilization of supportive care interventions and their relationship with the myeloprotective agent, trilaciclib. Methods: Data were pooled from three independent randomized phase 2 clinical trials of trilaciclib or placebo administered prior to chemotherapy in patients with extensive‐stage small cell lung cancer (ES‐SCLC). The impact of supportive care on the duration of severe neutropenia (DSN), occurrence of severe neutropenia (SN), and occurrence of RBC transfusions on/after week 5 was analyzed across cycles 1–4. Concordance and association between grade 3/4 anemia, RBC transfusions on/after week 5, and ESA administration was also evaluated. Results: The use of G‐CSFs, ESAs, or RBC transfusions on/after week 5 was significantly lower among patients receiving trilaciclib versus placebo (28.5% vs. 56.3%, p < 0.0001; 3.3% vs. 11.8%, p = 0.0254; and 14.6% vs. 26.1%, p = 0.0252, respectively). Compared with placebo, trilaciclib significantly reduced DSN and SN, irrespective of G‐CSF administration. RBC transfusions and ESAs were most often administered in patients with grade 3/4 anemia; however, patients typically received RBC transfusions over ESA administration. Conclusions: By improving CIM and reducing the need for associated supportive care, trilaciclib has the potential to reduce the burden of myelosuppression on patients receiving myelosuppressive chemotherapy for the treatment of ES‐SCLC. Trial registration: ClinicalTrials.gov (NCT02499770; NCT03041311; NCT02514447). [ABSTRACT FROM AUTHOR]

Monoclonal antibody therapies are an important approach for the treatment of hematologic malignancies, but typically show low single‐agent activity. Bispecific antibodies, however, redirect immune cells to the tumor for subsequent lysis, and preclinical and accruing clinical data support single‐agent efficacy of these agents in hematologic malignancies, presaging an exciting era in the development of novel bispecific formats. This review discusses recent developments in this area, highlighting the challenges in delivering effective immunotherapies for patients. [ABSTRACT FROM AUTHOR]

Glioblastomas (high-grade astrocytomas) are highly aggressive brain tumors with poor prognosis and limited treatment options. In the present studies, we have defined the role of fetuin-A, a liver-derived multifunctional serum protein, in the growth of an established glioblastoma cell line, LN229. We hereby demonstrate that these cells synthesize ectopic fetuin-A which supports their growth in culture in the absence of serum. We have demonstrated that a panel of tissue microarray ( TMA) of glioblastomas also express ectopic fetuin-A. Knocking down fetuin-A using sh RNA approach in LN229, significantly reduced their in vitro growth as well as growth and invasion in vivo. The fetuin-A knockdown subclones of LN229 (A and D) also had reduced motility and invasive capacity. Treatment of LN229 cells with asialofetuin ( ASF), attenuated their uptake of labeled fetuin-A, and induced senescence in them. Interestingly, the D subclone that had ~90% reduction in ectopic fetuin-A, underwent senescence in serum-free medium which was blunted in the presence of purified fetuin-A. Uptake of labeled exosomes was attenuated in fetuin-A knockdown subclones A and D. Taken together, the studies demonstrate the impact of fetuin-A as significant node of growth, motility, and invasion signaling in glioblastomas that can be targeted for therapy. [ABSTRACT FROM AUTHOR]

Rejection with acute hemodynamic compromise after OHT is rare in children, and is associated with poor survival. We retrospectively reviewed the management, course and outcome of recipients with late (following initial hospital discharge) rejection with acute hemodynamic compromise who were supported on ECLS. Of 197 consecutive children undergoing OHT (84 male; mean [SD] age 8.3 [5.7] [range 0.1-18.8 yr]) between 2/2002 and 10/2012, 187 children survived and were discharged from hospital. Mean (SD) follow-up was 5.0 (3.1) (range 0.1-10.6) yr. During follow-up, seven presented with severe hemodynamic compromise after transplantation (of whom one patient had been transplanted elsewhere). All seven children, who presented in hemodynamic collapse with poor cardiac function refractory to inotropic support, were placed on ECLS-two following in-hospital cardiac arrest. The median duration of ECLS was 6 (range 5-15) days. All survived to decannulation, with one death from overwhelming sepsis 20 days after presentation. The median (range) duration (in days) of inotropic requirement post ECLS was 11 (5-27), the median ventilation time was 8 (7-30), median ICU length of stay was 14 (10-54), and median hospitalization was 24 (19-118). In all, ventricular function normalized ( FS >28%) within 10 (7-22) days. There was significant short-term morbidity; however, over a median follow-up of 5.9 (range 0.7-9.2) yr, all survivors have good functional status with no significant apparent neurological sequelae. ECLS thus appears to be a good rescue therapy for children with severe acute rejection post OHT, refractory to conventional treatment, leading to good medium-term outcome. [ABSTRACT FROM AUTHOR]

The renal betaine transporter (BGT1) protects cells in the hypertonic medulla by mediating uptake and accumulation of the osmolyte betaine. Transcription plays an essential role in upregulating BGT1 transport in MDCK cells subjected to hypertonic stress. During hypertonic stress, the abundance of the transcription factor TonEBP increases and it shifts from the cytoplasm to the nucleus where it activates transcription of the BGT1 gene. Little is known about post-transcriptional regulation of BGT1 protein. In the presence of the proteasome inhibitor MG-132, which blocked nuclear translocation of TonEBP, the hypertonic upregulation of BGT1 protein and transport was prevented and cell viability in hypertonic medium was impaired over 24 h. Urea also prevented the hypertonic upregulation of BGT1 protein and transport, but did not interfere with TonEBP translocation and cell viability. Shorter treatments of hypertonic cells with MG-132 avoided viability problems and produced dose-dependent inhibition of translocation and transport. When stably transfected MDCK cells that over-expressed BGT1 were treated for 6 h with hypertonic medium containing 3 µ M MG-132, there was 43% inhibition of nuclear translocation, 83% inhibition of BGT1 transport, and no change in viability. While other proteasome functions may be involved, these data are consistent with a critical role for nuclear translocation of TonEBP in upregulation and membrane insertion of BGT1 protein. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This essay examines William Temple's defense of the British bombing of German cities during the Second World War. After detailing Temple's position in defense of the bombing, the essay raises a number of questions from within the just war tradition. First, does the just war tradition have to be understood deontologically, or is it possible to interpret it in a utilitarian fashion? If the former, then considerations of the means of warfare are still important. Second, how should we characterize the relationship of the citizen and the state during modern warfare? Is it as close as Temple claimed, so that we can no longer distinguish between citizens and states? Third, has the practice of deception of citizens by their leaders on questions of the means of warfare led to a situation in which it is no longer prudent to trust political leaders when they report to their peoples on these matters? The paper ends with a suggestion for further discussion on the third question. [ABSTRACT FROM AUTHOR]

This paper is an analysis of Michael Walzer's (1977) argument concerning British bombing policy during the Second World War. Walzer had argued that the British bombing early in the war was morally permissible as an example of a “supreme emergency.” The argument here is twofold. First, Walzer's historical reconstruction of the British situation is judged inadequate. Second, even assuming Walzer's factual description, his theoretical argument is incomplete. Walzer fails to appreciate the moral difficulty of the politician who acts in such a way as to initiate an immoral social practice in order to defeat an evil political system, especially when this social practice becomes a feature of our common life. Certain other features of Walzer's account are also explored. [ABSTRACT FROM AUTHOR]

In this article the author comments on the ethical nature of keeping a dead body in an intensive care unit (ICU) and denying a living patient access to the ICU. Setting aside cultural differences, he believes that the dead body no longer gets medical benefits from the ICU, while a living patient has every right to receive an ICU-level care. Also investigated is the possibility for hospitals to review their policies when it comes to caring for patients with diverse cultural backgrounds.

Book reviewed in this article: The Limits of Love: Some Theological Explorations. By Gilbert Meilaender. [ABSTRACT FROM AUTHOR]