Effect of 15-deoxyspergualin on experimental organ transplantation

DSPG had a definite but relatively feeble immunosuppressive effect in rats undergoing heterotopic heart transplantation and in dogs after renal transplantation. The drug was toxic in both species, although less so in rats. In dogs, synergistic interactions with cyclosporine and steroids were not evident

Inner and Outer Portions of Colonic Circular Muscle: Ultrastructural and Immunohistochemical Changes in Rat Chronically Treated with Otilonium Bromide

Rat colonic circular muscle, main target of otilonium bromide (OB) spasmolytic activity, is subdivided in an inner and outer portion. Since the inner one is particularly rich in organelles involved in calcium availability (caveolae, smooth endoplasmic reticulum, mitochondria), the expression of specific markers (Caveolin-1, eNOS, calreticulin, calsequestrin) in comparison with the outer portion was investigated. The possible changes of these organelles and related markers, and of muscarinic receptors (Mr2) were then studied after OB chronic exposition. Rats were treated with 2-20 mg/kg/OB for 10 or 30 days. Proximal colon was processed by electron microscopy, immunohistochemistry, and western blot. In colon strips the stimulated contractility response to muscarinic agonist was investigated. The inner portion showed a higher expression of Caveolin-1 and Mr2, but not of eNOS, calreticulin and calsequestrin, compared to the outer portion. Chronic OB treatment caused similar ultrastructural and immunohistochemical changes in both portions. Organelles and some related markers were increased at 10 days; Mr2 expression and muscle contractility induced by methacholine was increased at 30 days. The present findings: 1) provide new information on the immunohistochemical properties of the inner portion of the circular layer that are in favour of a role it might play in colonic motility distinct from that of the outer portion; 2) demonstrate that chronically administered OB interferes with cell structures and molecules responsible for calcium handling and storage, and modifies cholinergic transmission. In conclusion, chronic OB administration in the colonic circular muscle layer directly interacts with the organelles and molecules calcium-related and with the Mr2

Intermediate Valence Model for the Colossal Magnetoresistance in Tl_{2}Mn_{2}O_{7}

The colossal magnetoresistance exhibited by Tl_{2}Mn_{2}O_{7} is an interesting phenomenon, as it is very similar to that found in perovskite manganese oxides although the compound differs both in its crystalline structure and electronic properties from the manganites. At the same time, other pyrochlore compounds, though sharing the same structure with Tl_{2}Mn_{2}O_{7}, do not exhibit the strong coupling between magnetism and transport properties found in this material. Mostly due to the absence of evidence for significant doping into the Mn-O sublattice, and the tendency of Tl to form conduction bands, the traditional double exchange mechanism mentioned in connection with manganites does not seem suitable to explain the experimental results in this case. We propose a model for Tl_{2}Mn_{2}O_{7} consisting of a lattice of intermediate valence ions fluctuating between two magnetic configurations, representing Mn-3d orbitals, hybridized with a conduction band, which we associate with Tl. This model had been proposed originally for the analysis of intermediate valence Tm compounds. With a simplified treatment of the model we obtain the electronic structure and transport properties of Tl_{2}Mn_{2}O_{7}, with good qualitative agreement to experiments. The presence of a hybridization gap in the density of states seems important to understand the reported Hall data.Comment: 8 pages + 5 postscript fig

Downstaging of Hepatocellular Carcinoma Prior to Liver Transplant: Is There a Role for Adjuvant Sorafenib in Locoregional Therapy?

Hepatocellular carcinoma (HCC) remains a common cause of mortality worldwide. Liver transplantation has emerged as the optimal treatment for cirrhotic patients with HCC; however, the shortage of donor organs leaves waitlisted patients at risk for disease progression beyond transplant criteria. Prevention of waitlist dropout has fueled investigation into a wide array of locoregional therapies for the management of HCC in candidates awaiting liver transplantation. We present a patient with HCC who underwent treatment with sorafenib, which resulted in a remarkable reduction in tumor burden to allow for liver transplant listing

Canine kidney transplantation with FK-506 alone or in combination with cyclosporine and steroids.

The immunosuppressive agent FK permitted increased kidney transplant survival in dogs over a wide dose range, but with weight loss and manifold evidence of toxicity. The best use of FK at low doses was in combination with CyA and Pred

Dynamical Mean-Field Solution for a Model of Metal-Insulator Transitions in Moderately Doped Manganites

We propose that a specific spatial configuration of lattice sites that energetically favor {\it 3+} or {\it 4+} Mn ions in moderately doped manganites constitutes approximately a spatially random two-energy-level system. Such an effect results in a mechanism of metal-insulator transitions that appears to be different from both the Anderson transition and the Mott-Hubbard transition. Correspondingly, a disordered Kondo lattice model is put forward, whose dynamical mean-field solution agrees reasonably with experiments.Comment: 4 pages, 2 eps figures, Revtex. First submitted to PRL on May 16, 199

Human Tumor-Derived Heat Shock Protein 96 Mediates In Vitro Activation and In Vivo Expansion of Melanoma- and Colon Carcinoma-Specific T Cells

Abstract Heat shock proteins (hsp) 96 play an essential role in protein metabolism and exert stimulatory activities on innate and adaptive immunity. Vaccination with tumor-derived hsp96 induces CD8+ T cell-mediated tumor regressions in different animal models. In this study, we show that hsp96 purified from human melanoma or colon carcinoma activate tumor- and Ag-specific T cells in vitro and expand them in vivo. HLA-A*0201-restricted CD8+ T cells recognizing Ags expressed in human melanoma (melanoma Ag recognized by T cell-1 (MART-1)/melanoma Ag A (Melan-A)) or colon carcinoma (carcinoembryonic Ag (CEA)/epithelial cell adhesion molecule (EpCAM)) were triggered to release IFN-γ and to mediate cytotoxic activity by HLA-A*0201-matched APCs pulsed with hsp96 purified from tumor cells expressing the relevant Ag. Such activation occurred in class I HLA-restricted fashion and appeared to be significantly higher than that achieved by direct peptide loading. Immunization with autologous tumor-derived hsp96 induced a significant increase in the recognition of MART-1/Melan-A27–35 in three of five HLA-A*0201 melanoma patients, and of CEA571–579 and EpCAM263–271 in two of five HLA-A*0201 colon carcinoma patients, respectively, as detected by ELISPOT and HLA/tetramer staining. These increments in Ag-specific T cell responses were associated with a favorable disease course after hsp96 vaccination. Altogether, these data provide evidence that hsp96 derived from human tumors can present antigenic peptides to CD8+ T cells and activate them both in vitro and in vivo, thus representing an important tool for vaccination in cancer patients

Charge Localization in Disordered Colossal-Magnetoresistance Manganites

The metallic or insulating nature of the paramagnetic phase of the colossal-magnetoresistance manganites is investigated via a double exchange Hamiltonian with diagonal disorder. Mobility edge trajectory is determined with the transfer matrix method. Density of states calculations indicate that random hopping alone is not sufficient to induce Anderson localization at the Fermi level with 20-30% doping. We argue that the metal-insulator transtion is likely due to the formation of localized polarons from nonuniform extended states as the effective band width is reduced by random hoppings and electron-electron interactions.Comment: 4 pages, RevTex. 4 Figures include

Microenvironment and tumor inflammatory features improve prognostic prediction in gastro-entero-pancreatic neuroendocrine neoplasms

Microenvironment-related immune and inflammatory markers, when combined with established Ki-67 and morphology parameters, can improve prognostic prediction in gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs). Therefore, we evaluated the prognostic value of microenvironment and tumor inflammatory features (MoTIFs) in GEP-NENs. For this purpose, formalin-fixed paraffin-embedded tissue sections from 350 patients were profiled by immunohistochemistry for immune, inflammatory, angiogenesis, proliferation, NEN-, and fibroblast-related markers. A total of 314 patients were used to generate overall survival (OS) and disease-free survival (DFS) MoTIFs prognostic indices (PIs). PIs and additional variables were assessed using Cox models to generate nomograms for predicting 5-year OS and DFS. A total of 36 patients were used for external validation of PIs and nomograms' prognostic segregations. From our analysis, G1/G2 versus G3 GEP-NENs showed phenotypic divergence with immune-inflammatory markers. HLA, CD3, CD8, and PD-1/PD-L1 IHC expression separated G3 into two sub-categories with high versus low adaptive immunity-related features. MoTIFs PI for OS based on COX-2Tumor(T) > 4, PD-1Stromal(S) > 0, CD8S < 1, and HLA-IS < 1 was associated with worst survival (hazard ratio [HR] 2.50; 95% confidence interval [CI], 2.12–2.96; p < 0.0001). MoTIFs PI for DFS was based on COX-2T > 4, PD-1S > 4, HLA-IS < 1, HLA-IT < 2, HLA-DRS < 6 (HR 1.77; 95% CI, 1.58–1.99; p < 0.0001). Two nomograms were developed including morphology (HR 4.83; 95% CI, 2.30–10.15; p < 0.001) and Ki-67 (HR 11.32; 95% CI, 5.28–24.24; p < 0.001) for OS, and morphology (PI = 0: HR 10.23; 95% CI, 5.67–18.47; PI = 5: HR 2.87; 95% CI, 1.21–6.81; p < 0.001) and MoTIFs PI for DFS in well-differentiated GEP-NENs (HR 6.21; 95% CI, 2.52–13.31; p < 0.001). We conclude that G1/G2 to G3 transition is associated with immune-inflammatory profile changes; in fact, MoTIFs combined with morphology and Ki-67 improve 5-year DFS prediction in GEP-NENs. The immune context of a subset of G3 poorly differentiated tumors is consistent with activation of adaptive immunity, suggesting a potential for responsiveness to immunotherapy targeting immune checkpoints