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In physics, two systems that radically differ at short scales can exhibit strikingly similar macroscopic behaviour: they are part of the same long-distance universality class 1 . Here we apply this viewpoint to geometry and initiate a program of classifying homogeneous metrics on group manifolds 2 by their long-distance properties. We show that many metrics on low-dimensional Lie groups have markedly different short-distance properties but nearly identical distance functions at long distances, and provide evidence that this phenomenon is even more robust in high dimensions. An application of these ideas of particular interest to physics and computer science is complexity geometry 3-7 -the study of quantum computational complexity using Riemannian geometry. We argue for the existence of a large universality class of definitions of quantum complexity, each linearly related to the other, a much finer-grained equivalence than typically considered. We conjecture that a new effective metric emerges at larger complexities that describes a broad class of complexity geometries, insensitive to various choices of microscopic penalty factors. We discuss the implications for recent conjectures in quantum gravity., (© 2023. The Author(s).)

Several factors unique to Fanconi anemia (FA) limit the success of allogeneic hematopoietic stem cell transplantation (HSCT) in this population. In this report, we describe a multi-center pilot study of five consecutive FA patients with high-risk features for transplant prepared with fludarabine, without radiation. Four patients engrafted quickly, experienced minimal toxicity and are well at 43-65 months post-transplant. One patient had a C-mismatched unrelated donor transplant and had unsustained engraftment. This fludarabine based regimen without radiation was safe and effective for four high-risk patients, suggesting that eliminating radiation should be further studied as an approach to HSCT in children with FA., ((c) 2009 Wiley-Liss, Inc.)

In 2007, the Hospital for Sick Children experienced a serious privacy breach when a laptop computer containing the personal health information of approximately 3,000 patients and research subjects was stolen from a physician-researcher's vehicle. This incident was reported to the information and privacy commissioner of Ontario (IPC). The IPC issued an order that required the hospital to examine and revise its policies, practices and research protocols related to the protection of personal health information and to educate staff on privacy-related matters.

We discuss generalizations of quantum spin Hamiltonians using anyonic degrees of freedom. The simplest model for interacting anyons energetically favors neighboring anyons to fuse into the trivial ("identity") channel, similar to the quantum Heisenberg model favoring neighboring spins to form spin singlets. Numerical simulations of a chain of Fibonacci anyons show that the model is critical with a dynamical critical exponent z=1, and described by a two-dimensional (2D) conformal field theory with central charge c=7/10. An exact mapping of the anyonic chain onto the 2D tricritical Ising model is given using the restricted-solid-on-solid representation of the Temperley-Lieb algebra. The gaplessness of the chain is shown to have topological origin.

Background: The Severe Chronic Neutropenia International Registry (SCNIR) was organized 10 years ago to improve understanding and treatment of the group of rare hematologic disorders causing blood neutrophil counts to be < 500/muL for months or years., Patients and Methods: Patients now enrolled include those with severe congenital neutropenia (n = 526), cyclic neutropenia (n = 205), idiopathic neutropenia (n = 349), autoimmune neutropenia (n = 68), and other (n = 15). More than 90% (1053 of 1163) of patients in the SCNIR have been treated with granulocyte colony-stimulating factor (G-CSF), median dose 3.33 mug/kg per day., Results: Granulocyte colony-stimulating factor has reduced the occurrence of infection, hospitalization, and antibiotics and improved patients' quality of life. Most patients have noted few adverse effects with G-CSF treatment. Osteoporosis/osteopenia has been reported in 14% of all patients, and myelodysplastic syndrome and acute myelocytic leukemia have occurred in 57 patients, including severe congenital neutropenia (11.8%; 50 of 422), Shwachman-Diamond syndrome (8.1%; 3 of 37), and 4 others. The SCNIR is an important resource for studies on the genetic and molecular basis for the disorders causing chronic neutropenia., Conclusion: The findings of mutations in the gene for neutrophil elastase as causing cyclic and congenital neutropenia, the role of mutations in the gene for the G-CSF receptor in the evolution of severe congenital neutropenia to acute myelocytic leukemia, and the importance of apoptosis as the cellular mechanism for several diseases causing severe chronic neutropenia have come from studies on these patients.

Bone marrow angiogenesis is increased in myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), but has not been studied in inherited or acquired marrow failure syndromes. Shwachman-Diamond syndrome (SDS) carries a high risk of MDS/AML and is characterised by marrow stromal dysfunction. Compared with controls, SDS patients without MDS/AML had higher marrow microvessel density. Stromal VEGF gene expression, stromal vascular endothelial growth factor (VEGF) secretion and VEGF levels in serum and marrow mononuclear cells were normal. Future studies should investigate the mechanism for increased angiogenesis in SDS, and whether SDS marrow, with its increased angiogenesis, promotes progression of malignant clones.

The poor prognosis for patients with metastatic osteosarcoma (OS) indicates that new therapeutic options should be explored. Studies with adenoviral-mediated p53 gene transfer have been conducted in many cancer types including cervical, ovarian, prostatic and head and neck tumors. However, limited work has been carried out with pediatric cancers, including OS. Using three viral constructs containing cDNA for wild-type p53, mutant p53 (Cys135Ser) and lacZ, we studied the effect of adenoviral-mediated gene therapy in four OS cell lines: Saos-2 (p53-/-), HOS (R156P), KHOS/NP (R156P) and MNNG (R156P, F270L). We demonstrated that the virus efficiently enters the cells using the beta-galactosidase assay. Using the MTT assay, we have shown a dose-dependent decrease in cell viability 72 h post-treatment that occurs with Ad-wtp53 but not with Ad-mutp53. We have also shown that treatment with Ad-wtp53 significantly increases sensitivity of the cell lines to cisplatin and doxorubicin, chemotherapeutic agents commonly used in the treatment of OS. Our results indicate that restoration of wt p53 function in OS cells provides a basis for novel approaches to treatment of this disease.

In a topological quantum computer, universal quantum computation is performed by dragging quasiparticle excitations of certain two dimensional systems around each other to form braids of their world lines in 2 + 1 dimensional space-time. In this Letter we show that any such quantum computation that can be done by braiding n identical quasiparticles can also be done by moving a single quasiparticle around n - 1 other identical quasiparticles whose positions remain fixed.

Background: Shwachman-Diamond syndrome (SDS) is associated with a high risk of myelodysplasia, acute myeloid leukemia (AML), and chromosome 7 abnormalities. Ninety percent of SDS patients have mutations in SBDS on 7q11. Herein, we studied the role of genetic alterations in SBDS in AML., Procedure: DNA was extracted from marrows of SDS patients with AML, as well as from children with de novo AML. Direct sequencing of PCR amplified genomic DNA was performed using specific primers flanking each exon. To study whether SBDS heterozygosity confers a risk for MDS/AML, data on family members of SDS patients on the Canadian Inherited Marrow Failure Registry (CIMFR) was analyzed., Results: Of two SDS patients with SDS/AML one was homozygous 258 + 2T > C, and one was compound heterozygous 183-184TA > CT/258 + 2T > C. To determine whether a subset of patients with SDS can present with AML, we analyzed 48 AML samples at remission, but no mutations were identified. To address whether acquired mutated SBDS gene is associated with leukemic transformation in de novo AML, we analyzed 77 AML samples at diagnosis or relapse (4 with -7 and 7q-) for SBDS mutations; no alterations were detected. Also, among the relatives of an SDS patient cohort on the registry no cases of MDS/AML were reported., Conclusions: Common mutations occurred in our SDS patients who develop AML, and thus, AML is not confined to a rare genetic subgroup of SDS. Newly diagnosed patients with AML are unlikely to have an underlying undiagnosed SDS. Acquired SBDS gene mutations also would appear unlikely to play a mechanistic role in de novo AML, and might not be involved in the pathogenesis of chromosome 7 abnormalities as well., (2005 Wiley-Liss, Inc.)

Myeloproliferative syndromes (MPSs) are clonal stem cell disorders resulting in excessive proliferation of one or more cell lineages. Since MPSs in children occur much less commonly than adults, one can argue that the biology and the categories of the various pediatric MPSs seem to be different from adults. Furthermore, confusion exists between pediatric MPS and other overlapping conditions, such as myelodysplastic syndrome. The authors' objectives were to develop a classification system with a list of disorders relevant to children and to characterize pediatric cases of MPS that were devised according to this classification. Based on the predominant proliferating cell lineage, the authors established a classification system for childhood MPS. Primary MPS was classified into granulocytic proliferation--chronic myelogenous leukemia (CML); monocytic--juvenile myelomonocytic leukemia (JMML); megakaryocytic--essential thrombocythemia (ET), familial thrombocytosis, transient myeloproliferative disorder of Down syndrome (TMD); erythrocytic--polycythemia vera, familial erythrocytosis; fibroblastic--idiopathic myelofibrosis (IMF); eosinophilic--idiopathic hypereosinophilic syndrome (IHES); and mast cells--mastocytosis. Secondary MPS was classified as non-clonal proliferation (eg, infections, drugs, toxins, autoimmune, non-hematologic neoplasm, and trauma), and these were excluded from the study. Next, the classification system was applied to the patient population at the authors' institution. One hundred two cases with primary MPS were identified between 1970 and 2001. Patients were evaluated for clinical manifestations, blood and bone marrow parameters, cytogenetics, and survival following different treatment modalities. Significant proportions of cases of childhood MPS (60%) were unique to the pediatric population and not seen in adults. The most common disorders were JMML (n = 31), TMD of Down syndrome (n = 30), and CML (n = 30); the other disorders were rare: four cases of ET, two of IMF, two of IHES, two of mastocytosis, and one primary erythrocytosis. In contrast to adults, MPS in children is more frequently treated with hematopoietic stem cell transplantation (HSCT), the only available curative option for most of these diseases. HSCT was particularly successful in the more recent cases due to more advanced techniques for HSCT. The authors found that all the cases could be easily classified. MPS in children is different from adult-type MPS in terms of biology, categories, classification, and prognosis.

Sarcomas, or tumors of connective tissue, represent roughly 20% of childhood cancers. Although the cure rate for sarcomas in general has significantly improved in the last 10 years, there continue to be subgroups that are difficult to treat. High-grade or metastatic soft-tissue sarcomas and rhabdomyosarcomas (RMS) of the extremities remain therapeutic challenges and their prognosis is often poor. The future of sarcoma therapy will likely include molecular approaches including gene/protein expression profiling and gene-based therapy. Most sarcomas harbor defects in the p53 or pRb pathways. The tumor suppressor p53 is central to regulation of cell growth and tumor suppression and restoring wild-type p53 function in pediatric sarcomas may be of therapeutic benefit. Studies with adenoviral-mediated p53 gene transfer have been conducted in many cancer types including cervical, ovarian, prostatic and head and neck tumors. Studies of this approach, however, remain limited in pediatric cancers, including sarcomas. Using three viral constructs containing cDNA for wild-type p53, mutant p53 (C135S) and lacZ, we studied the effect of adenoviral-mediated gene therapy in four pediatric sarcoma cell lines, RD and Rh4 (RMS), Rh1 (Ewing's sarcoma) and A204 (undifferentiated sarcoma). Using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay, we have shown a dose-dependent decrease in cell viability 72 h post-treatment that occurs with Ad-wtp53 but not with Ad-mutp53. Cells treated with Ad-wtp53 show upregulation of the p53 downstream targets, p21(CIP1/WAF1) and bax. Growth curves demonstrate suppression of cell growth over a period of 4 days and cells treated with Ad-wtp53 demonstrate a significant increase in sensitivity to the chemotherapeutic agents, cisplatin and doxorubicin. Our results indicate that restoration of wild-type p53 function in pediatric sarcoma cells could provide a basis for novel approaches to treatment of this disease.

The development of myeloid leukemias and myelodysplastic syndrome (MDS) is common in children with trisomy 8 mosaicism. However, the mechanisms by which the presence of an additional chromosome 8 translates to an increased risk of leukemias and MDS is currently unknown. The authors describe the analysis of stromal cells from a pediatric MDS patient with constitutional trisomy 8. Patient and control marrow stromal cells were analyzed for alterations in cytokine production. Clonogenic assays were used to examine stromal support for hematopoiesis. The interplay between leukemia cells and stroma was studied by co-culture experiments. The results indicate that stromal cell function in this patient was seriously altered in favor of progenitor cell proliferation and expansion. This indicates that constitutional trisomy 8 in stromal cells plays a critical role in the pathogenesis of MDS.

Purine nucleoside phosphorylase (PNP) deficiency is an autosomal recessive metabolic disorder characterized by severe combined immunodeficiency and by complex neurologic symptomatology including ataxia, developmental delay, and spasticity. Herein we report severe marrow dysplasia in a patient with PNP deficiency. Drug-related marrow dysfunction was unlikely, and marrow virological studies were negative. A preleukemic myelodysplastic syndrome was also unlikely due to normal marrow CD34+ cells, colony growth in clonogenic assay of marrow mononuclear cells, apoptosis rate, and Fas expression on marrow nucleated cells, as well as morphologic improvement of the marrow dysplasia after normal red blood cell transfusion. The patient's marrow stroma showed hypersensitivity to irradiation and undetectable PNP enzyme activity similar to peripheral lymphocytes. This is the first report of PNP deficiency associated with increased lymphocyte and marrow stromal sensitivity to irradiation. We conclude that marrows from patients with PNP deficiency might have hypersensitivity to irradiation and can develop dysplastic morphology, caused either directly or indirectly by the inherited enzymatic defect.

Allogeneic bone marrow transplant (BMT) with an MRD in complete remission (CR)1 is the preferred treatment for children with Philadelphia-positive (Ph(+)) ALL. The role of MUD BMT in CR1 is still controversial. We compared the outcomes of two treatment strategies: BMT using an MRD or MUD vs chemotherapy in children with Ph(+) ALL in CR1. In total, 21 children were treated from 1985 to 2001. In all, 10 received chemotherapy and 11 received allogeneic BMT: four MRD, seven MUD. In the MRD group, one relapsed 12 months after BMT and died; the remaining three are long-term event-free survivors (median follow-up, 6.1 years). In the MUD group four died; the remaining three are long-term event-free survivors (median follow-up, 7.2 years). The 4-year event-free survival (EFS) for the BMT group was 53+/-15%. In the chemotherapy group, seven relapsed after a median period of 12.5 months and three remain in continuous CR (median follow-up, 2.4 years). Four chemotherapy patients received CR2 transplants; all died. The 4-year EFS for the chemotherapy and MUD groups was 33+/-17 and 35.7+/-20%, respectively. This difference was not statistically significant. We continue to support treating children with Ph(+) ALL with MRD BMT in CR1. The effectiveness of MUD BMT vs chemotherapy merits further study.

The development of a non-toxic selective cytoprotective agent that preferentially protects normal tissues from chemotherapy toxicity, without protecting malignant tissues, is a major challenge in cancer chemotherapy research. The available cytoprotective agents are either toxic or lack selective cytoprotective activity. Here, we report the in vitro selective cytoprotective activity of squalene, an isoprenoid molecule with antioxidant properties. Normal human bone marrow (BM) derived colony-forming unit (CFU) growth was increased by squalene in a dose-dependent manner. Squalene (12.5-25 microM) treatment significantly protected the CFUs from cisplatin-induced toxicity; the protective effect was equivalent to reduced glutathione (GSH), a known cytoprotective agent. Squalene also increased the long-term survival of cisplatin-treated 4-week-old CFUs. Cisplatin-induced apoptosis of CFUs as measured by the TUNEL assay was reduced by squalene. To examine the squalene-induced protection of tumours, several neuroblastoma cell lines, including five MYCN-amplified cell lines, were grown in monolayers, as well as in anchorage-independent cultures, in the presence of squalene and cisplatin. Squalene did not protect the neuroblastoma (NBL) cell lines from cisplatin-induced toxicity. In addition, squalene did not protect the NBL cells from carboplatin, cyclophosphamide, etoposide and doxorubicin-induced toxicity. In conclusion, our results suggest that squalene has a selective in vitro cytoprotective effect on BM-derived haematopoietic stem cells that is equipotent to GSH.

After failing a trial of corticosteroid therapy, molecularly proven identical twins were treated for transfusion-dependent Diamond-Blackfan anemia with cyclosporine A, resulting in a robust erythropoietic response and a reversal of anemia. Clonogenic assays of marrow hematopoietic progenitors from both patients showed exuberant growth of BFU-E colonies but absent CFU-E. Clinically, the response has been sustained, and both patients have continued cyclosporine therapy and have been transfusion-independent for more than 27 months.

Myelodysplastic syndrome (MDS) in childhood is a rare hematological condition that is often associated with cytogenetic abnormalities, the most common being monosomy 7/del(7q). The clinical course of MDS can vary from stable disease to rapid progression into acute leukemia. Rarely, spontaneous remission of MDS has been observed. The authors report the first case of a transient MDS associated with a clonal marrow cytogenetic abnormality consisting of isochromosome 7q in a previously well child. Without intervention, the bone marrow cytogenetics reverted to normal and there was complete hematologic recovery. This case illustrates the importance of close follow-up in a child presenting with MDS, to detect spontaneous recovery or evolution of the disease.

Objective: Genetic alterations, including p53 mutations, have been identified in the stroma of solid tumors and are thought be involved in the induction of tumor growth and metastasis. We tested the hypothesis that somatic molecular alterations in bone marrow stromal cells provide a favorable growth environment for leukemic cells., Materials and Methods: We established an in vitro model consisting of stroma expressing mutant p53 (Cys135Ser) to study its ability to support growth of cells from a pre-B acute lymphoblastic leukemia (ALL) cell line. Normal and leukemic bone marrow stromal cells were screened for p53 mutations by mutant-specific ELISA, SSCP, and direct sequencing. Secretion of vascular endothelial growth factor (VEGF) was measured by quantitative ELISA., Results: Transfection of stromal cells with mutant p53 increased synthesis of VEGF and supported the growth of leukemic cells. An ELISA-based assay suggested the occurrence of in vivo p53 alterations in bone marrow stromal cells from 2 of 12 ALL patients screened. Direct sequencing of one of these samples revealed a somatic heterozygous p53 gene mutation (Asp49His). This sample secreted more VEGF and provided increased growth support to leukemic cells. The ability of Asp 49His-p53 to increase the expression of VEGF was confirmed with transfection experiments in a p53-null cell line., Conclusion: Our findings indicate that genetic alterations, such as p53 mutations, in stromal cells can increase stromal-derived support of leukemia growth. Increased synthesis of pro-angiogenic cytokines, such as VEGF, may constitute one possible pathway by which this process is mediated.