Vehicle Minimization for the Multimodal Pickup and Delivery Problem with Time Windows

The algorithm proposed here is used for heuristic solutions for the Multimodal Multiple Vehicle Routing Problem with Unloading Capacity, Pickup and Dropoff, and Time Windows, solved so as to minimize the number of vehicles used, subject to varying objective function values for each vehicle. The MVRP is simplified and split into a routing problem and a scheduling problem. The routing problem is addressed by Dijkstra\u27s Algorithm. This generates a new network for the second stage of the algorithm. It is assumed that the shortest path is the correct path to use, and shipments each travel unimodally. The scheduling problem is addressed by treating the various paths as though they were machines, with vehicle number being treated approximately as capacity for the machines, and unloading capacity being treated as a second stage in the processing. The problem is analyzed by assigning all shipments which can be assigned elsewhere away from the most expensive mode and then assigning only leftover shipments to the most expensive mode. Multiple resolutions of the scheduling problem result in feasible solutions for less expensive modes, which results in a feasible solution for every mode, and a low cost solution in terms of vehicles used

Small Bowel Obstruction After FloSeal Use

The authors present a series of small bowel obstruction after FloSeal use and suggest prompt reexploration if early small bowel obstruction is found after FloSeal use for hemostasis

Superior Mesenteric Artery Syndrome After Roux-en-Y Gastric Bypass

Superior mesenteric artery syndrome caused by weight loss after gastric bypass surgery may be successfully treated with laparoscopic intestinal bypass procedures

A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential

Chemopreventative celecoxib fails to prevent schwannoma formation or sensorineural hearing loss in genetically engineered murine model of neurofibromatosis type 2

Mutations in the tumor suppressor gene NF2 lead to Neurofibromatosis type 2 (NF2), a tumor predisposition syndrome characterized by the development of schwannomas, including bilateral vestibular schwannomas with complete penetrance. Recent work has implicated the importance of COX-2 in schwannoma growth. Using a genetically engineered murine model of NF2, we demonstrate that selective inhibition of COX-2 with celecoxib fails to prevent the spontaneous development of schwannomas or sensorineural hearing loss in vivo, despite elevated expression levels of COX-2 in Nf2-deficient tumor tissue. These results suggest that COX-2 is nonessential to schwannomagenesis and that the proposed tumor suppressive effects of NSAIDs on schwannomas may occur through COX-2 independent mechanisms

A Collaborative Model for Accelerating the Discovery and Translation of Cancer Therapies

Preclinical studies using genetically engineered mouse models (GEMM) have the potential to expedite the development of effective new therapies; however, they are not routinely integrated into drug development pipelines. GEMMs may be particularly valuable for investigating treatments for less common cancers, which frequently lack alternative faithful models. Here, we describe a multicenter cooperative group that has successfully leveraged the expertise and resources from philanthropic foundations, academia, and industry to advance therapeutic discovery and translation using GEMMs as a preclinical platform. This effort, known as the Neurofibromatosis Preclinical Consortium (NFPC), was established to accelerate new treatments for tumors associated with neurofibromatosis type 1 (NF1). At its inception, there were no effective treatments for NF1 and few promising approaches on the horizon. Since 2008, participating laboratories have conducted 95 preclinical trials of 38 drugs or combinations through collaborations with 18 pharmaceutical companies. Importantly, these studies have identified 13 therapeutic targets, which have inspired 16 clinical trials. This review outlines the opportunities and challenges of building this type of consortium and highlights how it can accelerate clinical translation. We believe that this strategy of foundation-academic-industry partnering is generally applicable to many diseases and has the potential to markedly improve the success of therapeutic development

Responses of arbuscular mycorrhizal fungi to long-term inorganic and organic nutrient addition in a lowland tropical forest

Improved understanding of the nutritional ecology of arbuscular mycorrhizal (AM) fungi is important in understanding how tropical forests maintain high productivity on low-fertility soils. Relatively little is known about how AM fungi will respond to changes in nutrient inputs in tropical forests, which hampers our ability to assess how forest productivity will be influenced by anthropogenic change. Here we assessed the influence of long-term inorganic and organic nutrient additions and nutrient depletion on AM fungi, using two adjacent experiments in a lowland tropical forest in Panama. We characterised AM fungal communities in soil and roots using 454-pyrosequencing, and quantified AM fungal abundance using microscopy and a lipid biomarker. Phosphorus and nitrogen addition reduced the abundance of AM fungi to a similar extent, but affected community composition in different ways. Nutrient depletion (removal of leaf litter) had a pronounced effect on AM fungal community composition, affecting nearly as many OTUs as phosphorus addition. The addition of nutrients in organic form (leaf litter) had little effect on any AM fungal parameter. Soil AM fungal communities responded more strongly to changes in nutrient availability than communities in roots. This suggests that the 'dual niches' of AM fungi in soil versus roots are structured to different degrees by abiotic environmental filters, and biotic filters imposed by the plant host. Our findings indicate that AM fungal communities are fine-tuned to nutrient regimes, and support future studies aiming to link AM fungal community dynamics with ecosystem function