Longitudinal Eigenvibration of Multilayer Colloidal Crystals and the Effect of Nanoscale Contact Bridges

Longitudinal contact-based vibrations of colloidal crystals with a controlled layer thickness are studied. These crystals consist of 390 nm diameter polystyrene spheres arranged into close packed, ordered lattices with a thickness of one to twelve layers. Using laser ultrasonics, eigenmodes of the crystals that have out-of-plane motion are excited. The particle-substrate and effective interlayer contact stiffnesses in the colloidal crystals are extracted using a discrete, coupled oscillator model. Extracted stiffnesses are correlated with scanning electron microscope images of the contacts and atomic force microscope characterization of the substrate surface topography after removal of the spheres. Solid bridges of nanometric thickness are found to drastically alter the stiffness of the contacts, and their presence is found to be dependent on the self-assembly process. Measurements of the eigenmode quality factors suggest that energy leakage into the substrate plays a role for low frequency modes but is overcome by disorder- or material-induced losses at higher frequencies. These findings help further the understanding of the contact mechanics, and the effects of disorder in three-dimensional micro- and nano-particulate systems, and open new avenues to engineer new types of micro- and nanostructured materials with wave tailoring functionalities via control of the adhesive contact properties

Spin dependent photoelectron tunnelling from GaAs into magnetic Cobalt

The spin dependence of the photoelectron tunnel current from free standing GaAs films into out-of- plane magnetized Cobalt films is demonstrated. The measured spin asymmetry (A) resulting from a change in light helicity, reaches +/- 6% around zero applied tunnel bias and drops to +/- 2% at a bias of -1.6 V applied to the GaAs. This decrease is a result of the drop in the photoelectron spin polarization that results from a reduction in the GaAs surface recombination velocity. The sign of A changes with that of the Cobalt magnetization direction. In contrast, on a (nonmagnetic) Gold film A ~ 0%

Enhanced Phenotype Definition for Precision Isolation of Precursor Exhausted Tumor-Infiltrating CD8 T Cells.

In the context of adoptive T cell transfer (ACT) for cancer treatment, it is crucial to generate in vitro large amounts of tumor-specific CD8 T cells with high potential to persist in vivo. PD-1, Tim3, and CD39 have been proposed as markers of tumor-specific tumor-infiltrating CD8 T lymphocytes (CD8 TILs). However, these molecules are highly expressed by terminally differentiated exhausted CD8 T cells (Tex) that lack proliferation potential. Therefore, optimized strategies to isolate tumor-specific TILs with high proliferative potential, such as Tcf1+ precursor exhausted T cells (Tpe) are needed to improve in vivo persistence of ACT. Here we aimed at defining cell surface markers that would unequivocally identify Types for precision cell sorting increasing the purity of tumor-specific PD-1+ Tcf1+ Tpe from total TILs. Transcriptomic analysis of Tpe vs. Tex CD8 TIL subsets from B16 tumors and primary human melanoma tumors revealed that Tpes are enriched in Slamf6 and lack Entpd1 and Havcr2 expression, which encode Slamf6, CD39, and Tim3 cell surface proteins, respectively. Indeed, we observed by flow cytometry that CD39- Tim3- Slamf6+ PD-1+ cells yielded maximum enrichment for tumor specific PD-1+ Tcf1+ OT1 TILs in B16.OVA tumors. Moreover, this population showed higher re-expansion capacity upon an acute infection recall response compared to the CD39+ counterparts or bulk PD-1+ TILs. Hence, we report an enhanced sorting strategy (CD39- Tim3- Slamf6+ PD-1+) of Tpes. In conclusion, we show that optimization of CD8 TIL cell sorting strategy is a viable approach to improve recall capacity and in vivo persistence of transferred cells in the context of ACT

Acute Hypersensitivity of Pluripotent Testicular Cancer-Derived Embryonal Carcinoma to Low-Dose 5-Aza Deoxycytidine Is Associated with Global DNA Damage-Associated p53 Activation, Anti-Pluripotency and DNA Demethylation

Human embryonal carcinoma (EC) cells are the stem cells of nonseminoma testicular germ cells tumors (TGCTs) and share remarkable similarities to human embryonic stem (ES) cells. In prior work we found that EC cells are hypersensitive to low nanomolar doses of 5-aza deoxycytidine (5-aza) and that this hypersensitivity partially depended on unusually high levels of the DNA methyltransferase, DNMT3B. We show here that low-dose 5-aza treatment results in DNA damage and induction of p53 in NT2/D1 cells. In addition, low-dose 5-aza results in global and gene specific promoter DNA hypomethylation. Low- dose 5-aza induces a p53 transcriptional signature distinct from that induced with cisplatin in NT2/D1 cells and also uniquely downregulates genes associated with pluripotency including NANOG, SOX2, GDF3 and Myc target genes. Changes in the p53 and pluripotency signatures with 5-aza were to a large extent dependent on high levels of DNMT3B. In contrast to the majority of p53 target genes upregulated by 5-aza that did not show DNA hypomethylation, several other genes induced with 5-aza had corresponding decreases in promoter methylation. These genes include RIN1, SOX15, GPER, and TLR4 and are novel candidate tumors suppressors in TGCTs. Our studies suggest that the hypersensitivity of NT2/D1 cells to low-dose 5-aza is multifactorial and involves the combined activation of p53 targets, repression of pluripotency genes, and activation of genes repressed by DNA methylation. Low-dose 5-aza therapy may be a general strategy to treat those tumors that are sustained by cells with embryonic stem-like properties. GEO number for the microarray data: GSE42647

Oral capecitabine as an alternative to i.v. 5-fluorouracil-based adjuvant therapy for colon cancer: safety results of a randomized, phase III trial

Background: Oral capecitabine achieves a superior response rate with an improved safety profile compared with bolus 5-fluorouracil-leucovorin (5-FU/LV) as first-line treatment for patients with metastatic colorectal cancer. We report here the results of a large phase III trial investigating adjuvant oral capecitabine compared with 5-FU/LV (Mayo Clinic regimen) in Dukes' C colon cancer. Patients and methods: Patients aged 18-75 years with resected Dukes' C colon carcinoma were randomized to receive 24 weeks of treatment with either oral capecitabine 1250 mg/m2 twice daily, days 1-14 every 21 days (n = 993), or i.v. bolus 5-FU 425 mg/m2 with i.v. leucovorin 20 mg/m2 on days 1-5, repeated every 28 days (n = 974). Results: Patients receiving capecitabine experienced significantly (P <0.001) less diarrhea, stomatitis, nausea/vomiting, alopecia and neutropenia, but more hand-foot syndrome than those receiving 5-FU/LV. Fewer patients receiving capecitabine experienced grade 3 or 4 neutropenia, febrile neutropenia/sepsis and stomatitis (P <0.001), although more experienced grade 3 hand-foot syndrome than those treated with 5-FU/LV (P <0.001). Capecitabine demonstrates a similar, favorable safety profile in patients aged <65 years or ≥65 years old. Conclusions: Based on its improved safety profile, capecitabine has the potential to replace 5-FU/LV as standard adjuvant treatment for patients with colon cancer. Efficacy results are expected to be available in 2004. Keywords: Adjuvant treatment, capecitabine, chemotherapy, colorectal cance

Survival benefit of chemotherapy in metastatic colorectal cancer: a meta-analysis of randomized controlled trials

To estimate the magnitude of benefit of chemotherapy in prolonging survival for patients with metastatic colorectal cancer, a meta-analysis of randomized controlled trial was performed. A systematic search was performed to identify randomized trials comparing chemotherapy with observation or supportive care alone. Trials were assessed for quality of reporting, publication bias and heterogeneity. Relative risks for outcomes from published data were pooled using a random-effects model. Seven trials with 614 patients were included. All trials used fluoropyrimidine-based chemotherapy, through a variety of routes and schedules, including intravenous, intra-portal and hepatic arterial infusion. Compared with the ‘no-chemotherapy’ arm, chemotherapy significantly reduced 1-year mortality (risk ratio 0.69; 95% confidence interval (CI) 0.60–0.81, P< 0.00001). The mortality at 2 years was not significantly different (risk ratio 0.93; 95% CI 0.87–1.00, P = 0.053). Between-trial comparisons demonstrated benefit with a variety of routes and schedules. Chemotherapy significantly prolongs 1-year survival for patients with metastatic colorectal cancer, and should be offered to those with good performance status. © 2000 Cancer Research Campaig