Increasing evidence supports the hypothesis that cancer stem cells (CSCs) are resistant to antiproliferative therapies, able to repopulate tumor bulk, and seed metastasis. NK cells are able to target stem cells as shown by their ability to reject allogeneic hematopoietic stem cells but not solid tissue grafts. Using multiple preclinical models, including NK coculture (autologous and allogeneic) with multiple human cancer cell lines and dissociated primary cancer specimens and NK transfer in NSG mice harboring orthotopic pancreatic cancer xenografts, we assessed CSC viability, CSC frequency, expression of death receptor ligands, and tumor burden. We demonstrate that activated NK cells are capable of preferentially killing CSCs identified by multiple CSC markers (CD24+/CD44+, CD133+, and aldehyde dehydrogenasebright) from a wide variety of human cancer cell lines in vitro and dissociated primary cancer specimens ex vivo. We observed comparable effector function of allogeneic and autologous NK cells. We also observed preferential upregulation of NK activation ligands MICA/B, Fas, and DR5 on CSCs. Blocking studies further implicated an NKG2D-dependent mechanism for NK killing of CSCs. Treatment of orthotopic human pancreatic cancer tumor-bearing NSG mice with activated NK cells led to significant reductions in both intratumoral CSCs and tumor burden. Taken together, these data from multiple preclinical models, including a strong reliance on primary human cancer specimens, provide compelling preclinical evidence that activated NK cells preferentially target cancer cells with a CSC phenotype, highlighting the translational potential of NK immunotherapy as part of a combined modality approach for refractory solid malignancies.

We examined the chronic effects of losartan (DuP 753), a novel orally active angiotensin II receptor antagonist, on blood pressure and renal function in eight hospitalized patients with essential hypertension. After a control period of 1 week, losartan was administered orally once a day for 2 to 4 weeks in increasing doses of 12.5, 25, 50, and 100 mg, until blood pressure in the supine position decreased more than 20 mm Hg (systolic) and 10 mm Hg (diastolic) (or 13 mm Hg in mean blood pressure). The average dose of losartan was 59.4 +/- 43.7 (mean +/- SD) mg/day. Systolic, diastolic, and mean blood pressures, according to 24 h monitoring, fell significantly, from 151.9 +/- 6.8 to 137.2 +/- 7.9 mm Hg, from 90.6 +/- 3.7 to 81.0 +/- 3.7 mm Hg, and from 111.1 +/- 4.6 to 99.7 +/- 5.0 mm Hg, respectively (mean +/- SE, P < .01 for each), with no change in circadian rhythm or variability of blood pressure. Reduction in blood pressure was slightly greater during daytime than during sleep time. Unlike peptide angiotensin II antagonists, losartan did not exert pressor action. No significant alterations were observed in body weight, serum electrolytes, creatinine clearance, urine volume, or urinary excretion of sodium. Losartan significantly lowered serum uric acid concentration from 5.5 +/- 0.4 to 4.8 +/- 0.3 mg/dL (P < .05). Urinary excretion of uric acid increased significantly from 498.9 +/- 64.4 to 540.6 +/- 66.6 mg/day (P < .05). Plasma renin activity rose significantly but plasma aldosterone concentration did not change with the losartan treatment. These results suggest that losartan has a long-acting hypotensive effect with a hypouricemic action in essential hypertension.

A high-flow nasal cannula (HFNC) is a newly developed device that enables high-flow oxygen therapy for patients with serious cardiopulmonary problems, but there are few data regarding its use in patients with hematological disease. The efficacy and tolerability of HFNCs for patients who developed ARF during the treatment of various hematological diseases was evaluated. Fifty-six patients underwent HFNC therapy during the last 2 years, and the causes of ARF were mainly pneumonia (n = 37) or acute congestive heart failure (n = 7). Only 11 patients (20 %) showed a good response to HFNC therapy, and remaining 45 patients (80 %) failed to respond to the initial HFNC therapy and, therefore, underwent second-line therapy including endotracheal intubation with mechanical ventilation (n = 15), non-invasive positive pressure ventilation (n = 1), or narcotic palliation alone (n = 29). Thus, HFNC appear not to be a viable treatment option in 4 out of 5 patients in this cohort of patients with hematological disease, but it was well tolerated in most patients (96 %); no major complications except for nasal soreness (n = 2) were observed. Multivariate analysis showed that the cause of ARF (pneumonia, odds ratio 11.2, 95 % CI 1.76–71.5, p = 0.01) was the only risk factor for treatment failure.

Bortezomib, a proteasome inhibitor capable of direct anti-tumor effects, has been shown to prevent acute graft-versus-host disease (aGVHD) when administered in a short course immediately after bone marrow transplantation (BMT) in mice. However, when given continuously, CD4+ T cell mediated gastrointestinal tract damages increase GVHD mortality. To investigate the protective effects of bortezomib on other organs, we have used a CD8 dependent aGVHD model of C3H.SW donor T cells engrafted into irradiated C57BL/6 recipients (minor MHC mismatch), which lack significant gut GVHD. Our data in this model show that bortezomib can be given continuously to prevent and treat aGVHD mediated by CD8+ T cells, but this effect is organ-specific such that only skin, but not liver, protection was observed. Despite the lack of hepatic protection, bortezomib still significantly improved survival primarily due to its skin protection. Reduced skin GVHD by bortezomib was correlated with reduced serum and skin IL-6 levels. Administration of a blocking IL-6 antibody in this model also resulted in similar cutaneous GVHD protection. These results indicate that bortezomib or blockade of IL-6 may prevent CD8+ T cell mediated cutaneous aGVHD.

The electronic structure of the outermost layer of “multilayer silicene” was investigated by metastable atom electron spectroscopy (MAES). It is usually difficult to elucidate the electronic structure of an ultrathin film grown on a solid substrate excluding the contribution from the substrate, especially such as “multilayer silicene” grown on a Ag(111) substrate. MAES used in this study thus provides a proper solution because the excitation source, He*­(23S) atom, cannot penetrate through the first layer. Comparing the MAES spectra of “multilayer silicene” and of the Si(111)√3 × √3-Ag surface where the Ag atoms are arranged to form a superlattice on the (111) surface of the Si diamond crystal, we find that these spectra are essentially identical to each other. This result indicates that the so-called “multilayer silicene” is actually not multilayered, i.e., a stack of honeycomb lattice layers.