Myeloablative autologous haematopoietic stem cell transplantation resets the B cell repertoire to a more naïve state in patients with systemic sclerosis.

OBJECTIVES: Myeloablative autologous haematopoietic stem cell transplant (HSCT) was recently demonstrated to provide significant benefit over cyclophosphamide (CYC) in the treatment of diffuse cutaneous systemic sclerosis (dcSSc) in the Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial. As dysregulation of the B cell compartment has previously been described in dcSSc, we sought to gain insight into the effects of myeloablative autologous HSCT as compared with CYC. METHODS: We sequenced the peripheral blood immunoglobulin heavy chain (IGH) repertoires in patients with dcSSc enrolled in the SCOT trial. RESULTS: Myeloablative autologous HSCT was associated with a sustained increase in IgM isotype antibodies bearing a low mutation rate. Clonal expression was reduced in IGH repertoires following myeloablative autologous HSCT. Additionally, we identified a underusage of immunoglobulin heavy chain V gene 5-51 in patients with dcSSc, and usage normalised following myeloablative autologous HSCT but not CYC treatment. CONCLUSIONS: Together, these findings suggest that myeloablative autologous HSCT resets the IGH repertoire to a more naïve state characterised by IgM-expressing B cells, providing a possible mechanism for the elimination of pathogenic B cells that may contribute to the benefit of HSCT over CYC in the treatment of dcSSc.

Characterising the autoantibody repertoire in systemic sclerosis following myeloablative haematopoietic stem cell transplantation.

OBJECTIVES: Results from the SCOT (Scleroderma: Cyclophosphamide Or Transplantation) clinical trial demonstrated significant benefits of haematopoietic stem cell transplant (HSCT) versus cyclophosphamide (CTX) in patients with systemic sclerosis. The objective of this study was to test the hypothesis that transplantation stabilises the autoantibody repertoire in patients with favourable clinical outcomes. METHODS: We used a bead-based array containing 221 protein antigens to profile serum IgG autoantibodies in participants of the SCOT trial. RESULTS: Comparison of autoantibody profiles at month 26 (n=23 HSCT; n=22 CTX) revealed antibodies against two viral antigens and six self-proteins (SSB/La, CX3CL1, glycyl-tRNA synthetase (EJ), parietal cell antigen, bactericidal permeability-increasing protein and epidermal growth factor receptor (EGFR)) that were significantly different between treatment groups. Linear mixed model analysis identified temporal increases in antibody levels for hepatitis B surface antigen, CCL3 and EGFR in HSCT-treated patients. Eight of 32 HSCT-treated participants and one of 31 CTX-treated participants had temporally varying serum antibody profiles for one or more of 14 antigens. Baseline autoantibody levels against 20 unique antigens, including 9 secreted proteins (interleukins, IL-18, IL-22, IL-23 and IL-27), interferon-α2A, stem cell factor, transforming growth factor-ß, macrophage colony-stimulating factor and macrophage migration inhibitory factor were significantly higher in patients who survived event-free to month 54. CONCLUSIONS: Our results suggest that HSCT favourably alters the autoantibody repertoire, which remains virtually unchanged in CTX-treated patients. Although antibodies recognising secreted proteins are generally thought to be pathogenic, our results suggest a subset could potentially modulate HSCT in scleroderma.

Lymphocyte subset abnormalities in early severe scleroderma favor a Th2 phenotype and are not altered by prior immunosuppressive therapy.

OBJECTIVES: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial compared hematopoietic stem cell transplant to CYC treatment in patients with early SSc with progressive skin and lung or kidney involvement. Here we describe lymphocyte phenotype abnormalities at study entry and the relation to prior DMARD therapy. METHODS: Lymphocyte subsets (n = 26) measured by flow cytometry were compared in 123 heathy controls and 71 SCOT participants, including those given (n = 57) or not given (n = 14) DMARDs within 12 months of randomization. RESULTS: Compared with healthy controls, individuals with SSc showed significant reductions in central memory CD8 T cells, activated total and CD4 T cells, γ/δ T cells, memory B cells, myeloid and plasmacytoid dendritic cells and FOXP3+CD25+ Treg cells and increases in naïve CD4 T cells, effector memory CD4 T cells and effector CD8 T cells. A greater bias towards a IL-4+ Th2/T cytotoxic 2 (Tc2) phenotype based on the Th2:Th1 CD4 ratio and Tc2:Tc1 CD8 T cells was also found. Notably, no difference in any lymphocyte subset was observed between those given or not given prior DMARDs. CONCLUSIONS: In patients with early, severe SSc, significant lymphocyte subset abnormalities were observed. Prior treatment with immunosuppressive therapy did not impact the immunophenotype, suggesting that lymphocyte disturbances in scleroderma appeared to be due to the disease itself. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov), NCT00114530.

Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma.

BACKGROUND: Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma. METHODS: We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score. RESULTS: In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group. CONCLUSIONS: Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).

Lemon sole Microstomus kitt in the northern North Sea: a multidisciplinary approach to the early life-history dynamics.

Lemon sole Microstomus kitt is a commercially valuable flatfish species that occurs in shelf waters around the northeast Atlantic. Only the most basic life-history information is available for the North Sea. Spawning is generally assumed to occur between early May and October, with a peak between May and August. Lemon sole larvae have been found in the water column in the northern North Sea in winter during standard surveys. Larvae captured in November/December 2016 and January/February 2017 using the International Council for the Exploration of the Seas standard 2 m Midwater Ring trawls (MIK) were analysed to gain a better understanding of the pelagic early life-history stages of lemon sole, especially in relation to the timing of spawning and the dispersal of overwintering larvae. Larval age was estimated from sagittal otolith primary increment counts. The larvae caught in November/December ranged in nominal age from 4 to 45 days post-hatching which suggests that spawning continues into late October and November. Most, but not all, of the larvae caught in January/February were post metamorphosis, and the difference in age between the two sampling dates was consistent with the elapsed time between samplings. The estimated hatching dates confirm that lemon sole spawning extends into late autumn in the northern North Sea, with overwintering larvae in all developmental stages. Drift modelling of eggs and larvae released at historically documented spawning grounds in the northern North Sea suggests that these grounds are also the source for all of the larvae sampled during the 2016-2017 surveys.

Development stage distribution as a proxy for feeding success and growth for first feeding Norwegian spring spawning herring larvae.

The estimation of growth rates in young herring larvae (Clupea harengus) in the field can be difficult because the primary increments in the otoliths may not be discernible or formed at a daily level. Likewise, the estimation of mortality rates of fish larvae in the field is very difficult to achieve, especially in a rigorous quantitative manner. In this study, the authors suggest the use of a stage-based proxy of feeding success, growth and potential survival or mortality risk of field-caught larvae. The stage-based proxy is derived based on observations from previous laboratory studies where larvae successfully completing start-feeding on external food sources will advance through the early development stages, whereas those that do not (unsuccessful larvae) remain and accumulate in the development stage preceding first feeding. The relative occurrence of larvae in the early development stages is therefore expected to reflect feeding conditions of the larvae, with higher ratios of unsuccessful larvae indicative of poor feeding success and higher mortality risk. Using field data on Norwegian spring spawning herring, the authors document that the relative occurrence of larvae in the late non-feeding stage is significantly higher at lower average zooplankton concentrations, in line with the predictions of the authors that this novel approach of using a stage-based proxy could be a useful indication of feeding success, growth and mortality in the field. Further, there was a significant interaction effect with ambient temperature, with the ratio being higher at low zooplankton concentrations at higher temperatures. This study also suggests that these findings are not population specific as the same accumulation of non-feeding larvae in the late non-feeding stage was observed in laboratory-reared larvae of both autumn and spring spawning herring populations.

Machine learning predicts stem cell transplant response in severe scleroderma.

OBJECTIVE: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial demonstrated clinical benefit of haematopoietic stem cell transplant (HSCT) compared with cyclophosphamide (CYC). We mapped PBC (peripheral blood cell) samples from the SCOT clinical trial to scleroderma intrinsic subsets and tested the hypothesis that they predict long-term response to HSCT. METHODS: We analysed gene expression from PBCs of SCOT participants to identify differential treatment response. PBC gene expression data were generated from 63 SCOT participants at baseline and follow-up timepoints. Participants who completed treatment protocol were stratified by intrinsic gene expression subsets at baseline, evaluated for event-free survival (EFS) and analysed for differentially expressed genes (DEGs). RESULTS: Participants from the fibroproliferative subset on HSCT experienced significant improvement in EFS compared with fibroproliferative participants on CYC (p=0.0091). In contrast, EFS did not significantly differ between CYC and HSCT arms for the participants from the normal-like subset (p=0.77) or the inflammatory subset (p=0.1). At each timepoint, we observed considerably more DEGs in HSCT arm compared with CYC arm with HSCT arm showing significant changes in immune response pathways. CONCLUSIONS: Participants from the fibroproliferative subset showed the most significant long-term benefit from HSCT compared with CYC. This study suggests that intrinsic subset stratification of patients may be used to identify patients with SSc who receive significant benefit from HSCT.

Autologous Hematopoietic Cell Transplantation for Treatment-Refractory Relapsing Multiple Sclerosis: Position Statement from the American Society for Blood and Marrow Transplantation.

Multiple sclerosis (MS) is a chronic, disabling, immune-mediated, demyelinating and degenerative disease of the central nervous system. Approved disease-modifying therapies may be incompletely effective in some patients with highly active relapsing disease and high risk of disability. The use of immunoablative or myeloablative therapy followed by autologous hematopoietic cell transplantation (AHCT) has been investigated in retrospective studies, clinical trials, and meta-analyses/systematic reviews as an approach to address this unmet clinical need. On behalf of the American Society for Blood and Bone Marrow Transplantation (ASBMT), a panel of experts in AHCT and MS convened to review available evidence and make recommendations on MS as an indication for AHCT. A review of recent literature identified 8 retrospective studies, 8 clinical trials, and 3 meta-analyses/systematic reviews. In aggregate, these studies indicate that AHCT is an efficacious and safe treatment for active relapsing forms of MS to prevent clinical relapse, magnetic resonance imaging-detectable lesion activity, and worsening disability and to reverse disability without unexpected adverse events. Based on the available evidence, the ASBMT recommends that treatment-refractory relapsing MS with high risk of future disability be considered a "standard of care, clinical evidence available" indication for AHCT. Collaboration of neurologists with expertise in treating MS and transplantation physicians with experience performing AHCT for autoimmune disease is crucial for ensuring appropriate patient selection and optimizing transplantation procedures to improve patient outcomes. Transplantation centers in the United States and Canada are strongly encouraged to report baseline and outcomes data on patients receiving AHCT for multiple sclerosis to the Center for International Blood and Marrow Transplant Research.

Myeloablation followed by autologous stem cell transplantation normalises systemic sclerosis molecular signatures.

OBJECTIVE: In the randomised scleroderma: Cyclophosphamide Or Transplantation (SCOT trial) (NCT00114530), myeloablation, followed by haematopoietic stem cell transplantation (HSCT), led to improved clinical outcomes compared with monthly cyclophosphamide (CYC) treatment in systemic sclerosis (SSc). Herein, the study aimed to determine global molecular changes at the whole blood transcript and serum protein levels ensuing from HSCT in comparison to intravenous monthly CYC in 62 participants enrolled in the SCOT study. METHODS: Global transcript studies were performed at pretreatment baseline, 8 months and 26 months postrandomisation using Illumina HT-12 arrays. Levels of 102 proteins were measured in the concomitantly collected serum samples. RESULTS: At the baseline visit, interferon (IFN) and neutrophil transcript modules were upregulated and the cytotoxic/NK module was downregulated in SSc compared with unaffected controls. A paired comparison of the 26 months to the baseline samples revealed a significant decrease of the IFN and neutrophil modules and an increase in the cytotoxic/NK module in the HSCT arm while there was no significant change in the CYC control arm. Also, a composite score of correlating serum proteins with IFN and neutrophil transcript modules, as well as a multilevel analysis showed significant changes in SSc molecular signatures after HSCT while similar changes were not observed in the CYC arm. Lastly, a decline in the IFN and neutrophil modules was associated with an improvement in pulmonary forced vital capacity and an increase in the cytotoxic/NK module correlated with improvement in skin score. CONCLUSION: HSCT contrary to conventional treatment leads to a significant 'correction' in disease-related molecular signatures.

Systemic Sclerosis as an Indication for Autologous Hematopoietic Cell Transplantation: Position Statement from the American Society for Blood and Marrow Transplantation.

Systemic sclerosis is a progressive inflammatory disease that is frequently fatal and has limited treatment options. High-dose chemotherapy with autologous hematopoietic cell transplantation (AHCT) has been evaluated as treatment for this disease in observational studies, multicenter randomized controlled clinical trials, and meta-analyses. On behalf of the American Society for Blood and Marrow Transplantation (ASBMT), a panel of experts in transplantation and rheumatology was convened to review available evidence and make a recommendation on AHCT as an indication for systemic sclerosis. Three randomized trials have compared the efficacy of AHCT with cyclophosphamide only, and all demonstrated benefit for the AHCT arm for their primary endpoint (improvement in the American Scleroderma Stem Cell versus Immune Suppression Trial, event-free survival in Autologous Stem Cell Transplantation International Scleroderma trial, and change in global rank composite score in Scleroderma: Cyclophosphamide or Transplantation trial). AHCT recipients also had better overall survival and a lower rate of disease progression. These findings have been confirmed in subsequent meta-analyses. Based on this high-quality evidence, the ASBMT recommends systemic sclerosis should be considered as a "standard of care" indication for AHCT. Close collaboration between rheumatologists and transplant clinicians is critical for optimizing patient selection and patient outcomes. Transplant centers in the United States are strongly encouraged to report patient and outcomes data to the Center for International Blood and Marrow Transplant Research on their patients receiving AHCT for this indication.

Manufacture of Autologous CD34+ Selected Grafts in the NIAID-Sponsored HALT-MS and SCOT Multicenter Clinical Trials for Autoimmune Diseases.

To ensure comparable grafts for autologous hematopoietic cell transplantation (HCT) in the National Institute of Allergy and Infectious Diseases-sponsored Investigational New Drug protocols for multiple sclerosis (HALT-MS) and systemic sclerosis (SCOT), a Drug Master File approach to control manufacture was implemented, including a common Master Production Batch Record and site-specific standard operating procedures with "Critical Elements." We assessed comparability of flow cytometry and controlled rate cryopreservation among sites and stability of cryopreserved grafts using hematopoietic progenitor cells (HPCs) from healthy donors. Hematopoietic Progenitor Cells, Apheresis-CD34+ Enriched, for Autologous Use (Auto-CD34+HPC) graft specifications included ≥70% viable CD34+ cells before cryopreservation. For the 2 protocols, 110 apheresis collections were performed; 121 lots of Auto-CD34+HPC were cryopreserved, and 107 of these (88.4%) met release criteria. Grafts were infused at a median of 25 days (range, 17 to 68) post-apheresis for HALT-MS (n = 24), and 25 days (range, 14 to 78) for SCOT (n = 33). Subjects received precryopreservation doses of a median 5.1 × 106 viable CD34+ cells/kg (range, 3.9 to 12.8) for HALT-MS and 5.6 × 106 viable CD34+ cells/kg (range, 2.6 to 10.2) for SCOT. Recovery of granulocytes occurred at a median of 11 days (range, 9 to 15) post-HCT for HALT-MS and 10 days (range, 8 to 12) for SCOT, independent of CD34+ cell dose. Subjects received their last platelet transfusion at a median of 9 days (range, 6 to 16) for HALT-MS and 8 days (range, 6 to 23) for SCOT; higher CD34+/kg doses were associated with faster platelet recovery. Stability testing of cryopreserved healthy donor CD34+ HPCs over 6 months of vapor phase liquid nitrogen storage demonstrated consistent 69% to 73% recovery of viable CD34+ cells. Manufacturing of Auto-CD34+HPC for the HALT-MS and SCOT protocols was comparable across all sites and supportive for timely recovery of granulocytes and platelets.

Synergies between climate and management for Atlantic cod fisheries at high latitudes.

The widespread depletion of commercially exploited marine living resources is often seen as a general failure of management and results in criticism of contemporary management procedures. When populations show dramatic and positive changes in population size, this invariably leads to questions about whether favorable climatic conditions or good management (or both) were responsible. The Barents Sea cod (Gadus morhua) stock has recently increased markedly and the spawning stock biomass is now at an unprecedented high. We identify the crucial social and environmental factors that made this unique growth possible. The relationship between vital rates of Barents Sea cod stock productivity (recruitment, growth, and mortality) and environment is investigated, followed by simulations of population size under different management scenarios. We show that the recent sustained reduction in fishing mortality, facilitated by the implementation of a "harvest control rule," was essential to the increase in population size. Simulations show that a drastic reduction in fishing mortality has resulted in a doubling of the total population biomass compared with that expected under the former management regime. However, management alone was not solely responsible. We document that prevailing climate, operating through several mechanistic links, positively reinforced management actions. Heightened temperature resulted in an increase in the extent of the suitable feeding area for Barents Sea cod, likely offering a release from density-dependent effects (for example, food competition and cannibalism) through prolonged overlap with prey and improved adult stock productivity. Management and climate may thus interact to give a positive outlook for exploited high-latitude marine resources.

Frequent skipped spawning in the world's largest cod population.

Life-history theory suggests that animals may skip reproductive events after initial maturation to maximize lifetime fitness. In iteroparous teleosts, verifying past spawning history is particularly difficult; the degree of skipped spawning at the population level therefore remains unknown. We unequivocally show frequent skipped spawning in Northeast Arctic cod (NEAC) in a massive field and laboratory effort from 2006 to 2008. This was verified by postovulatory follicles in temporarily arrested ovaries close to the putative spawning period. At the population level, "skippers" were estimated to be approximately equally abundant as spawning females in 2008, constituting ∼24% of the females 60-100 cm. These females never truly started vitellogenesis and principally remained on the feeding grounds when spawners migrated southward, avoiding any migration costs. The proximate cause of skipping seems to be insufficient energy to initiate oocyte development, indicating that skipped spawning may partly be a density-dependent response important in population regulation. Our data also indicate more skipping among smaller females and potential tradeoffs between current and future reproductive effort. We propose that skipped spawning is an integral life-history component for NEAC, likely varying annually, and it could therefore be an underlying factor causing some of the currently unexplained large NEAC recruitment variation. The same may hold for other teleosts.

Direction-dependent bending resistance of 3D printed bio-inspired composites with asymmetric 3D articulated tiles.

Inspired by the protective armors in nature, composites with asymmetric 3D articulated tiles attached to a soft layer are designed and fabricated via a multi-material 3D printer. The bending resistance of the new designs are characterized via three-point bending experiments. Bending rigidity, strength, and final deflection of the designs are quantified and compared when loaded in two different in-plane and two different out-of-plane directions. It is found that in general, the designs with articulated tiles show direction-dependent bending behaviors with significantly increased bending rigidity, strength, and deflection to final failure in certain loading directions, as is attributed to the asymmetric tile articulation (asymmetric about the mid-plane of tiles) and an interesting sliding-induced auxetic effect. Analytical, numerical, and experimental analyses are conducted to unveil the underlying mechanisms.

Successful Autologous Hematopoietic Stem Cell Transplant in Glycine Receptor Antibody-Positive Stiff Person Syndrome: A Case Report

BACKGROUND AND OBJECTIVES: To describe a case of glycine receptor (GlyR) antibody-positive stiff person syndrome (SPS) treated with autologous hematopoietic stem cell transplant (aHSCT). METHODS: This was a multicenter collaboration for the treatment of a single patient who underwent aHSCT as part of a clinical trial (NCT00716066). To objectively assess the response to transplantation, several clinical outcome measures were evaluated pretransplant and up to 18 months post-transplant, including modified Rankin Score (mRS), stiffness index, Hauser Ambulation Score (HAS), hypersensitivity index, timed 25-foot walk, and Montreal Cognitive Assessment. RESULTS: After transplant, the patient achieved sustained clinical improvement evidenced across various clinical scales, including mRS, stiffness index, HAS, and 25-foot walk time. DISCUSSION: aHSCT represents a promising treatment option for SPS, including for GlyR-positive patients. In addition, this case represents the need to validate and standardize best clinical outcome measures for patients with SPS. CLASSIFICATION OF EVIDENCE: Class IV; this is a single observational study without controls.

Myeloablation Followed by Hematopoietic Stem Cell Transplantation and Long-Term Normalization of Systemic Sclerosis Molecular Signatures.

OBJECTIVE: In the randomized Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial, myeloablation, followed by hematopoietic stem cell transplantation (HSCT), led to the normalization of systemic sclerosis (SSc) peripheral blood cell (PBC) gene expression signature at the 26-month visit. Herein, we examined long-term molecular changes ensuing 54 months after randomization for individuals receiving an HSCT or 12 months of intravenous cyclophosphamide (CYC). METHODS: Global PBC transcript studies were performed in study participants at pretreatment baseline and at 38 months and 54 months after randomization, as well as in healthy controls using Illumina HT-12 arrays. RESULTS: Thirty (HSCT = 19 and CYC = 11) participants had 38-month samples available, and 26 (HSCT = 16 and CYC = 11) had 54-month samples available. In the paired comparison to baseline, a significant down-regulation of interferon modules and an up-regulation of cytotoxic/natural killer module were observed at the 38-month and 54-month visits in the HSCT arm, indicating a long-term normalization of baseline SSc gene expression signature. No differentially expressed modules were detected in the CYC arm. In comparison to samples from healthy controls, 38-month visit samples in the HSCT arm showed an up-regulation of B cell and plasmablast modules and a down-regulation of myeloid and inflammation modules. Importantly, 54-month HSCT samples did not show any differentially expressed modules compared to healthy control samples, suggesting completion of immune reconstitution. Participants in the CYC arm continued to show an SSc transcript signature in comparison to controls at both time points. CONCLUSION: Paralleling the observed clinical benefit, HSCT leads to durable long-term normalization of the molecular signature in SSc, with completion of immune resetting to 54 months after HSCT.

Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria.

Risk factors for grades 2-4 acute graft-versus-host disease (GVHD) and for chronic GVHD as defined by National Institutes of Health consensus criteria were evaluated and compared in 2941 recipients of first allogeneic hematopoietic cell transplantation at our center. In multivariate analyses, the profiles of risk factors for acute and chronic GVHD were similar, with some notable differences. Recipient human leukocyte antigen (HLA) mismatching and the use of unrelated donors had a greater effect on the risk of acute GVHD than on chronic GVHD, whereas the use of female donors for male recipients had a greater effect on the risk of chronic GVHD than on acute GVHD. Total body irradiation was strongly associated with acute GVHD, but had no statistically significant association with chronic GVHD, whereas grafting with mobilized blood cells was strongly associated with chronic GVHD but not with acute GVHD. Older patient age was associated with chronic GVHD, but had no effect on acute GVHD. For all risk factors associated with chronic GVHD, point estimates and confidence intervals were not significantly changed after adjustment for prior acute GVHD. These results suggest that the mechanisms involved in acute and chronic GVHD are not entirely congruent and that chronic GVHD is not simply the end stage of acute GVHD.

Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B.

Mosaic variegated aneuploidy is a rare recessive condition characterized by growth retardation, microcephaly, childhood cancer and constitutional mosaicism for chromosomal gains and losses. In five families with mosaic variegated aneuploidy, including two with embryonal rhabdomyosarcoma, we identified truncating and missense mutations of BUB1B, which encodes BUBR1, a key protein in the mitotic spindle checkpoint. These data are the first to relate germline mutations in a spindle checkpoint gene with a human disorder and strongly support a causal link between aneuploidy and cancer development.

Clinical and Molecular Findings After Autologous Stem Cell Transplantation or Cyclophosphamide for Scleroderma: Handling Missing Longitudinal Data.

OBJECTIVE: Among individuals with systemic sclerosis (SSc) randomized to cyclophosphamide (CYC) (n = 34) or hematopoietic stem cell transplantation (HSCT) (n = 33), we examined longitudinal trends of clinical, pulmonary function, and quality of life measures while accounting for the influence of early failures on treatment comparisons. METHODS: Assuming that data were missing at random, mixed-effects regression models were used to estimate longitudinal trends for clinical measures when comparing treatment groups. Results were compared to observed means and to longitudinal trends estimated from shared parameter models, assuming that data were missing not at random. Longitudinal trends for SSc intrinsic molecular subsets defined by baseline gene expression signatures (normal-like, inflammatory, and fibroproliferative signatures) were also studied. RESULTS: Available observed means for pulmonary function tests appeared to improve over time in both arms. However, after accounting for participant loss, forced vital capacity in HSCT recipients increased by 0.77 percentage points/year but worsened by -3.70/year for CYC (P = 0.004). Similar results were found for diffusing capacity for carbon monoxide and quality of life indicators. Results for both analytic models were consistent. HSCT recipients in the inflammatory (n = 20) and fibroproliferative (n = 20) subsets had superior long-term trends compared to CYC for pulmonary and quality of life measures. HSCT was also superior for modified Rodnan skin thickness scores in the fibroproliferative subset. For the normal-like subset (n = 22), superiority of HSCT was less apparent. CONCLUSION: Longitudinal trends estimated from 2 statistical models affirm the efficacy of HSCT over CYC in severe SSc. Failure to account for early loss of participants may distort estimated clinical trends over the long term.