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The article discusses the imminent transformation of preclinical drug development driven by emerging technologies and regulatory changes, particularly the shift away from traditional animal testing in favor of innovative 3D organotypic culture systems.It mentions that these advancements aim to enhance the predictiveness of drug testing, address environmental and ethical concerns, and mark the beginning of a new era in drug development.

The article discusses the role of sex in evolution. Topics include research that suggests sexual reproduction is nearly ubiquitous in nature, research at the Interface of evolution and computer science (CS) suggesting evolution under sex possesses a multifaceted computational nature, the universal nature of sex in life among animals and plants, and the search in population genetics for a quantity optimized by natural selection. INSETS: Charles Babbage on Evolution;The Equation that Reconciled Darwin and Mendel;The Red-Blue Tree Theorem.

LISTEN: PUBLISHERS WEEKLY ASKED US TO DO A 3-PAGE ESSAY ON WHY WE WROTE "LOGICOMIX" WHY WE "WROTE IT"? I'VE NO IDEA, I JUST DREW IT! AND I COLORED ZE [...]

BackgroundGene panel testing has become the norm for assessing breast cancer (BC) susceptibility, but actual cancer risks conferred by genes included in panels are not established. Contrarily, deciphering the missing hereditability on BC, through identification of novel candidates, remains a challenge. We aimed to investigate the mutation prevalence and spectra in a highly selected cohort of Greek patients with BC, questioning an extensive number of genes, implicated in cancer predisposition and DNA repair, while calculating gene-specific BC risks that can ultimately lead to important associations.MethodsTo further discern BC susceptibility, a comprehensive 94-cancer gene panel was implemented in a cohort of 1382 Greek patients with BC, highly selected for strong family history and/or very young age (<35 years) at diagnosis, followed by BC risk calculation, based on a case–control analysis.ResultsHerein, 31.5% of patients tested carried pathogenic variants (PVs) in 28 known, suspected or candidate BC predisposition genes. In total, 24.8% of the patients carried BRCA1/2loss-of-function variants. An additional 6.7% carried PVs in additional genes, the vast majority of which can be offered meaningful clinical changes. Significant association to BC predisposition was observed for ATM, PALB2, TP53, RAD51Cand CHEK2PVs. Primarily, compared with controls, RAD51CPVs and CHEK2damaging missense variants were associated with high (ORs 6.19 (Exome Aggregation Consortium (ExAC)) and 12.6 (Fabulous Ladies Over Seventy (FLOSSIES)), p<0.01) and moderate BC risk (ORs 3.79 (ExAC) and 5.9 (FLOSSIES), p<0.01), respectively.ConclusionStudying a large and unique cohort of highly selected patients with BC, deriving from a population with founder effects, provides important insight on distinct associations, pivotal for patient management.

Goodness–of–fit tests for the distribution of the composed error term in a Stochastic Frontier Model (SFM) are suggested. The focus is on the case of a normal/gamma SFM and the heavy–tailed stable/gamma SFM. In the first case the moment generating function is used as tool while in the latter case the characteristic function of the error term is employed. In both cases our test statistics are formulated as weighted integrals of properly standardized data. The new normal/gamma test is consistent, and is shown to have an intrinsic relation to moment–based tests. The finite–sample behavior of resampling versions of both tests is investigated by Monte Carlo simulation, while several real–data applications are also included.

PALB2loss-of-function variants play an important role in breast, pancreatic and possibly, ovarian and gastric cancer susceptibility. Their frequency can be influenced by founder effects, already described in some populations. Herein, we have assessed the possible founder effect of PALB2c.2257C>T (p.Arg753*) truncating variant among Greek breast cancer patients, while investigating possible correlations with cancer diagnoses. Following a lead deriving from a background study of highly selected Greek breast cancer patients, a total of 2496 breast and 697 ovarian cancer patients were directly genotyped for the PALB2c.2257C>T truncating variant. Consequently, haplotype analysis was conducted on identified carriers, using seven microsatellite markers. The prevalence of the PALB2variant was 0.24% (6/2496) and 0.14% (1/697) among breast and ovarian cases, respectively. Family history seems to be an important factor for the variant identification, although not reaching statistical significance. Microsatellite analysis on 12 carriers revealed a common shared haplotype, spanning a chromosomal region of ~1.2 Mb; the variant was possibly introduced in the Greek population ~1600 years ago. The variant confers high breast cancer risk, as illustrated by comparison with publicly available control groups. Genetic testing for PALB2, especially for the Greek founder c.2257C>T truncating variant, should be seriously considered in Greek breast cancer cases, since such findings could assist appropriate clinical management for the patients and their families.

The article focuses on the use of algorithms for computing complex mathematical and logical problems. In principle, a problem by which and algorithm can be devised, may be solved mechanically. However, there are problems that can be solved in principle, but for which there are only inefficient algorithms. The Eulerian graph, a solution named after its proponent, mathematician Leonhard Euler, which determines the size and shape of islands and the length of bridges is presented. Mathematical figures called polynomials are discussed.

The article discusses the use of computational complexity and intractability to assist scientists in better understanding the means by which humans make decisions and process information. A discussion of the differences between a Turing machine and real computers is presented including issues of finite storage space and limits of time needed to find an answer. Other topics include complexity theory used to classify the hardness of problems, problems that can be solved in polynomial time, and nondeterministic Turing machines performing factorization.

RAD51Dgene’s protein product is known to be involved in the DNA repair mechanism by homologous recombination. RAD51Dgermline mutations have been recently associated with ovarian and breast cancer (OC and BC, respectively) predisposition. Our aim was to evaluate the frequency of hereditary RAD51Dmutations in Greek patients. To address this, we have screened for RAD51Dgermline mutations 609 BRCA1- and BRCA2-negative patients diagnosed with OC, unselected for age or family history, and 569 BC patients diagnosed under 55 years and with an additional relative with BC or OC. We identified four pathogenic mutations in four unrelated individuals with family history of BC and/or OC. Three of the RAD51Dcarriers had developed BC, while the other one was an OC patient, thus accounting for a mutation frequency of 0.16% in the OC cohort and 0.53% in the BC cohort. One of the detected mutations is novel (c.738 + 1G > A), whereas the rest had been detected previously (p.Gln151Ter, p.Arg186Ter, and p.Arg300Ter). It is noteworthy that the 4 carrier families had 13 BC cases and only 4 OC cases. Our data support that RAD51Dshould be implemented into the comprehensive multigene panel, as mutation carriers may benefit from the administration of PARP inhibitors.

A response is offered to letters to the editor, which commented on the article "Sex As an Algorithm:The Theory of Evolution Under the Lens of Computation,” by this letter's authors in the November 2016 issue.

Scientific Freedom and Human Rights of Computer Professionals--1989 As was the case in previous reports published by this editor, the focus of this report is restricted to computer professionals whose […]

During the past decade the theory that high-grade extrauterine pelvic tumors originate from the fallopian tube has been strongly suggested. Our study, aims to illuminate the possible role of tubal cytology as an accessory identification tool for gynecological extrauterine malignancies allowing in the long term the implementation of population-level cytologic tube evaluation during all benign gynecologic surgeries that do not result in salpingectomy.

Human brains are prone to neurodegeneration, given that endogenous neural stem/progenitor cells (NSPCs) fail to support neurogenesis. To investigate the molecular programs potentially mediating neurodegeneration-induced NSPC plasticity in regenerating organisms, we generated an Amyloid-β42 (Aβ42)-dependent neurotoxic model in adult zebrafish brain through cerebroventricular microinjection of cell-penetrating Aβ42 derivatives. Aβ42 deposits in neurons and causes phenotypes reminiscent of amyloid pathophysiology: apoptosis, microglial activation, synaptic degeneration, and learning deficits. Aβ42 also induces NSPC proliferation and enhanced neurogenesis. Interleukin-4 (IL4) is activated primarily in neurons and microglia/macrophages in response to Aβ42 and is sufficient to increase NSPC proliferation and neurogenesis via STAT6 phosphorylation through the IL4 receptor in NSPCs. Our results reveal a crosstalk between neurons and immune cells mediated by IL4/STAT6 signaling, which induces NSPC plasticity in zebrafish brains.

Competitive equilibrium from equal incomes (CEEI) is a well-known fair allocation mechanism with desirable fairness and efficiency properties; however, with indivisible resources, a CEEI may not exist [Foley 1967; Varian 1974; Thomson and Varian 1985]. It was shown in Budish [2011] that in the case of indivisible resources, there is always an allocation, called A-CEEI, that is approximately fair, approximately truthful, and approximately efficient for some favorable approximation parameters. A heuristic search that attempts to find this approximation is used in practice to assign business school students to courses. In this article, we show that finding the A-CEEI allocation guaranteed to exist by Budish’s theorem is PPAD-complete. We further show that finding an approximate equilibrium with better approximation guarantees is even harder: NP-complete.

Two years ago, the theatre company Complicite celebrated the capacity of art to explore complex mathematics with a kaleidoscopic bricolage of original staging and technology it called A Disappearing Number. [...]

Pancreatic cancer is the fourth leading cause of cancer-related death. Most patients present with an advanced stage of disease that has a dismal outcome, with a median survival of approximately 6 months. Evidently, there is a clear need for the development of new agents with novel mechanisms of action in this disease. A number of biological agents modulating different signal transduction pathways are currently in clinical development, inhibiting angiogenesis and targeting epidermal growth factor receptor, cell cycle, matrix metalloproteinases, cyclooxygenase-2, mammalian target of rapamycin, or proteasome. This is the first systematic review of the literature to synthesize all available data coming from trials and evaluate the efficacy and safety of molecular targeted drugs in unresectable and metastatic pancreatic cancer. However, it should be stressed that although multiple agents have been tested, only 9 phase 3 trials have been conducted and one agent (erlotinib) has been approved by the Food and Drug Administration for use in clinical practice. As knowledge accumulates on the molecular mechanisms underlying carcinogenesis in the pancreas, the anticipated development and assessment of molecularly targeted agents may offer a promising perspective for a disease which, to date, remains incurable.

We show that the widely used homotopy method for solving fixpoint problems, as well as the Harsanyi-Selten equilibrium selection process for games, are PSPACE-complete to implement. Extending our result for the Harsanyi-Selten process, we show that several other homotopy-based algorithms for finding equilibria of games are also PSPACE-complete to implement. A further application of our techniques yields the result that it is PSPACE-complete to compute any of the equilibria that could be found via the classical Lemke-Howson algorithm, a complexity-theoretic strengthening of the result in Savani and von Stengel [2006]. These results show that our techniques can be widely applied and suggest that the PSPACE-completeness of implementing homotopy methods is a general principle.

The main indication of prophylactic mastectomy pertains to BRCA1 or BRCA2 mutation carriers. Prophylactic mastectomy includes the simple method and the subcutaneous method. Both methods can be followed by breast plastic reconstruction either at the same time or later. This review examines key issues regarding prophylactic mastectomy: the selection of patients, its effectiveness, its limitations, convergence/divergence in existing guidelines, and future perspectives.

Background and aims Primary malignant peritoneal mesothelioma is a rare malignancy with an unfavorable prognosis. Pemetrexed has proven effective in the treatment of malignant mesothelioma, alone or in combination with platinum agents. In the present study, chemo-naïve patients were evaluated for the efficacy and safety of the pemetrexed-cisplatin combination.Methods Six patients with diffuse peritoneal mesothelioma were treated with 6 cycles of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2). Chemotherapy was administered on an outpatient basis every 3 weeks.Results Complete response was observed in 2 patients (33%) and partial response was observed in 3 patients (50%). The estimated median overall survival was 24 months and the estimated median time to disease progression was 9.5 months. The regimen was well tolerated.Conclusions Though our data reflect a small sample size, pemetrexed plus cisplatin accomplished a particularly high clinical benefit rate on chemo-naïve patients. Free full text available at www.tumorionline.it

Abstract: Currently, randomized phase III trials have demonstrated that docetaxel is an effective strategy in the adjuvant treatment of breast cancer. However, previous attempts to incorporate docetaxel with an anthracycline in a dosedense regimen have been unsuccessful. Therefore, new schedules containing both drugs should be explored. Forty-four patients with high-risk operable breast cancer entered this feasibility study. They were treated with three cycles of epirubicin 110 mg/m2 every 2 wk with G-CSF followed by three cycles of “intensified” CMF (840 mg/m2 cyclophosphamide; 57 mg/m2 methotrexate; 840 mg/m2 fluorouracil) every 2 wk with G-CSF followed 3 wk later by nine weekly cycles of 35 mg/m2 docetaxel (E-CMF-doc). Totally, 39 patients (89%) received all cycles of chemotherapy. The vast majority (92%) of cycles were administered at full dose. Therefore, dose intensity was sufficiently maintained for all drugs. Toxicity was generally mild to moderate. Most frequently recorded side effects apart from alopecia were neutropenia (54%) and nausea/vomiting (89%). Infection developed in nine patients. Two cases of febrile neutropenia were reported. The E-CMF-doc regimen, as used in this study, is feasible and well tolerated. Its impact on survival should be evaluated in phase III trials.

We present a cubic-time algorithm for the following problem: Given a simple graph, decide whether it is realized by adjacencies of countries in a map without holes, in which at most four countries meet at any point.We present a cubic-time algorithm for the following problem: Given a simple graph, decide whether it is realized by adjacencies of countries in a map without holes, in which at most four countries meet at any point.

We show that the traveling salesman problem with triangle inequality cannot be approximated with a ratio better than $$ \frac{{117}} {{116}} $$when the edge lengths are allowed to be asymmetric and $$ \frac{{220}} {{219}} $$when the edge lengths are symmetric, unless P=NP. The best previous lower bounds were $$ \frac{{2805}} {{2804}} $$and $$ \frac{{3813}} {{3812}} $$respectively. The reduction is from Håstad’s maximum satisfiability of linear equations modulo 2, and is nonconstructive.We show that the traveling salesman problem with triangle inequality cannot be approximated with a ratio better than $$ \frac{{117}} {{116}} $$when the edge lengths are allowed to be asymmetric and $$ \frac{{220}} {{219}} $$when the edge lengths are symmetric, unless P=NP. The best previous lower bounds were $$ \frac{{2805}} {{2804}} $$and $$ \frac{{3813}} {{3812}} $$respectively. The reduction is from Håstad’s maximum satisfiability of linear equations modulo 2, and is nonconstructive.

Summary Paclitaxel (TaxolR) and carboplatin are an effective combination regimen for treating advanced breast cancer. Gefitinib (IRESSA) is the first epidermal growth factor receptor tyrosine kinase inhibitor to be approved for cancer treatment. This multicenter phase II trial treated 68 patients with advanced breast cancer with paclitaxel (175 mg/m2 over 3 h) and 3-weekly carboplatin (area under the curve of 6) for six cycles, and 250 mg/day gefitinib orally. Median age was 57 (range 35–77) years, patients had performance status 0 (69.1%), 1 (27.9%) 2 (2.9%), 82.4% of patients had visceral metastases and 63.2% had received adjuvant chemotherapy. Forty-eight (70.6%) patients completed six cycles of chemotherapy and 20 (29.4%) patients discontinued treatment (seven [10.3%] due to disease progression, seven [10.3%] due to toxicity, five [7.4%] withdrew consent and one [1.5%] died after the first cycle). Sixty-three (92.7%) patients were evaluable for response; nine (13.2%) had complete responses, 30 (44.1%) had partial responses, 21 (30.9%) had stable disease and three (4.4%) had disease progression. Grade 3/4 adverse events in =5% of patients except of alopecia, included neutropenia (17.7%), anemia (10.3%), diarrhea (7.4%), thrombocytopenia (5.9%) and peripheral neuropathy (5.9%). Of those tumor biopsies available for immunohistochemical analysis (n=60), 5.0% were positive and 35.0% negative for expression of all HER-family receptors. Comparable numbers of tumor biopsies were nuclear p27kipl positive and negative (39.7 and 42.7%, respectively), with the majority (72.1%) negative for cytoplasmic p27kipl. The observed efficacy data in this study were similar to those reported for the combination of paclitaxel and carboplatin alone.

The author presents a personal narrative of the history of his admiration for mathematician Alan Turing which includes studying the Turing machine as an engineering student, attending Princeton University, and writing the novel "Turing."

For years, the conventional wisdom [7, 22] has been that the continued stability of the Internet depends on the widespread deployment of "socially responsible" congestion control. In this paper, we seek to answer the following fundamental question: If network end-points behaved in a selfish manner, would the stability of the Internet be endangered?.We evaluate the impact of greedy end-point behavior through a game-theoretic analysis of TCP. In this "TCP Game" each flowattempts to maximize the throughput it achieves by modifying its congestion control behavior. We use a combination of analysis and simulation to determine the Nash Equilibrium of this game. Our question then reduces to whether the network operates efficiently at these Nash equilibria.Our findings are twofold. First, in more traditional environments -- where end-points use TCP Reno-style loss recovery and routers use drop-tail queues -- the Nash Equilibria are reasonably efficient. However, when endpoints use more recent variations of TCP (e.g., SACK) and routers employ either RED or drop-tail queues, the Nash equilibria are very inefficient. This suggests that the Internet of the past could remain stable in the face of greedy end-user behavior, but the Internet of today is vulnerable to such behavior. Second, we find that restoring the efficiency of the Nash equilibria in these settings does not require heavy-weight packet scheduling techniques (e.g., Fair Queuing) but instead can be done with a very simple stateless mechanism based on CHOKe [21].

Synthetic and isolation procedures are described that allow access to the new complexes [Ln(O 2 CMe)(bicH 2 )(phen)(H 2 O)](ClO 4 )·phen·3H 2 O, where Ln=Gd( 1 ), Er( 2 ), Pr( 3 ) and Nd( 4 ), bicH 2 =the monoanion of N , N -bis(2-hydroxyethyl)glycine (bicine) and phen=1,10-phenanthroline. The structure of 1 has been determined by single-crystal X-ray crystallography. The Gd ion is in a 9-coordinate, tricapped trigonal prismatic ligand environment. The acetate and phen ligands are bidentate chelating, while the bicinate(−1) ion functions as a tetradentate chelate with the ligated atoms being the nitrogen, the two hydroxyl oxygens and one of the carboxylate oxygens. The crystal structure is stabilized by H bonds and aromatic stacking interactions. Complexes 2 , 3 and 4 seem to be isostructural with 1 . The complexes were characterized by elemental analyses, thermal techniques, room temperature magnetic moments and spectroscopic (IR, far-IR, solid state f - f ) methods. All data are discussed in terms of the nature of bonding and known or assigned structures.

Given a set of communication tasks (best described in terms of a weighted bipartite graph where one set of nodes denotes the senders, the other set the receivers, edges are communication tasks, and the weight of an edge is the time required for transmission), we wish to minimize the total time required for the completion of all communication tasks assuming that tasks can be preempted (that is, each edge can be subdivided into many edges with weights adding up to the edge's original weight) and that preemption comes with a cost. In this paper, we first prove that one cannot approximate this problem within a factor smaller than $$\frac{7}{6}$$ unless P=NP. It is known that a simple approximation algorithm achieves within a ratio of two (H. Choi and S.L. Hakimi, Algorithmica, vol. 3, pp. 223–245, 1988). However, our experimental results show that its performance is worse than the originally proposed heuristic algorithm (I.S. Gopal and C.K. Wong, IEEE Transactions on Communications, vol. 33, pp. 497–501, 1985). We devise a more sophisticated algorithm, called the potential function algorithmwhich, on the one hand, achieves a provable approximation ratio of two, and on the other hand, shows very good experimental performance. Moreover, the way in which our more sophisticated algorithm derives from the simple one, suggests a hierarchy of algorithms, all of which have a worst-case performance at most two, but which we suspect to have increasingly better performance, both in worst case and with actual instances.

We investigate cost-sharing algorithms for multicast transmission. Economic considerations point to two distinct mechanisms, marginal costand Shapley value, as the two solutions most appropriate in this context. We prove that the former has a natural algorithm that uses only two messages per link of the multicast tree, while we give evidence that the latter requires a quadratic total number of messages. We also show that the welfare value achieved by an optimal multicast tree is NP-hard to approximate within any constant factor, even for bounded-degree networks. The lower-bound proof for the Shapley value uses a novel algebraic technique for bounding from below the number of messages exchanged in a distributed computation; this technique may prove useful in other contexts as well.

A 21‐year‐old man had histologically‐confirmed diffuse cutaneous leiomyomatosis. The lesions showed a peculiar distribution in that they predominantly involved several segments of the right side of his body; in addition, less extensive, nonsegmental lesions were present on both sides of the body. Although this case was apparently sporadic, the genetic mechanism of loss of heterozygosity provides a plausible explanation for this unusual presentation. If the patient were heterozygous for the underlying mutation, at an early developmental stage a postzygotic event of loss of heterozygosity would have given rise to a type 2 segmental involvement, resulting in pronounced lesions superimposed on the disseminated tumors of the ordinary phenotype.

Reaction of CuIIsalts with phenanthroline and oxalate (ox) or oxamate (oxm) gives [Cu(phen)(ox)(H2O)] · H2O or [Cu(phen)(oxm)(H2O)] · H2O complexes while direct treatment of CuIIsalts with oxalate or oxamate gives [NH4]2[Cu(ox)2] and [Cu(oxm)2(H2O)2] respectively. The X-ray structures of one example of each system, aquo-oxamato-phenanthroline-copper(II)-dihydrate and the polymeric ammonium-bis(aquo)-tetraoxalato-dicopper(II)-dihydrate, are reported.

Comparative genomic hybridization (CGH) is a laboratory method to measure gains and losses in the copy number of chromosomal regions in tumor cells. It is hypothesized that certain DNA gains and losses are related to cancer progression and that the patterns of these changes are relevant to the clinical consequences of the cancer. It is therefore of interest to develop models which predict the occurrence of these events, as well as techniques for learning such models from CGH data. We continue our study of the mathematical foundations for inferring a model of tumor progression from a CGH data set that we started in Desper et al. (1999). In that paper, we proposed a class of probabilistic tree models and showed that an algorithm based on maximum-weight branching in a graph correctly infers the topology of the tree, under plausible assumptions. In this paper, we extend that work in the direction of the so-called distance-based trees, in which events are leaves of the tree, in the style of models common in phylogenetics. Then we show how to reconstruct the distance-based trees using tree-fitting algorithms developed by researchers in phylogenetics. The main advantages of the distance-based models are that 1) they represent information about co-occurrences of all pairs of events, instead of just some pairs, 2) they allow quantitative predictions about which events occur early in tumor progression, and 3) they bring into play the extensive methodology and software developed in the context of phylogenetics. We illustrate the distance-based tree method and how it complements the branching tree method, with a CGH data set for renal cancer.

Abstract.:  The construction of a liquid triphenyltetrazolium cation (TT+) ion-selective electrode (ISE) based on [TT+]3[P(W3O10)4] salt dissolved in 2-nitrotoluene is described. The liquid membrane electrode exhibits a rapid and almost Nernstian response to triphenyltetrazolium cations in the concentration range from 2×10−4 to 1×10−2 mol l−1. The Nernstian slope is 56–58 mV decade−1 which remains constant for at least two months. The response is virtually unaffected by pH changes in the range 3–12. Major interferents are periodate and malate. Deviation from linearity is also observed in the presence of bromide, iodide and thiocyanate, due to their precipitation with triphenyltetrazolium cations. Analytical applications such as direct potentiometry for the determination of TT+ in aqueous solutions and indirect potentiometry for the assay of ascorbic acid (vitamin C) in pharmaceutical preparations are described. Ascorbic acid in the range of 150–500 mg l−1, under specified experimental conditions, can be determined with mean relative error of 1.9%.

Latent semantic indexing (LSI) is an information retrieval technique based on the spectral analysis of the term-document matrix, whose empirical success had heretofore been without rigorous prediction and explanation. We prove that, under certain conditions, LSI does succeed in capturing the underlying semantics of the corpus and achieves improved retrieval performance. We propose the technique of random projectionas a way of speeding up LSI. We complement our theorems with encouraging experimental results. We also argue that our results may be viewed in a more general framework, as a theoretical basis for the use of spectral methods in a wider class of applications such as collaborative filtering.

Objectives.Both paclitaxel and cisplatin have moderate activity in patients with metastatic or recurrent carcinoma of the endometrium, and the combination of these two agents has shown activity in a variety of solid tumors. We administered this combination to patients with metastatic or recurrent carcinoma of the endometrium to evaluate its activity and to define its toxicity.

High-dose chemotherapy with autologous peripheral blood progenitor cell (PBPC) support has become a widely used treatment strategy. In order to simplify the procedure, a single very large-volume leukapheresis programme combined with short-term refrigerated storage of the PBPC was developed. Seventy-two patients suffering from various relatively chemosensitive malignancies received high-dose chemotherapy, consisting of agents with short in vivo half-lives and 24 to 48 hours later, the refrigerated PBPC were reinfused. A single very large-volume apheresis was sufficient to obtain at least 2 × 10⁶/kg CD34+ cells in 58 patients (81%), and 63% had at least 2.5 × 10⁶ CD34+ cells/kg. Only two patients (3%) were transplanted with less than 1 × 10⁶ CD34+ cells/kg. In three patients (4%) leukapheresis was repeated because of insufficient number of PBPC. The median CD34+ cell count was 3 × 10⁶/kg. A median of 38.5 L blood (range, 21 to 59) was processed, which accounted for a median of 9 × patient's total blood volume. Very large-volume leukapharesis was well tolerated with symptomatic hypocalcemia being the most common (18%) side-effect. The median time to neutrophils >1.5 × 10⁹/L, and to self-supporting platelet count >25 × 10⁹/L, was 10 and 12 days after reinfusion of PBPC graft, respectively. There were no treatment-related deaths. Our results indicate that this simplified approach of PBPC transplantation can be associated with prompt hematologic recovery in most patients and that it can be useful in settings where facilities are limited or for certain diseases where conditioning regimens with short half-life are appropriate. J. Clin. Apheresis, 15:236–241, 2000. © 2000 Wiley-Liss, Inc.

We present a rigorous framework, based on optimization, for evaluating data mining operations such as associations and clustering, in terms of their utility in decision-making. This framework leads quickly to some interesting computational problems related to sensitivity analysis, segmentation and the theory of games.

We revisit the issue of the complexity of database queries, in the light of the recent parametricrefinement of complexity theory. We show that, if the query size (or the number of variables in the query) is considered as a parameter, then the relational calculus and its fragments (conjunctive queries, positive queries) are classified at appropriate levels of the so-called W hierarchy of Downey and Fellows. These results strongly suggest that the query size is inherently in the exponent of the data complexity of any query evaluation algorithm, with the implication becoming stronger as the expressibility of the query language increases. On the positive side, we show that this exponential dependence can be avoided for the extension of acyclic queries with ≠ (but not <) inequalities.

We wish to explore all edges of an unknown directed, strongly connected graph. At each point, we have a map of all nodes and edges we have visited, we can recognize these nodes and edges if we see them again, and we know how many unexplored edges emanate from each node we have visited, but we cannot tell where each leads until we traverse it. We wish to minimize the ratio of the total number of edges traversed divided by the optimum number of traversals, had we known the graph. For Eulerian graphs, this ratio cannot be better than two, and two is achievable by a simple algorithm. In contrast, the ratio is unbounded when the deficiency of the graph (the number of edges that have to be added to make it Eulerian) is unbounded. Our main result is an algorithm that achieves a bounded ratio when the deficiency is bounded. © 1999 John Wiley & Sons, Inc. J Graph Theory 32: 265–297, 1999

Interleukin-4 (IL-4) plays an important role in activating the immune system against malignant cells. The human interleukin-4 receptor (hIL-4R) is not only expressed by hematopoietic cells but also on a large number of tissue specimens which include colon, breast and lung carcinomas. In this study we report that rhlL-4 has m antiproliferative effect on 2 out of 3 non-small cell lung carcinoma (NSCLC) cell lines in vitro as measured by human tumor cloning assays (HTCA). In comparison, rhIL-4 had no effect on the growth of small cell lung carcinoma cell lines (SCLC) in vitro. The re-sponse towards the cytokine is correlated with expression of at least I500 high affinity receptordcell for hIL-4 on the responsive cell lines. Xenotransplanting the human lung tumor cell lines into nude mice followed by 12 days of systemic treatment of the mice with rhIL-4 revealed a significant growth retardation of the IL-4R positive NSCLC cell lines when compared with the controls, whereas the growth of the IL-4R negative SCLC cell lines was unaffected also in vivo. Studies of possible mechanisms involved in the antiproliferative effect of rhlL-4 showed that rhlL-4 does not induce apoptosis or modulation of the transcription factor c-myc in the responsive NSCLC cell lines. Additionally, the expression of the epidermal growth factor receptor (EGFR), which is discussed as mediating autocrine/paracrine growth stimulation of NSCLC, is unaffected by rhlL-4. However, we have observed that rhIL-4 inhibited GI-S-phase cell cycle progression. We conclude that rhIL-4 has an antiproliferative effect on the growth of some NSCLC in vitro and in vivo. The mechanisms involved remain to be further elucidated.

We characterize precisely the complexity of several natural computational problems in NP, which have been proposed but not categorized satisfactorily in the literature: Computing the Vapnik–Chervonenkis dimension of a 0–1 matrix; finding the minimum dominating set of a tournament; satisfying a Boolean expression by perturbing the default truth assignment; and several others. These problems can be solved innO(logn)time, and thus, they are probably not NP-complete. We define two new complexity classes between P and NP, very much in the spirit of MAXNP and MAXSNP. We show that computing the V–C dimension is complete for the more general class, while the other two problems are complete for the weaker class.

The problem of determining shortest paths through a weighted planar polygonal subdivision with n vertices is considered. Distances are measured according to a weighted Euclidean metric: The length of a path is defined to be the weighted sum of (Euclidean) lengths of the subpaths within each region. An algorithm that constructs a (restricted) “shortest path map” with respect to a given source point is presented. The output is a partitioning of each edge of the subdivion into intervals of ε-optimality, allowing an ε-optimal path to be traced from the source to any query point along any edge. The algorithm runs in worst-case time O(ES) and requires O(E) space, where E is the number of “events” in our algorithm and S is the time it takes to run a numerical search procedure. In the worst case, E is bounded above by O(n4) (and we give an Ω(n4) lower bound), but it is likeky that E will be much smaller in practice. We also show that S is bounded by O(n4L), where L is the precision of the problem instance (including the number of bits in the user-specified tolerance ε). Again, the value of S should be smaller in practice. The algorithm applies the “continuous Dijkstra” paradigm and exploits the fact that shortest paths obey Snell's Law of Refraction at region boundaries, a local optimaly property of shortest paths that is well known from the analogous optics model. The algorithm generalizes to the multi-source case to compute Voronoi diagrams.

We consider the problem of determining whether two traveling salesman tours correspond to non-adjacent vertices of the convex polytope associated with the traveling salesman problem. This problem is shown to be NP-Complete for both the symmetric and nonsymmetric traveling salesman problem. Several implications are discussed.

Extensions in prerequisite‐free, disjunction‐free default theories have been shown to be in direct correspondence with kernels of directed graphs; hence default theories without odd cycles always have a “standard” kind of an extension. We show that, although all “standard” extensions can be enumerated explicitly, several other problems remain intractable for such theories: Telling whether a non‐standard extension exists, enumerating all extensions, and finding the minimal standard extension. We also present a new graph‐theoretic algorithm, based on vertex feedback sets, for enumerating all extensions of a general prerequisite‐free, disjunction‐free default theory (possibly with odd cycles). The algorithm empirically performs well for quite large theories.