Tumor growth is associated with the inhibition of host antitumor immune responses that can impose serious obstacles to cancer immunotherapy. To define the potential contribution of Qa-1-restricted ...CD8 regulatory T cells (Treg) to the development of tumor immunity, we studied B6.Qa-1 D227K mice that harbor a point mutation in the MHC class Ib molecule Qa-1 that impairs CD8 Treg suppressive activity. Here, we report that the growth of B16 melanoma is substantially delayed in these Qa-1-mutant mice after therapeutic immunization with B16 melanoma cells engineered to express granulocyte macrophage colony-stimulating factor compared with Qa-1 B6-WT controls. Reduced tumor growth is associated with enhanced expansion of follicular T helper cells, germinal center B cells, and high titers of antitumor autoantibodies, which provoke robust antitumor immune responses in concert with tumor-specific cytolytic T cells. Analysis of tumor-infiltrating T cells revealed that the Qa-1 DK mutation was associated with an increase in the ratio of CD8(+) T effectors compared with CD8 Tregs. These data suggest that the CD8(+) T effector-Treg ratio may provide a useful prognostic index for cancer development and raise the possibility that depletion or inactivation of CD8 Tregs represents a potentially effective strategy to enhance antitumor immunity.
To evaluate the time dependent changes of microcirculation in hepatocellular carcinoma (HCC) lesions during degradable starch microsphere (DSM)-TACE using contrast enhanced ultrasound (CEUS).
A total ...of 48 CEUS examinations were performed (1-5 MHz, convex probe) in 6 selected patients who underwent DSM-TACE with EmboCept®S for the treatment of HCC lesions. I.v. application of ultrasound contrast media was performed before and 24 hours post embolization. In addition i.a. contrast application was performed via the angiographic catheter right before and after the embolization and during a follow up time of 2 hours every 30 minutes. The capillary circulation of the treated HCC lesions was analyzed and quantitative perfusion analysis was performed using a perfusion software by two experienced radiologists in consensus.
A significantly reduced microvascularization was seen right after DSM-TACE in all cases using CEUS. The reduction of PEAK, RBV (regional blood volume) and RBF (regional blood flow) compared to preembolization values was highly significant. Mean PEAK was 34.3 ± 13.1 prior to embolization and 9.4 ± 9.1 post embolization (p < 0.001). Mean RBV was 446.5 ± 122.4 prior to embolization and 70.9 ± 23.8 post embolization (p < 0.001). The corresponding figures for RBF were 34.7 ± 13.4 prior- and 4.8 ± 3.4 post embolization (p < 0.001). During follow up a stepwise revascularization of the lesions was documented: 90 minutes post embolization perfusion parameters were not significantly different from prae-embolization values.
In this feasibility study, capillary perfusion quantification of HCC lesions after DSM-TACE could be demonstrated using CEUS. Using quantitative perfusion analysis it was possible to quantify the transient embolizing effect of DSM-TACE.
Percutaneous coronary revascularization (PCI) has been increasingly applied to unprotected left main trunk (LMT) lesions, with varied long-term success. This study attempts to define the predictors ...of outcome in this population.
Two hundred seventy-nine consecutive patients who had LMT PCI at 1 of 25 sites between 1993 and 1998 were studied. Forty-six percent of these patients were deemed inoperable or at high surgical risk. Thirty-eight patients (13.7%) died in hospital, and the rest were followed up for a mean of 19 months. The 1-year incidence was 24.2% for all-cause mortality, 20.2% for cardiac mortality, 9.8% for myocardial infarction, and 9.4% for CABG. Independent correlates of all-cause mortality were left ventricular ejection fraction </=30%, mitral regurgitation grade 3 or 4, presentation with myocardial infarction and shock, creatinine >/=2.0 mg/dL, and severe lesion calcification. For the 32% of patients <65 years old with left ventricular ejection fraction >30% and without shock, the prevalence of these adverse risk factors was low. No periprocedural deaths were observed in this low-risk subset, and the 1-year mortality was only 3.4%.
Patients undergoing unprotected LMT PCI have frequent serious comorbidities and consequently have high event rates. PCI may be an alternative to CABG for a select proportion of elective patients and may also be appropriate for highly symptomatic inoperable patients. Meticulous follow-up of hospital survivors is required because of the rather high mortality during the first few months after treatment.
► We study the potential anti-tumor effects of Lycopodium serratum on HL-60 cells. ► LSE and SE could inhibit proliferation and induce apoptosis in HL-60 cells. ► The SE induced apoptosis via ...regulating the ratio of Bax/Bcl-xL in HL-60 cells.
In this study, we investigate a plant commonly used in herbal medicines, Lycopodium serratum, which is believed to have anti-cancer properties. An alcoholic extract of L. serratum (LSE) was investigated for its ability to induce apoptosis in cultured human promyelocytic leukemia HL-60 cells. Treatment of HL-60 cells with various concentrations of LSE (6–100μg/mL) resulted in a sequence of events characteristic of apoptosis, including loss of cell viability, morphological changes, and increased sub-G1 DNA content. Serratenediol (SE), a known biologically active agent, was isolated from MC fraction of LSE and was able to demonstrate significant and dose-dependent growth inhibitory effects on HL-60 cells. Similar to the effects observed with the crude LSE, the SE-related effects included the formation of apoptotic bodies and fragmented DNA, as well as the accumulation of DNA in the sub-G1 phase of the cell cycle. Analysis of the mechanism of these events indicated that SE treated cells had an increased ratio of Bax/Bcl-xL, released the cytochrome c, activated caspase-9, -3, and cleaved poly-ADP-ribose polymerase (PARP); these observations are hallmarks of apoptotic events. Thus, the results suggest that SE can induce apoptosis via regulating the ratio of Bax/Bcl-xL in HL-60 cell lines.
G protein-coupled receptors (GPCRs) mediate our sense of vision, smell, taste, and pain. They are also involved in cell recognition and communication processes, and hence have emerged as a prominent ...superfamily for drug targets. Unfortunately, the atomic-level structure is available for only one GPCR (bovine rhodopsin), making it difficult to use structure-based methods to design drugs and mutation experiments. We have recently developed first principles methods (MembStruk and HierDock) for predicting structure of GPCRs, and for predicting the ligand binding sites and relative binding affinities. Comparing to the one case with structural data, bovine rhodopsin, we find good accuracy in both the structure of the protein and of the bound ligand. We report here the application of MembStruk and HierDock to β1-adrenergic receptor, endothelial differential gene 6, mouse and rat 17 olfactory receptors, and human sweet receptor. We find that the predicted structure of β1-adrenergic receptor leads to a binding site for epinephrine that agrees well with the mutation experiments. Similarly the predicted binding sites and affinities for endothelial differential gene 6, mouse and rat I7 olfactory receptors, and human sweet receptor are consistent with the available experimental data. These predicted structures and binding sites allow the design of mutation experiments to validate and improve the structure and function prediction methods. As these structures are validated they can be used as targets for the design of new receptor-selective antagonists or agonists for GPCRs.
Strong spin–orbit semiconductor nanowires coupled to a superconductor are predicted to host Majorana zero modes. Exchange (braiding) operations of Majorana modes form the logical gates of a ...topological quantum computer and require a network of nanowires. Here, we utilize an in-plane selective area growth technique for InSb–Al semiconductor–superconductor nanowire networks. Transport channels, free from extended defects, in InSb nanowire networks are realized on insulating, but heavily mismatched InP (111)B substrates by full relaxation of the lattice mismatch at the nanowire/substrate interface and nucleation of a complete network from a single nucleation site by optimizing the surface diffusion length of the adatoms. Essential quantum transport phenomena for topological quantum computing are demonstrated in these structures including phase-coherence lengths exceeding several micrometers with Aharonov–Bohm oscillations up to five harmonics and a hard superconducting gap accompanied by 2e-periodic Coulomb oscillations with an Al-based Cooper pair island integrated in the nanowire network.Indium-Antimonide (InSb) possesses specific properties that makes it a suitable candidate for realizing Majorana-based topological quantum computers. The authors describe a method to fabricate single crystalline InSb nanowire networks from single nuclei enabling them to realize high-quality quantum transport in their devices.
Herpes zoster, a frequent complication following autologous hematopoietic stem cell transplantation (HSCT), is associated with significant morbidity. A nonlive adjuvanted recombinant zoster vaccine ...has been developed to prevent posttransplantation zoster.
To assess the efficacy and adverse event profile of the recombinant zoster vaccine in immunocompromised autologous HSCT recipients.
Phase 3, randomized, observer-blinded study conducted in 167 centers in 28 countries between July 13, 2012, and February 1, 2017, among 1846 patients aged 18 years or older who had undergone recent autologous HSCT.
Participants were randomized to receive 2 doses of either recombinant zoster vaccine (n = 922) or placebo (n = 924) administered into the deltoid muscle; the first dose was given 50 to 70 days after transplantation and the second dose 1 to 2 months thereafter.
The primary end point was occurrence of confirmed herpes zoster cases.
Among 1846 autologous HSCT recipients (mean age, 55 years; 688 37% women) who received 1 vaccine or placebo dose, 1735 (94%) received a second dose and 1366 (74%) completed the study. During the 21-month median follow-up, at least 1 herpes zoster episode was confirmed in 49 vaccine and 135 placebo recipients (incidence, 30 and 94 per 1000 person-years, respectively), an incidence rate ratio (IRR) of 0.32 (95% CI, 0.22-0.44; P < .001), equivalent to 68.2% vaccine efficacy. Of 8 secondary end points, 3 showed significant reductions in incidence of postherpetic neuralgia (vaccine, n=1; placebo, n=9; IRR, 0.1; 95% CI, 0.00-0.78; P = .02) and of other prespecified herpes zoster-related complications (vaccine, n=3; placebo, n=13; IRR, 0.22; 95% CI, 0.04-0.81; P = .02) and in duration of severe worst herpes zoster-associated pain (vaccine, 892.0 days; placebo, 6275.0 days; hazard ratio, 0.62; 95% CI, 0.42-0.89; P = .01). Five secondary objectives were descriptive. Injection site reactions were recorded in 86% of vaccine and 10% of placebo recipients, of which pain was the most common, occurring in 84% of vaccine recipients (grade 3: 11%). Unsolicited and serious adverse events, potentially immune-mediated diseases, and underlying disease relapses were similar between groups at all time points.
Among adults who had undergone autologous HSCT, a 2-dose course of recombinant zoster vaccine compared with placebo significantly reduced the incidence of herpes zoster over a median follow-up of 21 months.
ClinicalTrials.gov Identifier: NCT01610414.
Aim of our pilot study was the application of a contrast-enhanced color-coded ultrasound perfusion analysis in patients with vascular malformations to quantify microcirculatory alterations.
28 ...patients (16 female, 12 male, mean age 24.9 years) with high flow (n = 6) or slow-flow (n = 22) malformations were analyzed before intervention. An experienced examiner performed a color-coded Doppler sonography (CCDS) and a Power Doppler as well as a contrast-enhanced ultrasound after intravenous bolus injection of 1 - 2.4 ml of a second-generation ultrasound contrast medium (SonoVue®, Bracco, Milan). The contrast-enhanced examination was documented as a cine sequence over 60 s. The quantitative analysis based on color-coded contrast-enhanced ultrasound (CEUS) images included percentage peak enhancement (%peak), time to peak (TTP), area under the curve (AUC), and mean transit time (MTT).
No side effects occurred after intravenous contrast injection. The mean %peak in arteriovenous malformations was almost twice as high as in slow-flow-malformations. The area under the curve was 4 times higher in arteriovenous malformations compared to the mean value of other malformations. The mean transit time was 1.4 times higher in high-flow-malformations compared to slow-flow-malformations. There was no difference regarding the time to peak between the different malformation types. The comparison between all vascular malformation and surrounding tissue showed statistically significant differences for all analyzed data (%peak, TTP, AUC, MTT; p < 0.01). High-flow and slow-flow vascular malformations had statistically significant differences in %peak (p < 0.01), AUC analysis (p < 0.01), and MTT (p < 0.05).
Color-coded perfusion analysis of CEUS seems to be a promising technique for the dynamic assessment of microvasculature in vascular malformations.
Human and mouse studies indicate that TLRs are important in mycobacterial infections. We investigated TLR gene expression in fresh unstimulated blood and bronchoalveolar lavage from patients with ...pulmonary tuberculosis using a well-validated, real-time PCR. A human splice variant of TLR1, designated hsTLR1, was found in all donors tested. hsTLR1 mRNA lacks exon 2, which is a 77-bp region of the 5'-untranslated region, but contains the same coding sequence as TLR1. Compared with the matched controls, whole blood from patients had increased levels of mRNA encoding TLR2 (p = 0.0006), TLR1 (p = 0.004), hsTLR1 (p = 0.0003), TLR6 (p < 0.0001), and TLR4 (p = 0.0002). By contrast, expression of these TLRs was not increased in bronchoalveolar lavage. An increased level of hsTLR1 mRNA was found in both CD3- (p = 0.0078) and CD4+ cells (p = 0.028), resulting in an increased ratio of hsTLR1 mRNA to TLR1 and to TLR6 mRNA. An in vitro study in THP1 cells suggested that this relative increase in hsTLR1 might be attributable to a direct effect of mycobacterial components because it could be mimicked by mycobacterial preparations in the absence of IFN-gamma or T cells and by the TLR1/2 agonist Pam3CysK4. Half-life studies using blood from patients with pulmonary tuberculosis and THP1 cells exposed to Myobacterium tuberculosis in vitro showed p38 MAPK-independent stabilization of mRNAs encoding hsTLR1 and TLR1. We conclude that M. tuberculosis exerts direct effects on patterns of TLR expression, partly via changes in mRNA half-life. The significance of these changes in the pathogenesis of disease deserves further investigation.
Charged particle multiplicity distributions in positron-proton deep inelastic scattering at a centre-of-mass energy
s
=
319
GeV are measured. The data are collected with the H1 detector at HERA ...corresponding to an integrated luminosity of 136 pb
-
1
. Charged particle multiplicities are measured as a function of photon virtuality
Q
2
, inelasticity
y
and pseudorapidity
η
in the laboratory and the hadronic centre-of-mass frames. Predictions from different Monte Carlo models are compared to the data. The first and second moments of the multiplicity distributions are determined and the KNO scaling behaviour is investigated. The multiplicity distributions as a function of
Q
2
and the Bjorken variable
x
bj
are converted to the hadron entropy
S
hadron
, and predictions from a quantum entanglement model are tested.
PDF
