Driven by the necessity to survive environmental pathogens, the human immune system has evolved exceptional diversity and plasticity, to which several factors contribute including inheritable ...structural polymorphism of the underlying genes. Characterizing this variation is challenging due to the complexity of these loci, which contain extensive regions of paralogy, segmental duplication and high copy-number repeats, but recent progress in long-read sequencing and optical mapping techniques suggests this problem may now be tractable. Here we assess this by using long-read sequencing platforms from PacBio and Oxford Nanopore, supplemented with short-read sequencing and Bionano optical mapping, to sequence DNA extracted from CD14
+
monocytes and peripheral blood mononuclear cells from a single European individual identified as HV31. We use this data to build a
de novo
assembly of eight genomic regions encoding four key components of the immune system, namely the human leukocyte antigen, immunoglobulins, T cell receptors, and killer-cell immunoglobulin-like receptors. Validation of our assembly using k-mer based and alignment approaches suggests that it has high accuracy, with estimated base-level error rates below 1 in 10 kb, although we identify a small number of remaining structural errors. We use the assembly to identify heterozygous and homozygous structural variation in comparison to GRCh38. Despite analyzing only a single individual, we find multiple large structural variants affecting core genes at all three immunoglobulin regions and at two of the three T cell receptor regions. Several of these variants are not accurately callable using current algorithms, implying that further methodological improvements are needed. Our results demonstrate that assessing haplotype variation in these regions is possible given sufficiently accurate long-read and associated data. Continued reductions in the cost of these technologies will enable application of these methods to larger samples and provide a broader catalogue of germline structural variation at these loci, an important step toward making these regions accessible to large-scale genetic association studies.
We describe outcomes after allogeneic hematopoietic cell transplantation (HCT) for mycosis fungoides and Sezary syndrome (MF/SS). Outcomes of 129 subjects with MF/SS reported to the Center for the ...International Blood and Marrow Transplant from 2000-2009. Median time from diagnosis to transplant was 30 (4-206) months and most subjects were with multiply relapsed/ refractory disease. The majority (64%) received non-myeloablative conditioning (NST) or reduced intensity conditioning (RIC). NST/RIC recipients were older in age compared with myeloablative recipients (median age 51 vs 44 years, P=0.005) and transplanted in recent years. Non-relapse mortality (NRM) at 1 and 5 years was 19% (95% confidence interval (CI) 12-27%) and 22% (95% CI 15-31%), respectively. Risk of disease progression was 50% (95% CI 41-60%) at 1 year and 61% (95% CI 50-71%) at 5 years. PFS at 1 and 5 years was 31% (95% CI 22-40%) and 17% (95% CI 9-26%), respectively. OS at 1 and 5 years was 54% (95% CI 45-63%) and 32% (95% CI 22-44%), respectively. Allogeneic HCT in MF/SS results in 5-year survival in approximately one-third of patients and of those, half remain disease-free.
Acute GVHD remains an important complication after allogeneic hematopoietic cell transplantation (HCT). Many efforts have been devoted to identifying potential noninvasive peripheral blood biomarkers ...to help improve the diagnosis or management of acute GVHD while avoiding invasive tissue biopsies. Early attempts to identify biomarkers focused on inflammatory cytokines, especially IL-2 or TNF-α, however, both of these and others were not specific for GVHD, often being elevated in the setting of generalized inflammation, accompanying other major complications of HCT as well. More recent efforts have focused on additional cytokines and other cell-surface molecules, which function in leukocyte trafficking and activation with the hope that these can also serve as targets for novel therapeutic approaches. Modern proteomic methods have allowed the screening of large numbers of patient samples and yielded several novel candidate biomarkers, including elafin and reg3α, which may not be directly involved in the immunological pathogenesis of GVHD, but may be unique biomarkers for end-organ injury. Combining these new molecules with traditionally identified cytokines to form an acute GVHD biomarker panel has recently shown the ability to predict outcomes in patients who develop acute GVHD. The ultimate goals of identifying a specific biomarker are to refine diagnosis, guide therapy and develop risk-adapted approaches in order to better treat patients and improve outcomes after allogeneic HCT. These approaches include differential treatment for patients who develop acute GVHD with a high-risk biomarker profile as well as pre-emptive therapy in patients after HCT prior to the development of symptoms. With the recent progress summarized below, these goals may soon be realized.
Purpose
The increasing interest and availability of non-standard positron-emitting radionuclides has heightened the relevance of radionuclide choice in the development and optimization of new ...positron emission tomography (PET) imaging procedures, both in preclinical research and clinical practice. Differences in achievable resolution arising from positron range can largely influence application suitability of each radionuclide, especially in small-ring preclinical PET where system blurring factors due to annihilation photon acollinearity and detector geometry are less significant. Some resolution degradation can be mitigated with appropriate range corrections implemented during image reconstruction, the quality of which is contingent on an accurate characterization of positron range.
Procedures
To address this need, we have characterized the positron range of several standard and non-standard PET radionuclides (As-72, F-18, Ga-68, Mn-52, Y-86, and Zr-89) through imaging of small-animal quality control phantoms on a benchmark preclinical PET scanner. Further, the Particle and Heavy Ion Transport code System (PHITS v3.02) code was utilized for Monte Carlo modeling of positron range-dependent blurring effects.
Results
Positron range kernels for each radionuclide were derived from simulation of point sources in ICRP reference tissues. PET resolution and quantitative accuracy afforded by various radionuclides in practicable imaging scenarios were characterized using a convolution-based method based on positron annihilation distributions obtained from PHITS. Our imaging and simulation results demonstrate the degradation of small animal PET resolution, and quantitative accuracy correlates with increasing positron energy; however, for a specific “benchmark” preclinical PET scanner and reconstruction workflow, these differences were observed to be minimal given radionuclides with average positron energies below ~ 400 keV.
Conclusion
Our measurements and simulations of the influence of positron range on PET resolution compare well with previous efforts documented in the literature and provide new data for several radionuclides in increasing clinical and preclinical use. The results will support current and future improvements in methods for positron range corrections in PET imaging.
The prognosis for patients with most forms of T-cell lymphoma is poor. Allogeneic hematopoietic stem-cell transplantation (HSCT) may improve the outcome.
This study examines the outcome of 52 ...patients who underwent ablative or nonablative allogeneic HSCT for peripheral T-cell lymphoma (PTCL) or advanced mycosis fungoides/Sezary syndrome over a 12-year period at a single institution. We divided the patients into those with predominantly nodal histologies: peripheral T-cell not otherwise specified (PTCL NOS), angioimmunoblastic (AITL), or anaplastic large cell lymphoma, T/null type (systemic) (ALCL), and predominantly extranodal histologies: natural killer (NK)/T cell, enteropathy type, hepatosplenic, subcutaneous panniculitic, mycosis fungoides, or T cell or NK cell other.
Median follow-up of survivors is 49 months. Non-relapse mortality and relapse at 3 years was 27% and 43%, respectively. The incidence of grade II–IV acute graft-versus-host disease (GVHD) was 21%. The incidence of extensive chronic GVHD at 2 years was 27%. The 3-year progression-free survival was 30%: 45% in patients with predominantly nodal histologies (PTCL NOS, AITL, and ALCL) and 6% in patients with predominantly extranodal histologies (P=0.016). Overall survival at 3 years was 41% for all patients.
Allogeneic HSCT can produce long-term remissions in relapsed/refractory T-cell lymphoma, especially those with nodal histologies.
We report here an innovative feature of green nanotechnology-focused work showing that mangiferin-a glucose functionalized xanthonoid, found in abundance in mango peels-serves dual roles of chemical ...reduction and in situ encapsulation, to produce gold nanoparticles with optimum in vivo stability and tumor specific characteristics. The interaction of mangiferin with a Au-198 gold precursor affords MGF-
AuNPs as the beta emissions of Au-198 provide unique advantages for tumor therapy while gamma rays are used for the quantitative estimation of gold within the tumors and various organs. The laminin receptor specificity of mangiferin affords specific accumulation of therapeutic payloads of this new therapeutic agent within prostate tumors (PC-3) of human prostate tumor origin induced in mice which overexpress this receptor subtype. Detailed in vivo therapeutic efficacy studies, through the intratumoral delivery of MGF-
AuNPs, show the retention of over 80% of the injected dose (ID) in prostate tumors up to 24 h. By three weeks post treatment, tumor volumes of the treated group of animals showed an over 5 fold reduction as compared to the control saline group. New opportunities for green nanotechnology and a new paradigm of using mangiferin as a tumor targeting agent in oncology for the application of MGF-
AuNPs in the treatment of cancer are discussed.
Aeromonas dhakensis, often phenotypically identified as Aeromonas hydrophila, is an important human pathogen. The present study aimed to compare the clinical and biological features of A. dhakensis ...and A. hydrophila isolates from human wounds. A total of 80 Aeromonas wound isolates collected between January 2004 and April 2011 were analysed. The species was identified by the DNA sequence matching of rpoD and gyrB (or rpoB if necessary). Most of the Aeromonas isolates were identified as A. dhakensis (37, 46.3%), and 13 (16.3%) as A. hydrophila. Both species alone can cause severe skin and soft-tissue infections. More A. dhakensis isolates were found in wounds exposed to environmental water (32.4% vs 0%, p 0.042). More biofilm formation was noted among A. dhakensis isolates (mean optical density at 570 nm, 1.23 ± 0.09 vs 0.78 ± 0.21, p 0.03). The MICs of ceftriaxone, imipenem and gentamicin for A. dhakensis isolates were higher (p <0.0001, <0.04, and <0.01, respectively). The survival rates of Caenorhabditis elegans co-incubated with A. dhakensis from day 1 to day 3 were lower than those of worms infected with A. hydrophila in liquid toxicity assays (all p values <0.01). Isolates of A. dhakensis exhibited more cytotoxicity, as measured by the released leucocyte lactate dehydrogenase levels in human normal skin fibroblast cell lines (29.6 ± 1.2% vs 20.6 ± 0.6%, p <0.0001). The cytotoxin gene ast was primarily present in A. hydrophila isolates (100% vs 2.7%, p <0.0001). In summary, A. dhakensis is the predominant species among Aeromonas wound isolates, and more virulent than A. hydrophila.
Bone marrow transplantation (BMT) can cure myelodysplastic syndrome (MDS), although transplantation carries significant risks of morbidity and mortality. Because the optimal timing of HLA-matched BMT ...for MDS is unknown, we constructed a Markov model to examine 3 transplantation strategies for newly diagnosed MDS: transplantation at diagnosis, transplantation at leukemic progression, and transplantation at an interval from diagnosis but prior to leukemic progression. Analyses using individual patient risk-assessment data from transplantation and nontransplantation registries were performed for all 4 International Prognostic Scoring System (IPSS) risk groups with adjustments for quality of life (QoL). For low and intermediate-1 IPSS groups, delayed transplantation maximized overall survival. Transplantation prior to leukemic transformation was associated with a greater number of life years than transplantation at the time of leukemic progression. In a cohort of patients under the age of 40 years, an even more marked survival advantage for delayed transplantation was noted. For intermediate-2 and high IPSS groups, transplantation at diagnosis maximized overall survival. No changes in the optimal transplantation strategies were noted when QoL adjustments were incorporated. For low- and intermediate-1-risk MDS, delayed BMT is associated with maximal life expectancy, whereas immediate transplantation for intermediate-2- and high-risk disease is associated with maximal life expectancy. (Blood. 2004;104:579-585)
BACKGROUND & AIMS: The miss rate of colonoscopy for neoplasms is poorly understood. The aim of this study was to determine the miss rate of colonoscopy by same day back-to-back colonoscopy.
METHODS: ...Two consecutive same day colonoscopies were performed in 183 patients. The patients were randomized to undergo the second colonoscopy by the same or a different endoscopist and in the same or different position.
RESULTS: The overall miss rate for adenomas was 24%, 27% for adenomas > or = 5 mm, 13% for adenomas 6-9 mm, and 6% for adenomas < or = 1 cm. Patients with two or more adenomas at the first examination were more likely than patients with no or one adenoma detected at the first examination to have one or more adenomas at the second examination (odds ratio, 3.3; 95% confidence interval, 1.69-6.46). Right colon adenomas were missed more often (27%) than left colon adenomas (21%), but the difference was not significant. There was evidence of variation in sensitivity between endoscopists, but significant miss rates for small adenomas were found among essentially all endoscopists.
CONCLUSIONS: Using current colonoscopic technology, there are significant miss rates for adenomas > 1 cm even with meticulous colonoscopy. Miss rates are low for adenomas < or = 1 cm. The results suggest the need for improvements in colonoscopic technology. (Gastroenterology 1997 Jan;112(1):24-8)
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