Maintenance olaparib rechallenge in patients with platinum-sensitive relapsed ovarian cancer previously treated with a PARP inhibitor (OReO/ENGOT-ov38): a phase IIIb trial.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the standard of care for some patients with advanced ovarian cancer. We evaluated the efficacy and safety of PARP inhibitor rechallenge. PATIENTS AND METHODS: This randomized, double-blind, multicenter trial (NCT03106987) enrolled patients with platinum-sensitive relapsed ovarian cancer who had received one prior PARP inhibitor therapy for ≥18 and ≥12 months in the BRCA-mutated and non-BRCA-mutated cohorts, respectively, following first-line chemotherapy or for ≥12 and ≥6 months, respectively, following a second or subsequent line of chemotherapy. Patients were in response following their last platinum-based chemotherapy regimen and were randomized 2 : 1 to maintenance olaparib tablets 300 mg twice daily or placebo. Investigator-assessed progression-free survival (PFS) was the primary endpoint. RESULTS: Seventy four patients in the BRCA-mutated cohort were randomized to olaparib and 38 to placebo, and 72 patients in the non-BRCA-mutated cohort were randomized to olaparib and 36 to placebo; >85% of patients in both cohorts had received ≥3 prior lines of chemotherapy. In the BRCA-mutated cohort, the median PFS was 4.3 months with olaparib versus 2.8 months with placebo [hazard ratio (HR) 0.57; 95% confidence interval (CI) 0.37-0.87; P = 0.022]; 1-year PFS rates were 19% versus 0% (Kaplan-Meier estimates). In the non-BRCA-mutated cohort, median PFS was 5.3 months for olaparib versus 2.8 months for placebo (HR 0.43; 95% CI 0.26-0.71; P = 0.0023); 1-year PFS rates were 14% versus 0% (Kaplan-Meier estimates). No new safety signals were identified with olaparib rechallenge. CONCLUSIONS: In ovarian cancer patients previously treated with one prior PARP inhibitor and at least two lines of platinum-based chemotherapy, maintenance olaparib rechallenge provided a statistically significant, albeit modest, PFS improvement over placebo in both the BRCA-mutated and non-BRCA-mutated cohorts, with a proportion of patients in the maintenance olaparib rechallenge arm of both cohorts remaining progression free at 1 year.

Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplantation-Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation, American Society for Transplantation and Cellular Therapy, Asia-Pacific Blood and Marrow Transplantation Group, and Center for International Blood and Marrow Transplant Research.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplantation (HCT) associated with significant morbidity and mortality. However, TA-TMA is a clinical diagnosis, and multiple criteria have been proposed without universal application. Although some patients have a self-resolving disease, others progress to multiorgan failure and/or death. Poor prognostic features also are not uniformly accepted. The lack of harmonization of diagnostic and prognostic markers has precluded multi-institutional studies to better understand incidence and outcomes. Even current interventional trials use different criteria, making it challenging to interpret the data. To address this urgent need, the American Society for Transplantation and Cellular Therapy, Center for International Bone Marrow Transplant Research, Asia-Pacific Blood and Marrow Transplantation, and European Society for Blood and Marrow Transplantation nominated representatives for an expert panel tasked with reaching consensus on diagnostic and prognostic criteria. The panel reviewed literature, generated consensus statements regarding diagnostic and prognostic features of TA-TMA using the Delphi method, and identified future directions of investigation. Consensus was reached on 4 key concepts: (1) TA-TMA can be diagnosed using clinical and laboratory criteria or tissue biopsy of kidney or gastrointestinal tissue; however, biopsy is not required; (2) consensus diagnostic criteria are proposed using the modified Jodele criteria with additional definitions of anemia and thrombocytopenia. TA-TMA is diagnosed when ≥4 of the following 7 features occur twice within 14 days: anemia, defined as failure to achieve transfusion independence despite neutrophil engraftment; hemoglobin decline by ≥1 g/dL or new-onset transfusion dependence; thrombocytopenia, defined as failure to achieve platelet engraftment, higher-than-expected transfusion needs, refractory to platelet transfusions, or ≥50% reduction in baseline platelet count after full platelet engraftment; lactate dehydrogenase (LDH) exceeding the upper limit of normal (ULN); schistocytes; hypertension; soluble C5b-9 (sC5b-9) exceeding the ULN; and proteinuria (≥1 mg/mg random urine protein-to-creatinine ratio [rUPCR]); (3) patients with any of the following features are at increased risk of nonrelapse mortality and should be stratified as high-risk TA-TMA: elevated sC5b-9, LDH ≥2 times the ULN, rUPCR ≥1 mg/mg, multiorgan dysfunction, concurrent grade II-IV acute graft-versus-host disease (GVHD), or infection (bacterial or viral); and (4) all allogeneic and pediatric autologous HCT recipients with neuroblastoma should be screened weekly for TA-TMA during the first 100 days post-HCT. Patients diagnosed with TA-TMA should be risk-stratified, and those with high-risk disease should be offered participation in a clinical trial for TA-TMA-directed therapy if available. We propose that these criteria and risk stratification features be used in data registries, prospective studies, and clinical practice across international settings. This harmonization will facilitate the investigation of TA-TMA across populations diverse in race, ethnicity, age, disease indications, and transplantation characteristics. As these criteria are widely used, we expect continued refinement as necessary. Efforts to identify more specific diagnostic and prognostic biomarkers are a top priority of the field. Finally, an investigation of the impact of TA-TMA-directed treatment, particularly in the setting of concurrent highly morbid complications, such as steroid-refractory GVHD and infection, is critically needed.

Augmenting salt tolerance in rice by regulating uptake and tissue specific accumulation of Na+ - through Ca2+ -induced alteration of biochemical events.

The protective effect of Ca2+ against NaCl toxicity was investigated in two rice varieties with contrasting for salt tolerance to understand the mechanistic details of the antagonism to address adverse effects of salinity on agriculture. The study primarily examined the influence of Ca2+ on expression/activity of the effectors and regulators involved in Na+ translocation. Calcium reduced uptake of Na+ concomitant with higher tissue K+ /Na+ in seedlings, comparatively more in salt-tolerant Nona Bokra than in salt-sensitive IR-64, together with a significant increase in root PM H+ ATPase in the former, but not in the latter. Increased antagonism in Nona Bokra could be the result of Ca2+ signalling-mediated phosphorylation of PM H+ ATPase in roots caused by a significant Ca2+ -dependent increase in expression of OsCIPK24, which did not occur in IR-64. Furthermore, significant Ca2+ -mediated NaCl-induced increase in transcription of 14-3-3 protein in Nona Bokra, but not in IR-64, might also lead to a greater protective effect of Ca2+ in the former, as 14-3-3 protein is essential for activating PM H+ ATPase. Thus, efficient functioning of PM H+ ATPase could be key in determining resistance of plants to salinity, implying that identification of the Ca2+ -dependent kinase phosphorylating the PM H+ ATPase threonine residue and manipulation of its expression, together with expression of 14-3-3 proteins could be an important strategy to improve salt tolerance of crops and their cultivation in salt-affected lands.

Absence of damaging effects of stem cell donation in unrelated donors assessed by FISH and gene variance screening.

ASTRACT: Granulocyte-Colony-Stimulating factor (G-CSF) is currently the standard mobilising agent for peripheral blood stem cell (PBSC) donation. Concerns that it may trigger chromosome aberrations similar to those observed in leukaemia patients were refuted but long-term effects of G-CSF mobilisation on genome integrity remains unclear. In the setting of a multi-centre clinical trial we screened blood samples from 50 PBSC donors at cellular and gene level for aberrations common in haematological malignancies using fluorescence in situ hybridisation (FISH) and next generation sequencing (NGS) assays. Analysis of samples collected before, on the day of donation, 90 and 180 days after G-CSF admission confirmed the absence of short-term effects in PBSC donors on both quiescent and dividing cells. This data did not differ from the results of 50 individuals tested 3-5 years after bone marrow donation and 50 healthy persons. NGS using a panel targeting 54 genes recurrently affected in myeloid disorders (TruSight Myeloid panel, Illumina) showed that the gene profiles of samples from 48 PBSC donors remained stable throughout the study period. These data strongly indicate absence of detrimental effects on the genome integrity caused by PBSC donation.

The face of postural tachycardia syndrome - insights from a large cross-sectional online community-based survey.

BACKGROUND: Patients with postural tachycardia syndrome (POTS) experience chronic symptoms of orthostatic intolerance. There are minimal data detailing the demographics, clinical features and clinical course of this condition. This online, community-based survey highlights patients' experience with POTS. It consists of the largest sample of POTS patients reported to date. OBJECTIVES: To describe the demographics, past medical history, medications, treatments and diagnostic journey for patients living with POTS. METHODS: Postural tachycardia syndrome patients completed an online, community-based, cross-sectional survey. Participants were excluded if they had not received a diagnosis of POTS from a physician. The questions focused on the patient experience and journey, rather than physiological responses. RESULTS: The final analysis included 4835 participants. POTS predominantly affects white (93%) females (94%) of childbearing age, with approximately half developing symptoms in adolescence (mode 14 years). POTS is a chronic multisystem disorder involving a broad array of symptoms, with many patients diagnosed with comorbidities in addition to POTS. POTS patients often experience lengthy delays [median (interquartile range) 24 (6-72) months] and misdiagnosis, but the diagnostic delay is improving. POTS patients can present with a myriad of symptoms most commonly including lightheadedness (99%), tachycardia (97%), presyncope (94%), headache (94%) and difficulty concentrating (94%). CONCLUSIONS: These data provide important insights into the background, clinical features and diagnostic journey of patients suffering from POTS. These data should serve as an essential step for moving forward with future studies aimed at early and accurate diagnoses of these patients leading to appropriate treatments for their symptoms.

The phospholipid flippase DnfD localizes to late Golgi and is involved in asexual differentiation in Aspergillus nidulans.

The maintenance of cell shape requires finely tuned and robust vesicle trafficking in order to provide sufficient plasma membrane materials. The hyphal cells of filamentous fungi are an extreme example of cell shape maintenance due to their ability to grow rapidly and respond to the environment while keeping a relatively consistent shape. We have previously shown that two phospholipid flippases, which regulate the asymmetry of specific phospholipids within the plasma membrane, are important for hyphal growth in Aspergillus nidulans. Here, we examine the rest of the phospholipid flippases encoded by A. nidulans by obtaining single and double deletions of all four family members, dnfA, dnfB, dnfC, and dnfD. We find that deleting dnfC does not impart a noticeable phenotype, by itself or with other deletions, but that dnfD, the homolog of the essential yeast gene neo1, is important for conidiation. dnfD deletion mutants form misshapen conidiophore vesicles that are defective in metulae formation. We localize DnfD to late Golgi equivalents, where it appears just before dissociation of this organelle. We propose that DnfD functions in a trafficking process that is specifically required for the morphological changes that take place during conidiation.

Influence of rib impact on thoracic gunshot trauma.

INTRODUCTION: The influence of rib impact on thoracic gunshot trauma remains unclear, despite its high occurrence. This study therefore investigates the effect of rib impact on a bullet's terminal properties and injury severity. METHODS: Two bullets were used: 5.56×45 mm (full charge and reduced charge) and 7.62×51 mm (full charge). For each bullet, three impact groups were tested: (1) plain 10% ballistic gelatin (control) conditioned at 4°C, (2) intercostal impact, and (3) rib impact, the latter two tested with samples of porcine thoracic walls embedded in gelatin. Analysis included penetration depth, trajectory change, yaw, fragmentation, velocity reduction, energy deposition and temporary and permanent cavity characteristics. RESULTS: No significant differences were observed for most variables. Differences were found between rib (and intercostal) impact and the control groups, suggesting that the inclusion of thoracic walls produces an effect more significant than the anatomical impact site. Effects were ammunition specific. For the 7.62×51 mm round, rib impact caused an earlier onset of yaw and more superficial permanent gelatin damage compared with plain gelatin. This round also formed a larger temporary cavity on rib impact than intercostal impact. Rib (and intercostal impact) created a smaller temporary cavity than the control for the 5.56×45 mm round. For the reduced-charge 5.56×45 mm round, rib and intercostal impact produced greater velocity reduction compared with plain gelatin. CONCLUSIONS: This study provides new insights into the role of rib impact in thoracic gunshot injuries, and indicates that the effects are ammunition dependent. Unlike the 5.56×45 mm rounds, rib impact with the 7.62×51 mm rounds increases the risk of severe wounding.

Dissociation between caloric and head impulse testing in patients with congenital abnormalities of the semicircular canals.

BACKGROUND: Dissociation between caloric and head impulse test results in patients with vestibular disorders has been well documented since the introduction of video head impulse testing. Prior to the introduction of video head impulse testing, vestibular diagnostic services relied mainly on caloric testing, and it is now known that the caloric testing shows more positive results than video head impulse testing. A dissipation model was proposed to explain this dissociation.Case reportsThis paper presents two cases in which caloric testing indicated an absent or significantly reduced response on the horizontal semicircular canal plane but video head impulse testing showed near-normal or normal vestibulo-ocular reflex gain on the same plane. CONCLUSION: This report supports the dissipation theory and questions the functional relevance of canal paresis values calculated from caloric test results.

High-resolution HLA allele and haplotype frequencies in majority and minority populations of Costa Rica and Nicaragua: Differential admixture proportions in neighboring countries.

The HLA system shows the most extensive polymorphism in the human genome. Allelic and haplotypic frequencies of HLA genes vary dramatically across human populations. Due to a complex history of migration, populations in Latin America show a broad variety of admixture proportions, usually varying not only between countries, but also within countries. Knowledge of HLA allele and haplotype frequencies is essential for medical fields such as transplantation, but also serves as a means to assess genetic diversity and ancestry in human populations. Here, we have determined high-resolution HLA-A, -B, -C, and -DRB1 allele and haplotype frequencies in a sample of 713 healthy subjects from three Mestizo populations, one population of African descent, and Amerindians of five different groups from Costa Rica and Nicaragua and compared their profiles to a large set of indigenous populations from Iberia, Sub-Saharan Africa, and the Americas. Our results show a great degree of allelic and haplotypic diversity within and across these populations, with most extended haplotypes being private. Mestizo populations show alleles and haplotypes of putative European, Amerindian, and Sub-Saharan African origin, albeit with differential proportions. Despite some degree of gene flow, Amerindians and Afro-descendants show great similarity to other Amerindian and West African populations, respectively. This is the first comprehensive study reporting high-resolution HLA diversity in Central America, and its results will shed light into the genetic history of this region while also supporting the development of medical programs for organ and stem cell transplantation.

Effect of ageing on the calibration of ballistic gelatin.

PURPOSE: Ballistic gelatin is commonly used as a validated surrogate for soft tissue during terminal ballistic testing. However, the effect of a delay between production and testing of a gelatin mould remains unknown. The aim of this study was to determine any potential effects of ageing on ballistic gelatin. METHODS: Depth of penetration (DoP) of 4.5 mm spherical fragment simulating projectiles was ascertained using mixtures of 10%, 11.25% and 20% Type A 250 Bloom ballistic gelatin. Testing was performed daily for 5 days using velocities between 75 and 210 m/s. DoP at day 5 was statistically compared with day 1, and net mass change was recorded daily. RESULTS: No significant difference was found for DoP observed with time in any of the samples (P>0.05). Spearman correlation was excellent in all moulds. The moulds with known standard calibrations remained in calibration throughout the study period. Mass loss of less than 1% was noted in all samples. CONCLUSION: Mass loss was the only quantifiable measure of changes in the blocks with time, but did not correlate with any changes in DoP. This may provide reassurance when undertaking such testing that an inadvertent delay will not significantly alter the penetration properties of the mould. Future research is recommended to determine any potential effect on the mechanical properties of gelatin at higher velocity impacts and whether the calibration corresponds to an adequate simulation under such conditions.

Second-harmonic generation imaging of collagen in ancient bone.

Second-harmonic generation imaging (SHG) captures triple helical collagen molecules near tissue surfaces. Biomedical research routinely utilizes various imaging software packages to quantify SHG signals for collagen content and distribution estimates in modern tissue samples including bone. For the first time using SHG, samples of modern, medieval, and ice age bones were imaged to test the applicability of SHG to ancient bone from a variety of ages, settings, and taxa. Four independent techniques including Raman spectroscopy, FTIR spectroscopy, radiocarbon dating protocols, and mass spectrometry-based protein sequencing, confirm the presence of protein, consistent with the hypothesis that SHG imaging detects ancient bone collagen. These results suggest that future studies have the potential to use SHG imaging to provide new insights into the composition of ancient bone, to characterize ancient bone disorders, to investigate collagen preservation within and between various taxa, and to monitor collagen decay regimes in different depositional environments.

Fermentation for Disinfesting Fruit Waste From Drosophila Species (Diptera: Drosophilidae).

Economic losses in a range of fruit crops due to the Drosophila suzukii (Matsumura) have become severe. Removal and treatment of fruit waste, which may harbor D. suzukii, is a key step in preventing reinfestation of fruit production. Natural fermentation for disinfesting fruit wastes from D. suzukii was examined at ambient air temperatures of 12-20 °C. Soft and stone fruit wastes infested with eggs, larvae, and pupae of Drosophila melanogaster (Meigen) or D. suzukii were placed in sealed vessels containing fruit wastes, and samples were retrieved at intervals and tested for the emergence of adults. Mean temperatures of the fruit waste in the sealed vessels during fermentation were 15-23 °C. Fermentation for 3 d was effective in disinfesting waste from different life stages of D. suzukii. Treatment for 4 d also ensured that the waste was free of viable life stages of D. melanogaster, which could be used as an indicator species for disinfestation of waste from D. suzukii owing to its greater tolerance of fermentation. The O2 concentration of the headspace air in the vessels became undetectable after 13-16 h, with a corresponding increase in CO2 concentration, which exceeded 80% vol/vol. The resulting hypoxia and hypercapnia may explain the efficacy of the fermentation treatment in disinfesting the waste. Fermented fruit remained attractive to D. suzukii and retained its capacity to rear a life cycle. Covering or mixing fermented fruit with a sufficient depth (0.1 m) or volume (×9) of soil or coir prevented the reinfestation of treated waste.

Meeting American Diabetes Association diabetes management targets: trends in Mauritius.

AIMS: To examine the proportion of people with diabetes in the multi-ethnic country of Mauritius meeting American Diabetes Association targets in 2009 and 2015. METHODS: Data from independent population-based samples of 858 and 656 adults with diagnosed diabetes in 2009 and 2015, respectively, were analysed with regard to recommended American Diabetes Association targets for HbA1c , blood pressure and LDL cholesterol. RESULTS: In 2015 compared with 2009, the proportion of people achieving American Diabetes Association targets for glycaemic control in Mauritius was higher in women (P≤0.01) and in those with only a primary education level (P=0.07), but not in men or people with a higher level of education. Achievement of blood pressure <140/90 mmHg was higher in 2015 compared with 2009 (60% vs 42%) in people of South Asian ethnicity (P<0.001), but not in those of African ethnicity (P=0.16). The percentages of people with LDL cholesterol <2.59 mmol/l were 42.1% and 50.4%, in 2009 and 2015, respectively (P=0.27). Better control of HbA1c and blood pressure was observed in groups in which that control was poorest in 2009. The use of glucose-, blood pressure- and LDL cholesterol-lowering medication was higher in 2015 than in 2009. CONCLUSIONS: In certain subgroups, namely women, those with poorer education and those of South Asian ethnicity, whose target achievement was the poorest in 2009, control of glycaemia and blood pressure was better in 2015 as compared with 2009. While these findings are encouraging, further work is required to improve outcomes.

Directionality of non-permissive HLA-DPB1 T-cell epitope group mismatches does not improve clinical risk stratification in 8/8 matched unrelated donor hematopoietic cell transplantation.

In 8/8 HLA-matched unrelated donor (UD) hematopoietic cell transplants (HCT), HLA-DPB1 mismatches between alleles from different T-cell epitope (TCE) groups (non-permissive mismatches) are associated with significantly higher risks of mortality compared with those between alleles from the same TCE group (permissive mismatches); however, the relevance of mismatch directionality, that is (host vs graft (uni-directional HvG), graft vs host (uni-directional GvH) or both (bi-directional) in the non-permissive setting is unknown. We show here significantly higher in vitro relative responses (RR) to bi-directional mismatches compared with uni-directional HvG or GvH mismatches in a total of 420 one-way mixed lymphocyte reactions between 10/10 matched pairs (RR 27.5 vs 7.5 vs 15.5, respectively, P<0.001). However, in 3281 8/8 matched UD HCT for leukemia or myelodysplastic syndrome, the hazards of transplant-related mortality (TRM) were similar for uni-directional HvG or GvH mismatches and bi-directional mismatches (hazard ratio (HR) 1.32, P=0.001 vs HR 1.28, P=0.005 and HR 1.34, P=0.046), compared with permissive mismatches. Similar results were observed for overall survival. No statistical differences between the uni- and the bi-directional non-permissive groups were detected in pairwise comparisons for any of the outcomes tested. We conclude that consideration of directionality does not improve risk stratification by non-permissive HLA-DPB1 TCE mismatches in UD searches.

Provision of long-term monitoring and late effects services following adult allogeneic haematopoietic stem cell transplant: a survey of UK NHS-based programmes.

Despite international guidelines, optimal delivery models of late effects (LE) services for HSCT patients are unclear from the clinical, organizational and economic viewpoints. To scope current LE service delivery models within the UK NHS (National Health Service), in 2014, we surveyed the 27 adult allogeneic HSCT centres using a 30-question online tool, achieving a 100% response rate. Most LE services were led and delivered by senior physicians (>80% centres). Follow-up was usually provided in a dedicated allograft or LE clinic for the first year (>90% centres), but thereafter attrition meant that only ~50% of patients were followed after 5 years. Most centres (69%) had a standard operating procedure for long-term monitoring but access to a LE Multi-Disciplinary Team was rare (19% centres). Access to medical specialities necessary for LE management was good, but specialist interest in long-term HSCT complications was uncommon. Some screening (endocrinopathy, cardiovascular) was near universal, but other areas were more limited (mammography, cervical smears). Funding of extra staff and investigations were the most commonly perceived barriers to implementation of LE services. This survey shows variation in the long-term follow-up of allogeneic HSCT survivors within the UK NHS and further work is warranted to optimize effective, sustainable and affordable models of LE service delivery among this group.

Recipient/donor HLA and CMV matching in recipients of T-cell-depleted unrelated donor haematopoietic cell transplants.

Improving haematopoietic cell transplantation outcomes by selection of an HLA-matched unrelated donor is best practice; however, donor selection by secondary characteristics is controversial. We studied 1271 recipients with haematological malignancies who underwent T-cell-depleted allografts and had complete data on HLA-matching status for six loci (HLA-A, -B, -C, -DRB1, -DQB1, -DPB1) and clinical outcome data. Five-year overall survival was 40.6%. HLA mismatching (at HLA-A, -B, -C, -DRB1, -DQB1) relative risk (RR) 1.22, 95% confidence interval (CI) 1.2-1.5, P=0.033 for 1 mismatch and RR 1.46, 95% CI 1.1-1.9, P=0.009 for >1 mismatch) and CMV mismatching (RR 1.37, 95% CI 1.2-1.6, P<0.001) were significantly associated with inferior survival. Donors aged <30 years showed a trend towards better survival. The multivariate model for mortality, combining CMV and HLA-match status, found an RR of 1.36 (95% CI 1.1-1.7, P=0.003) for HLA matched/CMV mismatched, an RR of 1.22 (95% CI 0.99-1.5, P=0.062) for HLA mismatched/CMV matched and an RR of 1.81 (95% CI 1.4-2.3, P=<0.001) for HLA/ CMV mismatched, compared with the HLA/CMV-matched recipients. These data suggest that HLA and CMV matching status should be considered when selecting unrelated donors and that CMV matching may abrogate the effect of an HLA mismatch.

Transforming growth factor-ß1 functional polymorphisms in myeloablative sibling hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) with sibling donors (s.d.) is a life-saving intervention for patients with hematological malignancies. Numerous genetic factors have a role in transplant outcome. Several functional polymorphisms have been identified in TGF-ß1 gene, such as single-nucleotide polymorphism (SNP) at +29C>T within exon 1. Two hundred and forty five patient/donor pairs who underwent a s.d. HSCT in our centers were genotyped for this SNP. In the myeloablative cohort, +29CC donors were associated with an increase in severe chronic GvHD (32% vs 16%, hazard ratio (HR) 9.0, P=0.02). Regarding survival outcomes, +29CC patients developed higher non relapse mortality (NRM) (1-5 years CC 28-32% vs TC/TT 7-10%; HR 5.1, P=0.01). Recipients of +29TT donors experienced a higher relapse rate (1-5 years TT 37-51% vs TC 19-25% vs CC 13%-19%; HR 2.4, P=0.01) with a decreased overall survival (OS) (1-5 years TT 69-50% vs TC/CC 77-69%; HR 1.9, P=0.05). Similar to previous myeloablative unrelated donors HSCT results, we confirmed that +29CC patients had higher NRM. In addition we found that +29TT donors might be associated with a higher relapse rate and lower OS. These results should be confirmed in larger series. Identification of these SNPs will allow personalizing transplant conditioning and immunosuppressant regimens, as well as assisting in the choice of the most appropriate donor.

Clathrin localization and dynamics in Aspergillus nidulans.

Cell growth necessitates extensive membrane remodeling events including vesicle fusion or fission, processes that are regulated by coat proteins. The hyphal cells of filamentous fungi concentrate both exocytosis and endocytosis at the apex. This investigation focuses on clathrin in Aspergillus nidulans, with the aim of understanding its role in membrane remodeling in growing hyphae. We examined clathrin heavy chain (ClaH-GFP) which localized to three distinct subcellular structures: late Golgi (trans-Golgi equivalents of filamentous fungi), which are concentrated just behind the hyphal tip but are intermittently present throughout all hyphal cells; the region of concentrated endocytosis just behind the hyphal apex (the "endocytic collar"); and small, rapidly moving puncta that were seen trafficking long distances in nearly all hyphal compartments. ClaH localized to distinct domains on late Golgi, and these clathrin "hubs" dispersed in synchrony after the late Golgi marker PHOSBP . Although clathrin was essential for growth, ClaH did not colocalize well with the endocytic patch marker fimbrin. Tests of FM4-64 internalization and repression of ClaH corroborated the observation that clathrin does not play an important role in endocytosis in A. nidulans. A minor portion of ClaH puncta exhibited bidirectional movement, likely along microtubules, but were generally distinct from early endosomes.