Global impacts of an extreme solar particle event under different geomagnetic field strengths.

Solar particle events (SPEs) are short-lived bursts of high-energy particles from the solar atmosphere and are widely recognized as posing significant economic risks to modern society. Most SPEs are relatively weak and have minor impacts on the Earth's environment, but historic records contain much stronger SPEs which have the potential to alter atmospheric chemistry, impacting climate and biological life. The impacts of such strong SPEs would be far more severe when the Earth's protective geomagnetic field is weak, such as during past geomagnetic excursions or reversals. Here, we model the impacts of an extreme SPE under different geomagnetic field strengths, focusing on changes in atmospheric chemistry and surface radiation using the atmosphere-ocean-chemistry-climate model SOCOL3-MPIOM and the radiation transfer model LibRadtran. Under current geomagnetic conditions, an extreme SPE would increase NOx concentrations in the polar stratosphere and mesosphere, causing reductions in extratropical stratospheric ozone lasting for about a year. In contrast, with no geomagnetic field, there would be a substantial increase in NOx throughout the entire atmosphere, resulting in severe stratospheric ozone depletion for several years. The resulting ground-level ultraviolet (UV) radiation would remain elevated for up to 6 y, leading to increases in UV index up to 20 to 25% and solar-induced DNA damage rates by 40 to 50%. The potential evolutionary impacts of past extreme SPEs remain an important question, while the risks they pose to human health in modern conditions continue to be underestimated.

Optimal reactive nitrogen control pathways identified for cost-effective PM2.5 mitigation in Europe.

Excess reactive nitrogen (Nr), including nitrogen oxides (NOx) and ammonia (NH3), contributes strongly to fine particulate matter (PM2.5) air pollution in Europe, posing challenges to public health. Designing cost-effective Nr control roadmaps for PM2.5 mitigation requires considering both mitigation efficiencies and implementation costs. Here we identify optimal Nr control pathways for Europe by integrating emission estimations, air quality modeling, exposure-mortality modeling, Nr control experiments and cost data. We find that phasing out Nr emissions would reduce PM2.5 by 2.3 ± 1.2 µg·m-3 in Europe, helping many locations achieve the World Health Organization (WHO) guidelines and reducing PM2.5-related premature deaths by almost 100 thousand in 2015. Low-ambition NH3 controls have similar PM2.5 mitigation efficiencies as NOx in Eastern Europe, but are less effective in Western Europe until reductions exceed 40%. The efficiency for NH3 controls increases at high-ambition reductions while NOx slightly decreases. When costs are considered, strategies for both regions uniformly shift in favor of NH3 controls, as NH3 controls up to 50% remain 5-11 times more cost-effective than NOx per unit PM2.5 reduction, emphasizing the priority of NH3 control policies for Europe.

An analysis of 30 years of surface ozone concentrations in Austria: temporal evolution, changes in precursor emissions and chemical regimes, temperature dependence, and lessons for the future.

Despite substantial reductions in anthropogenic emissions of nitrogen oxides (NO x ) and non-methane volatile organic compounds (NMVOCs) in Austria over the 30 year time period 1990-2019, summertime surface ozone (O3) concentrations still exceed frequently and over wide areas the ozone maximum 8 hour mean target value for the protection of human health. We present a detailed analysis of in situ observations of O3 and NO x to (1) disentangle the main processes propelling O3 formation such as precursor emissions and meteorology and (2) quantify the impact of NO x reductions and (3) estimate the effect of climate warming. The temperature sensitivity of surface O3 production is assessed separately for NO x and VOC limited regimes. The temperature sensitivity of ozone increases with temperature in spring and summer. On average, the evaluated absolute values of the sensitivities are a factor of 2.5 larger in summer than in spring. The analysis of ambient O3 burdens during hot summers indicates that rising temperatures in a warming climate might largely offset the benefit of future emission reductions. MAX-DOAS formaldehyde (HCHO) measurements in Vienna from 2017 to 2019 are used as a proxy for VOC emissions. The seasonal and the temperature dependence of the observed HCHO mixing ratios indicate that biogenic VOCs (BVOCs) are the dominant source of hydrocarbons in the urban setting during the ozone season. The result agrees well with VOC emission estimates that show BVOCs to be the dominant VOC source in Austria since the early 2000s. Accordingly, anthropogenic NO x emission reductions remain, outside of urban cores, the most effective instrument for policymakers to lower surface ozone concentrations in the short term.

How will air quality effects on human health, crops and ecosystems change in the future?

Future air quality will be driven by changes in air pollutant emissions, but also changes in climate. Here, we review the recent literature on future air quality scenarios and projected changes in effects on human health, crops and ecosystems. While there is overlap in the scenarios and models used for future projections of air quality and climate effects on human health and crops, similar efforts have not been widely conducted for ecosystems. Few studies have conducted joint assessments across more than one sector. Improvements in future air quality effects on human health are seen in emission reduction scenarios that are more ambitious than current legislation. Larger impacts result from changing particulate matter (PM) abundances than ozone burdens. Future global health burdens are dominated by changes in the Asian region. Expected future reductions in ozone outside of Asia will allow for increased crop production. Reductions in PM, although associated with much higher uncertainty, could offset some of this benefit. The responses of ecosystems to air pollution and climate change are long-term, complex, and interactive, and vary widely across biomes and over space and time. Air quality and climate policy should be linked or at least considered holistically, and managed as a multi-media problem. This article is part of a discussion meeting issue 'Air quality, past present and future'.

[A review of the state of the climate crisis in the midst of the COVID-19 pandemic]. / Eine Bestandsaufnahme zur Klimakrise inmitten der COVID-19-Pandemie.

The atmospheric concentration of well-mixed greenhouse gases has drastically increased since 1850. The prime cause for this increase is anthropogenic activity, particularly the burning of fossil fuels. As a consequence of the changing atmospheric composition, we observe a net positive radiative forcing, which manifests in global warming. The global mean surface temperature has increased since the preindustrial by about 1.0 °C. Under the assumption of continued greenhouse gas emissions, climate models project a temperature increase between 3.7 °C and 4.8 °C until 2100 (compared to the 1850-1900 mean). The assessment reports of the Intergovernmental Panel on Climate Change detail the catastrophic consequences of global warming of such extent for both ecosystems and mankind. As a consequence, the Paris Agreement aims to limit global warming to below 2 °C, ideally 1.5 °C, when compared to the preindustrial. To achieve this goal, fast and ambitious emission controls are required, reaching net zero emission by 2050 at the latest. Examining the global greenhouse gas emissions of recent decades, it becomes obvious how far away we are at present from reaching this goal. Also, the currently determined national contributions for emission reduction do not suffice to meet the 1.5 °C target. Thus, it is of uttermost importance to raise the global ambition in climate protection. The 1.5 °C target can still be reached, however, the time to set the required measures will expire within this decade.

Distinctive mutational spectrum and karyotype disruption in long-term cisplatin-treated urothelial carcinoma cell lines.

The DNA-damaging compound cisplatin is broadly employed for cancer chemotherapy. The mutagenic effects of cisplatin on cancer cell genomes are poorly studied and might even contribute to drug resistance. We have therefore analyzed mutations and chromosomal alterations in four cisplatin-resistant bladder cancer cell lines (LTTs) by whole-exome-sequencing and array-CGH. 720-7479 genes in the LTTs contained point mutations, with a characteristic mutational signature. Only 53 genes were mutated in all LTTs, including the presumed cisplatin exporter ATP7B. Chromosomal alterations were characterized by segmented deletions and gains leading to severely altered karyotypes. The few chromosomal changes shared among LTTs included gains involving the anti-apoptotic BCL2L1 gene and losses involving the NRF2 regulator KEAP1. Overall, the extent of genomic changes paralleled cisplatin treatment concentrations. In conclusion, bladder cancer cell lines selected for cisplatin-resistance contain abundant and characteristic drug-induced genomic changes. Cisplatin treatment may therefore generate novel tumor genomes during patient treatment.

Clinical and genetic characterization of de novo double-hit B cell precursor leukemia/lymphoma.

The 2016 revised World Health Organization (WHO) classification of lymphoid neoplasms included the category of high-grade B cell lymphomas (HGBLs) with combined MYC and BCL2 and/or BCL6 rearrangements (double-hit, DH). However, the clinical features of B cell precursor leukemia (BCP-ALL) that harbor DH genetics remain widely unknown. We performed a retrospective analysis of the German Multicenter Study Group for Adult ALL registry and a literature search for de novo DH-BCP-ALLs. We identified 6 patients in the GMALL registry and 11 patients published in the literature between 1983 and June 2018. Patients of all ages (range, 15-86 years) are affected. There is a high incidence of meningeal disease and other extramedullary disease manifestations. Current treatment approaches are mainly ALL-based and are sufficient to induce first complete remissions, but progression-free survival is only 4.0 months (95% CI, 1.5-6.5 months) and all patients succumb to their disease, once relapsed, with a median survival of 5.0 months (95% CI, 3.1-6.9 months), despite intensive salvage and targeted therapy approaches. Of all patients, only two that attained an initial complete remission were alive at data cutoff. In all cases, the BCL2 gene was rearranged to be in proximity to the IGH locus, whereas MYC had various translocation partners juxtaposed. There was no significant survival difference between IG and non-IG translocation partners (HR, 1.03; 95% CI, 0.33-3.2; p = 0.89). In conclusion, de novo DH-BCP-ALL is an aggressive B cell malignancy with deleterious outcome. Physicians have to be aware of this rare disease subset due to the atypical clinical behavior and especially because latest classification systems do not cover this sub-entity.

Coupling of urban energy balance model with 3-D radiation model to derive human thermal (dis)comfort.

While capabilities in urban climate modeling have substantially increased in recent decades, the interdependency of changes in environmental surface properties and human (dis)comfort have only recently received attention. The open-source solar long-wave environmental irradiance geometry (SOLWEIG) model is one of the state-of-the-art models frequently used for urban (micro-)climatic studies. Here, we present updated calculation schemes for SOLWEIG allowing the improved prediction of surface temperatures (wall and ground). We illustrate that parameterizations based on measurements of global radiation on a south-facing vertical plane obtain better results compared to those based on solar elevation. Due to the limited number of ground surface temperature parameterizations in SOLWEIG, we implement the two-layer force-restore method for calculating ground temperature for various soil conditions. To characterize changes in urban canyon air temperature (Tcan), we couple the calculation method as used in the Town Energy Balance (TEB) model. Comparison of model results and observations (obtained during field campaigns) indicates a good agreement between modeled and measured Tcan, with an explained variance of R2 = 0.99. Finally, we implement an energy balance model for vertically mounted PV modules to contrast different urban surface properties. Specifically, we consider (i) an environment comprising dark asphalt and a glass facade and (ii) an environment comprising bright concrete and a PV facade. The model results show a substantially decreased Tcan (by up to - 1.65°C) for the latter case, indicating the potential of partially reducing/mitigating urban heat island effects.

Winter storm intensity, hazards, and property losses in the New York tristate area.

Winter storms pose numerous hazards to the Northeast United States, including rain, snow, strong wind, and flooding. These hazards can cause millions of dollars in damages from one storm alone. This study investigates meteorological intensity and impacts of winter storms from 2001 to 2014 on coastal counties in Connecticut, New Jersey, and New York and underscores the consequences of winter storms. The study selected 70 winter storms on the basis of station observations of surface wind strength, heavy precipitation, high storm tide, and snow extremes. Storm rankings differed between measures, suggesting that intensity is not easily defined with a single metric. Several storms fell into two or more categories (multiple-category storms). Following storm selection, property damages were examined to determine which types lead to high losses. The analysis of hazards (or events) and associated damages using the Storm Events Database of the National Centers for Environmental Information indicates that multiple-category storms were responsible for a greater portion of the damage. Flooding was responsible for the highest losses, but no discernible connection exists between the number of storms that afflict a county and the damage it faces. These results imply that losses may rely more on the incidence of specific hazards, infrastructure types, and property values, which vary throughout the region.

The New Immortalized Uroepithelial Cell Line HBLAK Contains Defined Genetic Aberrations Typical of Early Stage Urothelial Tumors.

Background: Cell culture models of normal urothelial cells are important for studying differentiation, disease mechanisms and anticancer drug development. Beyond primary cultures with their limitations in lifespan, interindividual heterogeneity and supply, few conditionally immortalized cell lines with limited applicability due to partial transformation or impaired differentiation capacity are available. We describe characteristics of the new spontaneously immortalized cell line HBLAK derived from a primary culture of uroepithelial cells. Objective: To characterize utility and limitations of HBLAK cells as an urothelial cell culture model. Methods: Differentiation markers were investigated by immunofluorescence and RT-PCR, genetic changes by standard karyotyping, array-CGH, PCR, RT-PCR and exome sequencing; expression of p53 and p21 by Western blotting. Results: HBLAK cells proliferated for >50 passages without senescing. They expressed cytokeratins of basal urothelial cells. Terminal differentiation markers appeared only after induction of differentiation by specific protocols. The karyotype was stable, with few chromosomal changes, especially gains of chromosomes 5 and 20 and a chromosome 9p21 deletion resulting in p16 INK4A loss. A C228T TERT promoter mutation was present, but no other mutation typical of urothelial carcinoma. TP53 was wild-type and the cell cycle was arrested in response to genomic stress. Conclusions: HBLAK cells retain some differentiation potential and respond to cytotoxic agents similar to normal urothelial cells, but contain genetic changes contributing to immortalization in urothelial tumors. HBLAK may be valuable for evaluating the tumor specificity of novel cancer drugs, but may also be applied as an urothelial in vitro carcinogenesis model.

Unscrambling the genomic chaos of osteosarcoma reveals extensive transcript fusion, recurrent rearrangements and frequent novel TP53 aberrations.

In contrast to many other sarcoma subtypes, the chaotic karyotypes of osteosarcoma have precluded the identification of pathognomonic translocations. We here report hundreds of genomic rearrangements in osteosarcoma cell lines, showing clear characteristics of microhomology-mediated break-induced replication (MMBIR) and end-joining repair (MMEJ) mechanisms. However, at RNA level, the majority of the fused transcripts did not correspond to genomic rearrangements, suggesting the involvement of trans-splicing, which was further supported by typical trans-splicing characteristics. By combining genomic and transcriptomic analysis, certain recurrent rearrangements were identified and further validated in patient biopsies, including a PMP22-ELOVL5 gene fusion, genomic structural variations affecting RB1, MTAP/CDKN2A and MDM2, and, most frequently, rearrangements involving TP53. Most cell lines (7/11) and a large fraction of tumor samples (10/25) showed TP53 rearrangements, in addition to somatic point mutations (6 patient samples, 1 cell line) and MDM2 amplifications (2 patient samples, 2 cell lines). The resulting inactivation of p53 was demonstrated by a deficiency of the radiation-induced DNA damage response. Thus, TP53 rearrangements are the major mechanism of p53 inactivation in osteosarcoma. Together with active MMBIR and MMEJ, this inactivation probably contributes to the exceptional chromosomal instability in these tumors. Although rampant rearrangements appear to be a phenotype of osteosarcomas, we demonstrate that among the huge number of probable passenger rearrangements, specific recurrent, possibly oncogenic, events are present. For the first time the genomic chaos of osteosarcoma is characterized so thoroughly and delivered new insights in mechanisms involved in osteosarcoma development and may contribute to new diagnostic and therapeutic strategies.

Climate variability modulates western US ozone air quality in spring via deep stratospheric intrusions.

Evidence suggests deep stratospheric intrusions can elevate western US surface ozone to unhealthy levels during spring. These intrusions can be classified as 'exceptional events', which are not counted towards non-attainment determinations. Understanding the factors driving the year-to-year variability of these intrusions is thus relevant for effective implementation of the US ozone air quality standard. Here we use observations and model simulations to link these events to modes of climate variability. We show more frequent late spring stratospheric intrusions when the polar jet meanders towards the western United States, such as occurs following strong La Niña winters (Niño3.4<-1.0 °C). While El Niño leads to enhancements of upper tropospheric ozone, we find this influence does not reach surface air. Fewer and weaker intrusion events follow in the two springs after the 1991 volcanic eruption of Mt. Pinatubo. The linkage between La Niña and western US stratospheric intrusions can be exploited to provide a few months of lead time during which preparations could be made to deploy targeted measurements aimed at identifying these exceptional events.

Hidden mutations in Cornelia de Lange syndrome limitations of sanger sequencing in molecular diagnostics.

Cornelia de Lange syndrome (CdLS) is a well-characterized developmental disorder. The genetic cause of CdLS is a mutation in one of five associated genes (NIPBL, SMC1A, SMC3, RAD21, and HDAC8) accounting for about 70% of cases. To improve our current molecular diagnostic and to analyze some of CdLS candidate genes, we developed and established a gene panel approach. Because recent data indicate a high frequency of mosaic NIPBL mutations that were not detected by conventional sequencing approaches of blood DNA, we started to collect buccal mucosa (BM) samples of our patients that were negative for mutations in the known CdLS genes. Here, we report the identification of three mosaic NIPBL mutations by our high-coverage gene panel sequencing approach that were undetected by classical Sanger sequencing analysis of BM DNA. All mutations were confirmed by the use of highly sensitive SNaPshot fragment analysis using DNA from BM, urine, and fibroblast samples. In blood samples, we could not detect the respective mutation. Finally, in fibroblast samples from all three patients, Sanger sequencing could identify all the mutations. Thus, our study highlights the need for highly sensitive technologies in molecular diagnostic of CdLS to improve genetic diagnosis and counseling of patients and their families.

Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial.

This largest prospective multicenter trial for adult patients with Burkitt lymphoma/leukemia aimed to prove the efficacy and feasibility of short-intensive chemotherapy combined with the anti-CD20 antibody rituximab. From 2002 to 2011, 363 patients 16 to 85 years old were recruited in 98 centers. Treatment consisted of 6 5-day chemotherapy cycles with high-dose methotrexate, high-dose cytosine arabinoside, cyclophosphamide, etoposide, ifosphamide, corticosteroids, and triple intrathecal therapy. Patients >55 years old received a reduced regimen. Rituximab was given before each cycle and twice as maintenance, for a total of 8 doses. The rate of complete remission was 88% (319/363); overall survival (OS) at 5 years, 80%; and progression-free survival, 71%; with significant difference between adolescents, adults, and elderly patients (OS rate of 90%, 84%, and 62%, respectively). Full treatment could be applied in 86% of the patients. The most important prognostic factors were International Prognostic Index (IPI) score (0-2 vs 3-5; P = .0005), age-adjusted IPI score (0-1 vs 2-3; P = .0001), and gender (male vs female; P = .004). The high cure rate in this prospective trial with a substantial number of participating hospitals demonstrates the efficacy and feasibility of chemoimmunotherapy, even in elderly patients. This trial was registered at www.clinicaltrials.gov as #NCT00199082.

A new workflow for whole-genome sequencing of single human cells.

Unbiased amplification of the whole-genome amplification (WGA) of single cells is crucial to study cancer evolution and genetic heterogeneity, but is challenging due to the high complexity of the human genome. Here, we present a new workflow combining an efficient adapter-linker PCR-based WGA method with second-generation sequencing. This approach allows comparison of single cells at base pair resolution. Amplification recovered up to 74% of the human genome. Copy-number variants and loss of heterozygosity detected in single cell genomes showed concordance of up to 99% to pooled genomic DNA. Allele frequencies of mutations could be determined accurately due to an allele dropout rate of only 2%, clearly demonstrating the low bias of our PCR-based WGA approach. Sequencing with paired-end reads allowed genome-wide analysis of structural variants. By direct comparison to other WGA methods, we further endorse its suitability to analyze genetic heterogeneity.

Target genes of recurrent chromosomal amplification and deletion in urothelial carcinoma.

BACKGROUND: Urothelial carcinoma (UC) is characterized by multiple recurrent chromosomal changes on a background of increasing genomic instability. To define target genes of recurrent deletions and amplifications, we explored which gene alterations are common in UC, in two recently established cell lines, BC44 and BC61. MATERIALS AND METHODS: Genes located in regions of gain or deletion in the cell lines were identified by array comparative genomic hybridization (aCGH). Six published microarray datasets were analyzed for genes differentially expressed between urothelial tumor vs. normal tissues. Gene expression and chromosomal changes were compared in BC61 cells. RESULTS: The cell lines share homozygous deletions at 9p21 around CDKN2A and amplifications at 11q13.2 around CCND1. In both cell lines 11 genes were commonly lost and 115 gained. Across UC in general, 230 genes were expressed stronger and 349 weaker; a subset displaying corresponding genetic changes in the cell lines. The commonly affected subset contains well-investigated genes like E2F1 and CCNE1, but also several genes not yet sufficiently investigated in UC. DISCUSSION: Our approach highlights genes involved in cell cycle regulation, apoptosis and signal transduction as commonly deregulated across UC. Nevertheless, many chromosomal regions undergoing recurrent changes harbor several commonly deregulated genes that may act jointly in UC development and progression.

The uncertainty of UTCI due to uncertainties in the determination of radiation fluxes derived from numerical weather prediction and regional climate model simulations.

In this study we examine the determination accuracy of both the mean radiant temperature (Tmrt) and the Universal Thermal Climate Index (UTCI) within the scope of numerical weather prediction (NWP), and global (GCM) and regional (RCM) climate model simulations. First, Tmrt is determined and the so-called UTCI-Fiala model is then used for the calculation of UTCI. Taking into account the uncertainties of NWP model (among others the HIgh Resolution Limited Area Model HIRLAM) output (temperature, downwelling short-wave and long-wave radiation) stated in the literature, we simulate and discuss the uncertainties of Tmrt and UTCI at three stations in different climatic regions of Europe. The results show that highest negative (positive) differences to reference cases (under assumed clear-sky conditions) of up to -21°C (9°C) for Tmrt and up to -6°C (3.5°C) for UTCI occur in summer (winter) due to cloudiness. In a second step, the uncertainties of RCM simulations are analyzed: three RCMs, namely ALADIN (Aire Limitée Adaptation dynamique Développement InterNational), RegCM (REGional Climate Model) and REMO (REgional MOdel) are nested into GCMs and used for the prediction of temperature and radiation fluxes in order to estimate Tmrt and UTCI. The inter-comparison of RCM output for the three selected locations shows that biases between 0.0 and ±17.7°C (between 0.0 and ±13.3°C) for Tmrt (UTCI), and RMSE between ±0.5 and ±17.8°C (between ±0.8 and ±13.4°C) for Tmrt (UTCI) may be expected. In general the study shows that uncertainties of UTCI, due to uncertainties arising from calculations of radiation fluxes (based on NWP models) required for the prediction of Tmrt, are well below ±2°C for clear-sky cases. However, significant higher uncertainties in UTCI of up to ±6°C are found, especially when prediction of cloudiness is wrong.

Involvement of the MLL gene in adult T-lymphoblastic leukemia.

While the MLL "recombinome" is relatively well characterized in B-cell precursor acute lymphoblastic leukemia (BCP ALL), available data for adult acute T-lymphoblastic leukemia (T-ALL) are scarce. We performed fluorescence in situ hybridization (FISH) for an MLL split signal on 223 adult T-ALL samples obtained within the framework of the German Multicenter ALL 07/2003 therapy trial. Three biphenotypic leukemias (T-ALL/AML) were also included in the analysis. Samples showing any alteration by FISH were further investigated to characterize the MLL aberration. In addition, they were investigated for common genetic lesions known in T-ALL. Twenty-two cases (9.5%) showed an abnormal MLL signal by FISH analysis. Most of these appeared to be deletions or gains but in five cases (2.1%) a chromosomal translocation involving the MLL gene was identified. The translocation partners and chromosomal breakpoints were molecularly characterized. Three T-ALLs had an MLL-AF6/t(6;11) and two biphenotypic leukemias had an MLL-ELL/t(11;19). The chromosomal breakpoints in two of the MLL-AF6-positive cases were located outside the classical MLL major breakpoint cluster known from BCP ALL. In conclusion, the spectrum of MLL translocation partners in adult T-ALL much more resembles that of AML than that of BCP ALL and thus the mechanisms by which MLL contributes to leukemogenesis in adult T-ALL appear to differ from those in BCP ALL. Proposals are made for the diagnostic assessment of MLL fusion genes in adult T-ALL.

Discovery of TP53 splice variants in two novel papillary urothelial cancer cell lines.

BACKGROUND: Using a novel cell culture technique, we established two new cell lines, BC44 and BC61, from papillary urothelial carcinoma and analyzed them for genetic changes typical of this tumor type. METHODS AND RESULTS: Karyotyping revealed aneuploid karyotypes with loss of chromosome 9 and rearranged chromosome 5p. Molecular analysis showed CDKN2A deletions but wild-type PIK3CA. BC61 contained a G372C FGFR3 mutation. TP53 was not mutated in either cell line and BC61 expressed normal full-length protein. In contrast, BC44 exclusively expressed cytoplasmic and nuclear p53Δ40 and 133 isoforms from the alternative promoter P2 as revealed by Western blotting, immunocytochemistry and PCR. The only discernible difference in TP53 in BC44 was homozygosity for the deletion allele of the rs17878362 polymorphism in the P2 promoter. Expression of p53 isoforms was also detected in a few other urothelial carcinoma cell lines and tumor cultures and in 4 out of 28 carcinoma tissues. CONCLUSION: In urothelial cancers, TP53 is typically inactivated by mutations in one allele and loss of the wildtype allele and more frequently in invasive compared to papillary carcinomas. We show that some urothelial carcinomas may predominantly or exclusively express isoforms which are not detected by commonly used antibodies to epitopes located in the p53 TA amino-terminal region. Expression of these isoforms may constitute a further mode of p53 inactivation in urothelial carcinoma. Our findings raise the question to which extent this mechanism may compromise wildtype p53 function in papillary tumors in particular, where point mutations in the gene are rare.

Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies.

Quantification of minimal residual disease (MRD) by real-time PCR directed to TCR and Ig gene rearrangements allows a refined evaluation of response in acute lymphoblastic leukemia (ALL). The German Multicenter Study Group for Adult ALL prospectively evaluated molecular response after induction/consolidation chemotherapy according to standardized methods and terminology in patients with Philadelphia chromosome-negative ALL. The cytologic complete response (CR) rate was 89% after induction phases 1 and 2. At this time point the molecular CR rate was 70% in 580 patients with cytologic CR and evaluable MRD. Patients with molecular CR after consolidation had a significantly higher probability of continuous complete remission (CCR; 74% vs 35%; P < .0001) and of overall survival (80% vs 42%; P = .0001) compared with patients with molecular failure. Patients with molecular failure without stem cell transplantation (SCT) in first CR relapsed after a median time of 7.6 months; CCR and survival at 5 years only reached 12% and 33%, respectively. Quantitative MRD assessment identified patients with molecular failure as a new high-risk group. These patients display resistance to conventional drugs and are candidates for treatment with targeted, experimental drugs and allogeneic SCT. Molecular response was shown to be highly predictive for outcome and therefore constitutes a relevant study end point. The studies are registered at www.clinicaltrials.gov as NCT00199056 and NCT00198991.