Irreducible triangulations of surfaces with boundary

A triangulation of a surface is irreducible if no edge can be contracted to produce a triangulation of the same surface. In this paper, we investigate irreducible triangulations of surfaces with boundary. We prove that the number of vertices of an irreducible triangulation of a (possibly non-orientable) surface of genus g>=0 with b>=0 boundaries is O(g+b). So far, the result was known only for surfaces without boundary (b=0). While our technique yields a worse constant in the O(.) notation, the present proof is elementary, and simpler than the previous ones in the case of surfaces without boundary

Machine learning liver-injuring drug interactions with non-steroidal anti-inflammatory drugs (NSAIDs) from a retrospective electronic health record (EHR) cohort

Drug-drug interactions account for up to 30% of adverse drug reactions. Increasing prevalence of electronic health records (EHRs) offers a unique opportunity to build machine learning algorithms to identify drug-drug interactions that drive adverse events. In this study, we investigated hospitalizations\u27 data to study drug interactions with non-steroidal anti-inflammatory drugs (NSAIDS) that result in drug-induced liver injury (DILI). We propose a logistic regression based machine learning algorithm that unearths several known interactions from an EHR dataset of about 400,000 hospitalization. Our proposed modeling framework is successful in detecting 87.5% of the positive controls, which are defined by drugs known to interact with diclofenac causing an increased risk of DILI, and correctly ranks aggregate risk of DILI for eight commonly prescribed NSAIDs. We found that our modeling framework is particularly successful in inferring associations of drug-drug interactions from relatively small EHR datasets. Furthermore, we have identified a novel and potentially hepatotoxic interaction that might occur during concomitant use of meloxicam and esomeprazole, which are commonly prescribed together to allay NSAID-induced gastrointestinal (GI) bleeding. Empirically, we validate our approach against prior methods for signal detection on EHR datasets, in which our proposed approach outperforms all the compared methods across most metrics, such as area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC)

Polytopality and Cartesian products of graphs

We study the question of polytopality of graphs: when is a given graph the graph of a polytope? We first review the known necessary conditions for a graph to be polytopal, and we provide several families of graphs which satisfy all these conditions, but which nonetheless are not graphs of polytopes. Our main contribution concerns the polytopality of Cartesian products of non-polytopal graphs. On the one hand, we show that products of simple polytopes are the only simple polytopes whose graph is a product. On the other hand, we provide a general method to construct (non-simple) polytopal products whose factors are not polytopal.Comment: 21 pages, 10 figure

Discovery of novel reductive elimination pathway for 10-hydroxywarfarin

Coumadin (R/S-warfarin) anticoagulant therapy is highly efficacious in preventing the formation of blood clots; however, significant inter-individual variations in response risks over or under dosing resulting in adverse bleeding events or ineffective therapy, respectively. Levels of pharmacologically active forms of the drug and metabolites depend on a diversity of metabolic pathways. Cytochromes P450 play a major role in oxidizing R- and S-warfarin to 6-, 7-, 8-, 10-, and 4\u27-hydroxywarfarin, and warfarin alcohols form through a minor metabolic pathway involving reduction at the C11 position. We hypothesized that due to structural similarities with warfarin, hydroxywarfarins undergo reduction, possibly impacting their pharmacological activity and elimination. We modeled reduction reactions and carried out experimental steady-state reactions with human liver cytosol for conversion o

An update on the Hirsch conjecture

The Hirsch conjecture was posed in 1957 in a letter from Warren M. Hirsch to George Dantzig. It states that the graph of a d-dimensional polytope with n facets cannot have diameter greater than n - d. Despite being one of the most fundamental, basic and old problems in polytope theory, what we know is quite scarce. Most notably, no polynomial upper bound is known for the diameters that are conjectured to be linear. In contrast, very few polytopes are known where the bound $n-d$ is attained. This paper collects known results and remarks both on the positive and on the negative side of the conjecture. Some proofs are included, but only those that we hope are accessible to a general mathematical audience without introducing too many technicalities.Comment: 28 pages, 6 figures. Many proofs have been taken out from version 2 and put into the appendix arXiv:0912.423

Phagocytosis by an HIV antibody is associated with reduced viremia irrespective of enhanced complement lysis

Increasingly, antibodies are being used to treat and prevent viral infections. In the context of HIV, efficacy is primarily attributed to dose-dependent neutralization potency and to a lesser extent Fc-mediated effector functions. It remains unclear whether augmenting effector functions of broadly neutralizing antibodies (bNAbs) may improve their clinical potential. Here, we use bNAb 10E8v4 targeting the membrane external proximal region (MPER) to examine the role of antibody-mediated effector and complement (C’) activity when administered prophylactically against SHIV challenge in rhesus macaques. With sub-protective dosing, we find a 78–88% reduction in post-acute viremia that is associated with 10E8v4-mediated phagocytosis acting at the time of challenge. Neither plasma nor tissue viremic outcomes in vivo is improved with an Fc-modified variant of 10E8v4 enhanced for C’ functions as determined in vitro. These results suggest that effector functions inherent to unmodified 10E8v4 contribute to efficacy against SHIVSF162P3 in the absence of plasma neutralizing titers, while C’ functions are dispensable in this setting, informing design of bNAb modifications for improving protective efficacy

There is no triangulation of the torus with vertex degrees 5, 6, ..., 6, 7 and related results: Geometric proofs for combinatorial theorems

There is no 5,7-triangulation of the torus, that is, no triangulation with exactly two exceptional vertices, of degree 5 and 7. Similarly, there is no 3,5-quadrangulation. The vertices of a 2,4-hexangulation of the torus cannot be bicolored. Similar statements hold for 4,8-triangulations and 2,6-quadrangulations. We prove these results, of which the first two are known and the others seem to be new, as corollaries of a theorem on the holonomy group of a euclidean cone metric on the torus with just two cone points. We provide two proofs of this theorem: One argument is metric in nature, the other relies on the induced conformal structure and proceeds by invoking the residue theorem. Similar methods can be used to prove a theorem of Dress on infinite triangulations of the plane with exactly two irregular vertices. The non-existence results for torus decompositions provide infinite families of graphs which cannot be embedded in the torus.Comment: 14 pages, 11 figures, only minor changes from first version, to appear in Geometriae Dedicat

Povećanje letalnog učinka bleomicina na stanice HeLa i V79 s pomoću pčelinjeg otrova

This study investigated possible growth-inhibiting effects of bee venom applied alone or in combination with a cytotoxic drug bleomycin on HeLa and V79 cells in vitro based on clone formation, cell counting, and apoptosis. Melittin, the key component of bee venom, is a potent inhibitor of calmodulin activity, and also a potent inhibitor cell growth and clonogenicity. Intracellular accumulation of melittin correlates with the cytotoxicity of antitumour agents. Previous studies indicated that some calcium antagonists and calmodulin inhibitors enhanced intracellular levels of antitumor agents by inhibiting their outward transport. In this study, treatment of exponentially growing HeLa and V79 cells with bleomycin caused a dose-dependent decrease in cell survival due to DNA damage. This lethal effect was potentiated by adding a non-lethal dose of the bee venom. By preventing repair of damaged DNA, bee venom inhibited recovery from potentially lethal damage induced by bleomycin in V79 and HeLa cells. Apoptosis, necrosis, and lysis were presumed as possible mechanisms by which bee venom inhibited growth and clonogenicity of V79 cells. HeLa cells, on the other hand, showed greater resistance to bee venom. Our findings suggest that bee venom might find a therapeutic use in enhancing cytotoxicity of antitumour agent bleomycin.U uvjetima in vitro istražen je inhibitorni učinak pčelinjeg otrova, samog ili združenog s citostatikom bleomicinom, na rast stanica HeLa i V79. Rabljene su sljedeće metode: brojenje stanica, metoda klonskog rasta i apoptoza. Poznato je da neki antagonisti kalcija i kalmodulinski inhibitori povisuju unutarstaničnu razinu protutumorskih lijekova inhibirajući njihov prijenos iz stanice. Unutarstanična akumulacija melitina izravno povećava citotoksični učinak protutumorskog lijeka. Obrada stanica HeLa i V79 u eksponencijalnoj fazi rasta bleomicinom uzrokuje oštećenje DNA ovisno o dozi te smanjenje broja živih stanica. Uočeno je da se letalni učinak bleomicina može pojačati dodatkom neletalne doze pčelinjeg otrova. Pčelinji otrov pritom inhibira popravak nastalih oštećenja u stanicama HeLa i V79 te sprječava oporavak stanica tretiranih bleomicinom. Apoptoza, nekroza i liza mogući su mehanizmi kojima pčelinji otrov inhibira rast i stvaranje kolonija stanica V79, dok HeLa-stanice pokazuju pojačanu otpornost na pčelinji otrov. Istraživanje također potvrđuje mogućnost uporabe pčelinjeg otrova u povećanju citotoksičnosti bleomicina

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