Idiopathic Pneumonia Syndrome Refractory to Ruxolitinib after Post-Transplant Cyclophosphamide-based Haploidentical Hematopoietic Stem Cell Transplantation: Lung Pathological Findings from an Autopsy Case.

A 69-year-old Japanese man with acute leukemia received post-transplant cyclophosphamide-based haploidentical stem cell transplantation (PTCY-haplo-SCT) but was readmitted with dyspnea and ground-glass-opacities of the lungs. Bronchoscopy showed inflammatory changes with no signs of infection. He received steroids but required intubation as his condition deteriorated. In addition to antithymocyte globulin and cyclophosphamide, we administered ruxolitinib but failed to save him. Autopsy findings revealed fibrotic nonspecific interstitial pneumonia (NSIP) without evidence of organizing pneumonia or infection. Thus, we diagnosed idiopathic pneumonia syndrome (IPS). As far as our knowledge, this is the first case of IPS with NSIP histology after PTCY-haplo-SCT.

Extending Treatment Intervals of R-CHOP Therapy Might Be Acceptable for Some Patients with Non-indolent Non-Hodgkin's B-cell Lymphoma.

R-CHOP therapy is generally performed every 3 weeks. We investigated the effects of extending the interval of R-CHOP therapy for > 1 week on the prognoses of patients with non-indolent non-Hodgkin's B-cell lymphoma. Among the 338 patients with non-indolent non-Hodgkin's B-cell lymphoma who received initial chemotherapy at our institution, we focused on 178 patients who received R-CHOP therapy and analyzed the outcomes of the patients stratified by the treatment intervals. The estimated 3-year overall survival (OS) for the entire population was 82.1%. Patients treated at intervals of ≥ 4 weeks were significantly older, and they had significantly longer follow-up periods and lower relative dose intensity. But the estimated 3-year OS was comparable to those treated at <4 weeks (83.3% vs. 80.5% p=0.947). In a multivariate analysis, age and the dose of anti-cancer agents had significant impacts on OS, but there was no significant relationship regarding the treatment intervals. Propensity score matching confirmed the same result. R-CHOP therapy every around 4 weeks could achieve relatively good survival in some selected patients with non-indolent non-Hodgkin's B-cell lymphoma.

A Disseminated Fusarium fujikuroi Species Complex Infection Prior to Allogeneic Hematopoietic Stem Cell Transplantation.

A 53-year-old man was diagnosed with acute myeloid leukemia, which was refractory to chemotherapies. Systemic papules appeared afterward. The skin biopsies revealed filamentous fungal infection including fusariosis. Despite antifungal therapy, the infection did not resolve, because neutropenia persisted with the leukemia. He underwent hematopoietic stem cell transplantation (HSCT) to overcome the leukemia and restore normal hematopoiesis but died from fusariosis just before engraftment. Fusarium fujikuroi species complex was detected in blood cultures with poor antifungal susceptibility. Because restoring normal hematopoiesis is important in the treatment of fusariosis, HSCT might be considered for patients with persistent pancytopenia.

[Pneumatosis cystoides intestinalis developing subsequent to allogeneic hematopoietic stem cell transplantation for mixed phenotype acute leukemia].

We present the case of a 39-year-old man with a primary diagnosis of mixed phenotype acute leukemia, T/myeloid not otherwise specified (T/M-MPAL). After achieving a complete remission (CR), he underwent allogeneic hematopoietic stem cell transplantation (HSCT). Subsequent evaluation of the cerebrospinal fluid suggested central nervous system graft versus host disease (GVHD); hence, prednisolone therapy was initiated. After 118 days on prednisolone, a routine follow-up thoracic and abdominal computed tomography (CT) revealed extensive pneumatosis in the wall of the colon. We diagnosed his condition as pneumatosis cystoides intestinalis (PCI). The patient was treated conservatively with high concentration oxygen. A CT scan performed 1 week later revealed that the pneumatosis had fully resolved; no relapse has been observed. Various etiologies of PCI have been reported previously. However, there are very few reports of PCI presenting in association with hematologic neoplasms or in response to allogeneic HSCT in adult patients.

Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design.

Protein N-glycosylation is a widespread post-translational modification. The first committed step in this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and disorders of glycosylation. In addition, naturally-occurring bactericidal nucleoside analogues such as tunicamycin are toxic to eukaryotes due to DPAGT1 inhibition, preventing their clinical use. Our structures of DPAGT1 with the substrate UDP-GlcNAc and tunicamycin reveal substrate binding modes, suggest a mechanism of catalysis, provide an understanding of how mutations modulate activity (thus causing disease) and allow design of non-toxic "lipid-altered" tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed the design of potent antibiotics for Mycobacterium tuberculosis, enabling treatment in vitro, in cellulo and in vivo, providing a promising new class of antimicrobial drug.

Palladium-mediated enzyme activation suggests multiphase initiation of glycogenesis.

Biosynthesis of glycogen, the essential glucose (and hence energy) storage molecule in humans, animals and fungi1, is initiated by the glycosyltransferase enzyme, glycogenin (GYG). Deficiencies in glycogen formation cause neurodegenerative and metabolic disease2-4, and mouse knockout5 and inherited human mutations6 of GYG impair glycogen synthesis. GYG acts as a 'seed core' for the formation of the glycogen particle by catalysing its own stepwise autoglucosylation to form a covalently bound gluco-oligosaccharide chain at initiation site Tyr 195. Precise mechanistic studies have so far been prevented by an inability to access homogeneous glycoforms of this protein, which unusually acts as both catalyst and substrate. Here we show that unprecedented direct access to different, homogeneously glucosylated states of GYG can be accomplished through a palladium-mediated enzyme activation 'shunt' process using on-protein C-C bond formation. Careful mimicry of GYG intermediates recapitulates catalytic activity at distinct stages, which in turn allows discovery of triphasic kinetics and substrate plasticity in GYG's use of sugar substrates. This reveals a tolerant but 'proof-read' mechanism that underlies the precision of this metabolic process. The present demonstration of direct, chemically controlled access to intermediate states of active enzymes suggests that such ligation-dependent activation could be a powerful tool in the study of mechanism.

Secondary central nervous system lymphoma surrounding a region injured by subarachnoid hemorrhage and subsequent aneurysmal clipping.

The present case study describes a rare case of secondary central nervous system (CNS) lymphoma that infiltrated the dura and leptomeninges around the area injured by subarachnoid hemorrhage and subsequent aneurysmal clipping. Invasion of the CNS was observed by computed tomography as slurred fissures of the right parietal lobe adjacent to the surgery area. Subdural and subarachnoid enhancement overlapping the area injured by past surgical procedures was observed by contrast-enhanced magnetic resonance imaging. Surgical resection revealed B-cell lymphoma infiltrating the dura and leptomeninges surrounding the post-hemorrhagic area. The patient was subsequently diagnosed with systemic lymphoma and bone marrow invasion, and multiple lymph node swelling. To the best of our knowledge, this is the first report of malignant lymphoma involving the CNS overlapping a previously injured area.

Dynamic Cooperative Glycan Assembly Blocks the Binding of Bacterial Lectins to Epithelial Cells.

Pathogens frequently rely on lectins for adhesion and cellular entry into the host. Since these interactions typically result from multimeric binding of lectins to cell-surface glycans, novel therapeutic strategies are being developed with the use of glycomimetics as competitors of such interactions. Herein we study the benefit of nucleic acid based oligomeric assemblies with PNA-fucose conjugates. We demonstrate that the interactions of a lectin with epithelial cells can be inhibited with conjugates that do not form stable assemblies in solution but benefit from cooperativity between ligand-protein interactions and PNA hybridization to achieve high affinity. A dynamic dimeric assembly fully blocked the binding of the fucose-binding lectin BambL of Burkholderia ambifaria, a pathogenic bacterium, to epithelial cells with an efficiency of more than 700-fold compared to l-fucose.

Allosterically Regulated Phosphatase Activity from Peptide-PNA Conjugates Folded Through Hybridization.

The importance of spatial organization in short peptide catalysts is well recognized. We synthesized and screened a library of peptides flanked by peptide nucleic acids (PNAs) such that the peptide would be constrained in a hairpin loop upon hybridization. A screen for phosphatase activity led to the discovery of a catalyst with >25-fold rate acceleration over the linear peptide. We demonstrated that the hybridization-enforced folding of the peptide is necessary for activity, and designed a catalyst that is allosterically controlled using a complementary PNA sequence.

One-Step Derivatization of Reducing Oligosaccharides for Rapid and Live-Cell-Compatible Chelation-Assisted CuAAC Conjugation.

We report a new reagent for the functionalization of unprotected oligosaccharides with a picolyl azide group at the anomeric position for chelation-assisted copper-catalyzed alkyne-azide cycloaddition (CuAAC) glycoconjugation. We show that oligosaccharides functionalized with this moiety react with an apparent second-order rate constant of 193 m(-1) s(-1) and can be used to functionalize biomolecules bearing alkyne moieties introduced through metabolic labeling, including in live cells.

Site-Specific Glycoconjugation of Protein via Bioorthogonal Tetrazine Cycloaddition with a Genetically Encoded trans-Cyclooctene or Bicyclononyne.

Efficient access to proteins modified site-specifically with glycans is important in glycobiology and for therapeutic applications. Herein, we report a biocompatible protein glycoconjugation by inverse demand Diels-Alder reaction between tetrazine and trans-cyclooctene. Tetrazine functionalized glycans were obtained in one step by CuAAC (Cu-catalyzed alkyne azide cycloaddition) between glycosyl azide and an alkyne-tetrazine adduct. Site-specific glycoconjugation was performed chemoselectively on a target protein in which a trans-cyclooctene derivatized lysine was genetically encoded. Glycoconjugation proceeded to completion on purified protein and was shown to be selective for the target protein in E. coli.

PNA-encoded synthesis (PES) of a 10 000-member hetero-glycoconjugate library and microarray analysis of diverse lectins.

Identification of selective and synthetically tractable ligands to glycan-binding proteins is important in glycoscience. Carbohydrate arrays have had a tremendous impact on profiling glycan-binding proteins and as analytical tools. We report a highly miniaturized synthetic format to access nucleic-acid-encoded hetero-glycoconjugate libraries with an unprecedented diversity in the combinations of glycans, linkers, and capping groups. Novel information about plant and bacterial lectin specificity was obtained by microarray profiling, and we show that a ligand identified on the array can be converted to a high-affinity soluble ligand by straightforward chemistry.

[Secondary chronic myelogenous leukemia following postoperative TS-1 therapy for advanced gastric cancer].

A 78-year-old man received total gastrectomy for advanced gastric cancer in September 2006, and was subsequently treated with oral anti-metabolite TS-1 for 38 months. He had no evidence of recurrence of gastric cancer, although he had a continuous poor appetite due to TS-1. Leukocytosis was found in November 2008. On the basis of bone marrow findings, Philadelphia chromosome and BCR-ABL fusion gene, he was diagnosed as having chronic phase of secondary chronic myeloid leukemia (CML). Two weeks after starting imatinib therapy, skin eruption, palpebral edema and appetite loss were observed; moreover, thrombocytopenia gradually worsened. He stopped taking imatinib and hydroxyurea was subsequently started. The above symptoms disappeared and the platelet count normalized. CML is rare in secondary leukemia. Our case is the second reported case of secondary CML following TS-1 treatment and suggests that therapy for secondary CML should be selected on the basis of QOL in patients with advanced cancer.

[Long-term complete remission after single therapy with gemtuzumab ozogamicin for refractory AML in an elderly patient].

Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 monoclonal antibody conjugated to calicheamicin, that is rapidly internalized after binding to CD33. This is followed by intracellular release of calicheamicin, which induces double-stranded DNA breaks, cell cycle arrest, and apoptosis. So GO is a more selective agent for acute myeloid leukemia (AML), because the CD33 antigen is expressed on AML, while it is not expressed on normal hematopoietic stem cells and nonhematopoietic tissues. However, some studies indicated that this agent showed resistance to refractory AML cells via various mechanisms, and that there were no potent effects. In this study, we report a 76-year-old female with recurrent AML who responded to single therapy with GO, achieving complete remission for more than 1 year after the start of administration, although additional remission induction was impossible. The response to GO can be stratified with reference to the response to conventional chemotherapy.