Solving ill-posed bilevel programs

This paper deals with ill-posed bilevel programs, i.e., problems admitting multiple lower-level solutions for some upper-level parameters. Many publications have been devoted to the standard optimistic case of this problem, where the difficulty is essentially moved from the objective function to the feasible set. This new problem is simpler but there is no guaranty to obtain local optimal solutions for the original optimistic problem by this process. Considering the intrinsic non-convexity of bilevel programs, computing local optimal solutions is the best one can hope to get in most cases. To achieve this goal, we start by establishing an equivalence between the original optimistic problem an a certain set-valued optimization problem. Next, we develop optimality conditions for the latter problem and show that they generalize all the results currently known in the literature on optimistic bilevel optimization. Our approach is then extended to multiobjective bilevel optimization, and completely new results are derived for problems with vector-valued upper- and lower-level objective functions. Numerical implementations of the results of this paper are provided on some examples, in order to demonstrate how the original optimistic problem can be solved in practice, by means of a special set-valued optimization problem

Persistence of pharmaceutical compounds and other organic wastewater contaminants in a conventional drinking-water-treatment plant

In a study conducted by the US Geological Survey and the Centers for Disease Control and Prevention, 24 water samples were collected at selected locations within a drinking-water-treatment (DWT) facility and from the two streams that serve the facility to evaluate the potential for wastewater-related organic contaminants to survive a conventional treatment process and persist in potable-water supplies. Stream-water samples as well as samples of raw, settled, filtered, and finished water were collected during low-flow conditions, when the discharge of effluent from upstream municipal sewage-treatment plants accounted for 37–67% of flow in stream 1 and 10–20% of flow in stream 2. Each sample was analyzed for 106 organic wastewater-related contaminants (OWCs) that represent a diverse group of extensively used chemicals.Forty OWCs were detected in one or more samples of stream water or raw-water supplies in the treatment plant; 34 were detected in more than 10% of these samples. Several of these compounds also were frequently detected in samples of finished water; these compounds include selected prescription and non-prescription drugs and their metabolites, fragrance compounds, flame retardants and plasticizers, cosmetic compounds, and a solvent. The detection of these compounds suggests that they resist removal through conventional water-treatment processes. Other compounds that also were frequently detected in samples of stream water and rawwater supplies were not detected in samples of finished water; these include selected prescription and non-prescription drugs and their metabolites, disinfectants, detergent metabolites, and plant and animal steroids. The non-detection of these compounds indicates that their concentrations are reduced to levels less than analytical detection limits or that they are transformed to degradates through conventional DWT processes. Concentrations of OWCs detected in finished water generally were low and did not exceed Federal drinking-water standards or lifetime health advisories, although such standards or advisories have not been established for most of these compounds. Also, at least 11 and as many as 17 OWCs were detected in samples of finished water. Drinking-water criteria currently are based on the toxicity of individual compounds and not combinations of compounds. Little is known about potential human-health effects associated with chronic exposure to trace levels of multiple OWCs through routes such as drinking water. The occurrence in drinking-water supplies of many of the OWCs analyzed for during this study is unregulated and most of these compounds have not been routinely monitored for in the Nation’s source- or potable-water supplies. This study provides the first documentation that many of these compounds can survive conventional water-treatment processes and occur in potable-water supplies. It thereby provides information that can be used in setting research and regulatory priorities and in designing future monitoring programs. The results of this study also indicate that improvements in water-treatment processes may benefit from consideration of the response of OWCs and other trace organic contaminants to specific physical and chemical treatments

The Transcriptional Response to DNA-Double-Strand Breaks in Physcomitrella patens

The model bryophyte Physcomitrella patens is unique among plants in supporting the generation of mutant alleles by facile homologous recombination-mediated gene targeting (GT). Reasoning that targeted transgene integration occurs through the capture of transforming DNA by the homology-dependent pathway for DNA double-strand break (DNA-DSB) repair, we analysed the genome-wide transcriptomic response to bleomycin-induced DNA damage and generated mutants in candidate DNA repair genes. Massively parallel (Illumina) cDNA sequencing identified potential participants in gene targeting. Transcripts encoding DNA repair proteins active in multiple repair pathways were significantly up-regulated. These included Rad51, CtIP, DNA ligase 1, Replication protein A and ATR in homology-dependent repair, Xrcc4, DNA ligase 4, Ku70 and Ku80 in non-homologous end-joining and Rad1, Tebichi/polymerase theta, PARP in microhomology-mediated end-joining. Differentially regulated cell-cycle components included up-regulated Rad9 and Hus1 DNA-damage-related checkpoint proteins and down-regulated D-type cyclins and B-type CDKs, commensurate with the imposition of a checkpoint at G2 of the cell cycle characteristic of homology-dependent DNA-DSB repair. Candidate genes, including ATP-dependent chromatin remodelling helicases associated with repair and recombination, were knocked out and analysed for growth defects, hypersensitivity to DNA damage and reduced GT efficiency. Targeted knockout of PpCtIP, a cell-cycle activated mediator of homology-dependent DSB resection, resulted in bleomycin-hypersensitivity and greatly reduced GT efficiency

Geologische Untersuchungen an Sedimenten des indisch-pakistanischen Kontinentalrandes (Arabischs Meer)

From the R./V. "Meteor" and the Pakistan F./V. "Machhera" sediments from the Indian-Pakistan continental margin habe been investigated in order to delineate the facies distribution of the recent deposits. One of the several objectives of this study was to find out how far the suspended matter of the Indus River is being transported into the Arabian Sea. A close genetic relationship was recognised between the oceanographic conditions of the water masses (chemistry and currents) and the characteristics of the sediments. The activity of the monsoons is reflected by the rhythmic lamination of the sediments of the upper continental slope. The suspended matter from the Indus River can be traced far into the Arabian Sea. The clay minerals show the following tendenciey from litoral to abyssal regions and from the top ot the cores downward: detrital clay minerals (chlorite, muscovite, illite) - degraded clay minerals (montmorillonite, mixed-layer minerals) - "re-formational" minerals (illite). The biostratigraphic investigations of the sedimentds combined with several C14-dates results in sedimentation rates from >50 cm/1000 years at the upper continental slope decreasing to about 1 cm/1000 years inhe faunal composition proves the existende of a climatic optimum during part of the Holocene. The geochemical investigation of the recent pore fluids demonstrates that their composition very soon assumes the characteristics of fossil inerstitial waters (cf. V. Marchig, in this vol.). The results will be published in Meteor-Forschungsergebnisse, Reihe C

Repurposing anthelmintic agents to eradicate resistant leukemia

Despite rapid progress in genomic profiling in acute lymphoblastic leukemia (ALL), identification of actionable targets and prediction of response to drugs remains challenging. To identify specific vulnerabilities in ALL, we performed a drug screen using primary human ALL samples cultured in a model of the bone marrow microenvironment combined with high content image analysis. Among the 2487 FDA-approved compounds tested, anthelmintic agents of the class of macrocyclic lactones exhibited potent anti-leukemia activity, similar to the already known anti-leukemia agents currently used in induction chemotherapy. Ex vivo validation in 55 primary ALL samples of both precursor B cell and T-ALL including refractory relapse cases confirmed strong anti-leukemia activity with IC50 values in the low micromolar range. Anthelmintic agents increased intracellular chloride levels in primary leukemia cells, inducing mitochondrial outer membrane depolarization and cell death. Supporting the notion that simultaneously targeting cell death machineries at different angles may enhance the cell death response, combination of anthelmintic agents with the BCL-2 antagonist navitoclax or with the chemotherapeutic agent dexamethasone showed synergistic activity in primary ALL. These data reveal anti-leukemia activity of anthelmintic agents and support exploiting drug repurposing strategies to identify so far unrecognized anti-cancer agents with potential to eradicate even refractory leukemia

Influence of CT dose reduction on AI-driven malignancy estimation of incidental pulmonary nodules

<jats:title>Abstract</jats:title><jats:sec> <jats:title>Objectives</jats:title> <jats:p>The purpose of this study was to determine the influence of dose reduction on a commercially available lung cancer prediction convolutional neuronal network (LCP-CNN).</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>CT scans from a cohort provided by the local lung cancer center (<jats:italic>n</jats:italic> = 218) with confirmed pulmonary malignancies and their corresponding reduced dose simulations (25% and 5% dose) were subjected to the LCP-CNN. The resulting LCP scores (scale 1–10, increasing malignancy risk) and the proportion of correctly classified nodules were compared. The cohort was divided into a low-, medium-, and high-risk group based on the respective LCP scores; shifts between the groups were studied to evaluate the potential impact on nodule management. Two different malignancy risk score thresholds were analyzed: a higher threshold of ≥ 9 (“rule-in” approach) and a lower threshold of > 4 (“rule-out” approach).</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>In total, 169 patients with 196 nodules could be included (mean age ± SD, 64.5 ± 9.2 year; 49% females). Mean LCP scores for original, 25% and 5% dose levels were 8.5 ± 1.7, 8.4 ± 1.7 (<jats:italic>p</jats:italic> > 0.05 vs. original dose) and 8.2 ± 1.9 (<jats:italic>p</jats:italic> < 0.05 vs. original dose), respectively. The proportion of correctly classified nodules with the “rule-in” approach decreased with simulated dose reduction from 58.2 to 56.1% (<jats:italic>p</jats:italic> = 0.34) and to 52.0% for the respective dose levels (<jats:italic>p</jats:italic> = 0.01). For the “rule-out” approach the respective values were 95.9%, 96.4%, and 94.4% (<jats:italic>p</jats:italic> = 0.12). When reducing the original dose to 25%/5%, eight/twenty-two nodules shifted to a lower, five/seven nodules to a higher malignancy risk group.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusion</jats:title> <jats:p>CT dose reduction may affect the analyzed LCP-CNN regarding the classification of pulmonary malignancies and potentially alter pulmonary nodule management.</jats:p> </jats:sec><jats:sec> <jats:title>Clinical relevance statement</jats:title> <jats:p>Utilization of a “rule-out” approach with a lower malignancy risk threshold prevents underestimation of the nodule malignancy risk for the analyzed software, especially in high-risk cohorts.</jats:p> </jats:sec><jats:sec> <jats:title>Key Points</jats:title> <jats:p><jats:italic>• LCP-CNN may be affected by CT image parameters such as noise resulting from low-dose CT acquisitions.</jats:italic></jats:p> <jats:p><jats:italic>• CT dose reduction can alter pulmonary nodule management recommendations by affecting the outcome of the LCP-CNN.</jats:italic></jats:p> <jats:p><jats:italic>• Utilization of a lower malignancy risk threshold prevents underestimation of pulmonary malignancies in high-risk cohorts.</jats:italic></jats:p> </jats:sec&gt

Phase I/Phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia

Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. Weevaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods This open-label study enrolled children , 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. Primary end points were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles (phase II). Results We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was 15 mg/m2d. Blinatumomab pharmacokinetics was linear across dosage levels and consistent among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 mg/m2d for the first 7 days, followed by 15 mg/m2d thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved complete minimal residual disease response. The most frequent grade $ 3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) interrupted treatment after grade 2 seizures. Conclusion This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important new treatment option in this setting, requiring further investigation in curative indications

Everolimus with or without mycophenolate mofetil for graft-versus-host disease prophylaxis after hematopoietic stem cell transplantation in children with acute kidney injury: a single-center retrospective Analysis

Hematopoietic stem cell transplantation (HSCT) serves as a therapeutic intervention for various pediatric diseases. Acute and chronic graft-versus-host disease (GVHD) are decisive determinants of successful allogeneic HSCT. The immunosuppressive agent cyclosporin A (CsA) is most often used to prevent GVHD in pediatric patients, but it is known to be nephrotoxic. Acute kidney injury (AKI) affects 17% to 47% of pediatric HSCT recipients, compromising clinical outcomes. This retrospective single-institution analysis scrutinized the practice of substituting nephrotoxic CsA with an everolimus/mycophenolate mofetil (MMF) combination as GVHD prophylaxis in 57 patients with AKI (n = 53) or central nervous system side effects due to calcineurin inhibitor (CNI) treatment (n = 4) following first allogeneic HSCT. This retrospective cohort study analyzed the clinical courses of 57 children who were switched from CNI-based GVHD prophylaxis (CsA or tacrolimus in single cases) to the everolimus/MMF combination (n = 48) or everolimus alone (n = 9) after undergoing their first allogeneic HSCT at the Charité University Medicine Berlin. Serving as a control group were 74 patients undergoing their first allogeneic HSCT during the same period who did not receive everolimus at any time post-transplantation. Patients undergoing mismatched family donor transplantation without subsequent CNI treatment for GVHD prophylaxis were excluded. Study endpoints encompassed the retention parameter course subsequent to the GVHD prophylaxis switch, overall survival (OS), and incidences of underlying disease relapse and acute and chronic GVHD in both treatment groups. Renal function improved significantly after switching from CsA to the everolimus/MMF combination. Crucially, the transition to everolimus did not adversely affect OS following HSCT (hazard ratio [HR], 1.6; 95% confidence interval [CI], 0.74 to 3.5; P = .23), especially for patients with nonmalignant diseases (HR, 1.4; 95% CI, 0.34 to 5.9; P = .64). The incidences of grade III-IV acute GVHD (HR, 1.82; 95% CI, 0.45 to 7.4; P = .40) and severe chronic GVHD (HR, 2.76; 95% CI, 0.69 to 11.0; P = .15) were comparable in patients treated with the everolimus/MMF combination and those receiving standard CsA treatment in the control group. OS in patients with malignant underlying diseases was lower in the everolimus group (HR, 2.7; 95% CI, 1.1 to 6.9; P = .03), however, event-free survival was similar in patients with an underlying malignant disease treated with either the everolimus/MMF combination or CsA (HR, 0.87; 95% CI, 0.39 to 1.9; P = .73). Renal function improved significantly in patients who switched their immunosuppression regimen from CsA to everolimus with or without MMF cotreatment after diagnosis of AKI. Patient outcomes in the everolimus group were comparable to those in the control group. This study provides compelling real-world clinical evidence to support replacing CsA with the everolimus/MMF combination in the management of AKI following HSCT in children