Endoscopic Self-Expandable Metal Stent Placement for Malignant Afferent Loop Obstruction After Pancreaticoduodenectomy: A Case Series and Review

In this study, we assessed a series of our cases in which endoscopic self-expandable metal stents (SEMSs) were used to treat malignant afferent loop obstruction (ALO) that arose after pancreaticoduodenectomy (PD). We retrospectively examined the records of 7 patients who underwent endoscopic SEMS placement for malignant ALO following PD. Clinical success was achieved in all cases. The median procedure time was 30 min (range, 15–50 min). There were no cases of stent occlusion, and no procedure-related adverse events were encountered. All patients died of their primary disease, and the median overall survival period was 155 days (range, 96–374 days). A re-intervention involving endoscopic ultrasound-guided hepaticogastrostomy combined with antegrade stenting was performed for obstructive jaundice and acute cholangitis in 1 case. In conclusion, endoscopic SEMS placement may be an effective and safe treatment for malignant ALO that arises after PD

Donor Treg expansion by liposomal alpha-galactosylceramide modulates Tfh cells and prevents sclerodermatous chronic graft-versus-host disease

Background and Aim: Chronic graft-versus-host disease (cGVHD) is a major cause of nonrelapse morbidity and mortality following hematopoietic stem cell transplantation (HSCT). alpha-Galactosylceramide (alpha-GC) is a synthetic glycolipid that is recognized by the invariant T-cell receptor of invariant natural killer T (iNKT) cells in a CD1d-restricted manner. Stimulation of iNKT cells by alpha-GC leads to the production of not only immune-stimulatory cytokines but also immune-regulatory cytokines followed by regulatory T-cell (Treg) expansion in vivo. Methods: We investigated the effect of iNKT stimulation by liposomal alpha-GC just after transplant on the subsequent immune reconstitution and the development of sclerodermatous cGVHD. Results: Our study showed that multiple administrations of liposomal alpha-GC modulated both host- and donor-derived iNKT cell homeostasis and induced an early expansion of donor Tregs. We also demonstrated that the immune modulation of the acute phase was followed by the decreased levels of CXCL13 in plasma and follicular helper T cells in lymph nodes, which inhibited germinal center formation, resulting in the efficient prevention of sclerodermatous cGVHD. Conclusions: These data demonstrated an important coordination of T- and B-cell immunity in the pathogenesis of cGVHD and may provide a novel clinical strategy for the induction of immune tolerance after allogeneic HSCT

Reduced dose of PTCy followed by adjuvant alpha-galactosylceramide enhances GVL effect without sacrificing GVHD suppression

Posttransplantation cyclophosphamide (PTCy) has become a popular option for haploidentical hematopoietic stem cell transplantation (HSCT). However, personalized methods to adjust immune intensity after PTCy for each patient's condition have not been well studied. Here, we investigated the effects of reducing the dose of PTCy followed by alpha -galactosylceramide (alpha -GC), a ligand of iNKT cells, on the reciprocal balance between graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect. In a murine haploidentical HSCT model, insufficient GVHD prevention after reduced-dose PTCy was efficiently compensated for by multiple administrations of alpha -GC. The ligand treatment maintained the enhanced GVL effect after reduced-dose PTCy. Phenotypic analyses revealed that donor-derived B cells presented the ligand and induced preferential skewing to the NKT2 phenotype rather than the NKT1 phenotype, which was followed by the early recovery of all T cell subsets, especially CD4(+)Foxp3(+) regulatory T cells. These studies indicate that alpha -GC administration soon after reduced-dose PTCy restores GVHD-preventing activity and maintains the GVL effect, which is enhanced by reducing the dose of PTCy. Our results provide important information for the development of a novel strategy to optimize PTCy-based transplantation, particularly in patients with a potential relapse risk

Hematopoietic stem cell-derived Tregs are essential for maintaining favorable B cell lymphopoiesis following posttransplant cyclophosphamide

Posttransplant cyclophosphamide (PTCy) is associated with a low incidence of chronic graft -versus-host disease (cGVHD) following hematopoietic stem cell (HSC) transplantation. Previous studies have shown the important roles of B cell immunity in cGVHD development. Here, we investigated the long-term reconstitution of B lymphopoiesis after PTCy using murine models. We first demonstrated that the immune homeostatic abnormality leading to cGVHD is characterized by an initial increase in effector T cells in the bone marrow and subsequent B and Treg cytopenia. PTCy, but not cyclosporine A or rapamycin, inhibits the initial alloreactive T cell response, which restores intra-bone marrow B lymphogenesis with a concomitant vigorous increase in Tregs. This leads to profound changes in posttransplant B cell homeostasis, including decreased B cell activating factors, increased transitional and regulatory B cells, and decreased germinal center B cells. To identify the cells responsible for PTCy-induced B cell tolerance, we selectively depleted Treg populations that were graft or HSC derived using DEREG mice. Deletion of either Treg population without PTCy resulted in critical B cytopenia. PTCy rescued B lymphopoiesis from graft-derived Treg deletion. In contrast, the negative effect of HSC-derived Treg deletion could not be overcome by PTCy, indicating that HSC-derived Tregs are essential for maintaining favorable B lymphopoiesis following PTCy. These findings define the mechanisms by which PTCy restores homeostasis of the B cell lineage and reestablishes immune tolerance

Aluminium reduces sugar uptake in tobacco cell cultures: a potential cause of inhibited elongation but not of toxicity

Aluminium is well known to inhibit plant elongation, but the role in this inhibition played by water relations remains unclear. To investigate this, tobacco (Nicotiana tabacum L.) suspension-cultured cells (line SL) was used, treating them with aluminium (50 μM) in a medium containing calcium, sucrose, and MES (pH 5.0). Over an 18 h treatment period, aluminium inhibited the increase in fresh weight almost completely and decreased cellular osmolality and internal soluble sugar content substantially; however, aluminium did not affect the concentrations of major inorganic ions. In aluminium-treated cultures, fresh weight, soluble sugar content, and osmolality decreased over the first 6 h and remained constant thereafter, contrasting with their continued increases in the untreated cultures. The rate of sucrose uptake, measured by radio-tracer, was reduced by approximately 60% within 3 h of treatment. Aluminium also inhibited glucose uptake. In an aluminium-tolerant cell line (ALT301) isogenic to SL, all of the above-mentioned changes in water relations occurred and tolerance emerged only after 6 h and appeared to involve the suppression of reactive oxygen species. Further separating the effects of aluminium on elongation and cell survival, sucrose starvation for 18 h inhibited elongation and caused similar changes in cellular osmolality but stimulated the production of neither reactive oxygen species nor callose and did not cause cell death. We propose that the inhibition of sucrose uptake is a mechanism whereby aluminium inhibits elongation, but does not account for the induction of cell death

Evidence for existence of an apoptosis‐inducing <scp>BH3</scp> ‐only protein, <i>sayonara</i> , in <i>Drosophila</i>

International audienceCells need to sense stresses to initiate the execution of the dormant cell death program. Since the discovery of the first BH3only protein Bad, BH3-only proteins have been recognized as indispensable stress sensors that induce apoptosis. BH3-only proteins have so far not been identified in Drosophila despite their importance in other organisms. Here, we identify the first Drosophila BH3-only protein and name it sayonara. Sayonara induces apoptosis in a BH3 motif-dependent manner and interacts genetically and biochemically with the BCL-2 homologous proteins, Buffy and Debcl. There is a positive feedback loop between Sayonaramediated caspase activation and autophagy. The BH3 motif of sayonara phylogenetically appeared at the time of the ancestral gene duplication that led to the formation of Buffy and Debcl in the dipteran lineage. To our knowledge, this is the first identification of a bona fide BH3-only protein in Drosophila, thus providing a unique example of how cell death mechanisms can evolve both through time and across taxa