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As prodrugs series of new sartan-derived molecules were designed, synthesized, and evaluated. Most of the synthesized compounds could decrease blood pressure efficiently in spontaneously hypertensive rats. It could be ratiocinated that the original drugs could be released from the prodrugs exactly at the connecting position catalyzed by the hydrolyzation enzymes. The maximal response of mean blood pressure (MBP) lowered 70.2 ± 5.0 mmHg (compound 1) and 61.2 ± 1.0 mmHg (compound 4) at 10 mg/kg after oral administration, and the antihypertensive effect lasted beyond 24 h, which performed better than Losartan and were similar with Telmisartan. Pharmacokinetics test results of 1 were consistent with its anti-hypertension effects in vivo. The safety of new compounds was confirmed by the influence on the rats’ heart rates and other symptoms which couldn’t been observed during whole process. Thence, compounds 1 and 4 may be considered as potential antihypertension drug candidates.

The Vehicle Routing Problem (VRP) is one of the most intensively studied combinatorial optimisation problems for which numerous models and algorithms have been proposed. To tackle the complexities, uncertainties and dynamics involved in real-world VRP applications, Machine Learning (ML) methods have been used in combination with analytical approaches to enhance problem formulations and algorithmic performance across different problem solving scenarios. However, the relevant papers are scattered in several traditional research fields with very different, sometimes confusing, terminologies. This paper presents a first, comprehensive review of hybrid methods that combine analytical techniques with ML tools in addressing VRP problems. Specifically, we review the emerging research streams on ML-assisted VRP modelling and ML-assisted VRP optimisation. We conclude that ML can be beneficial in enhancing VRP modelling, and improving the performance of algorithms for both online and offline VRP optimisations. Finally, challenges and future opportunities of VRP research are discussed., Submitted to International Journal of Production Research

Purpose Esophageal cancer is the most common gastrointestinal tumor and is difficult to be eradicated with conventional treatment. Porphyrin-based photosensitizers (PSs) mediated photodynamic therapy (PDT) could kill tumor cells with less damage to normal cells. As the most widely used porphyrin-based photosensitizer in clinics, Photofrin II has excellent anti-tumor effect. However, it has some disadvantages such as weak absorption at near infrared region, the complexity of components and prolonged skin photosensitivity. Here series novel 5,15-diaryl-10,20-dihalogeno porphyrin derivatives were afforded and evaluated to develop more effective and safer photosensitizers for tumor therapy.Methods The photophysical properties and singlet oxygen generation rates of 5,15-diaryl-10,20-dihalogeno porphyrins (I1-6, II1-4) were tested. The cytotoxicity of I1-6 and II1-4 were measured by MTT assay. The pathway of cell death was studied by flow cytometry. In vivo photodynamic efficacy of I3 and II2-4 in Eca-109 tumor-bearing BABL/c nude mice were measured and histopathological analysis were examined.Results 5,15-Diaryl-10,20-dihalogeno porphyrins I1-6 and II1-4 were synthesized. The longest absorption wavelength of these halogenated porphyrins (λmax = 660 nm) displayed a red shift around 30 nm compared to the unhalogenated porphyrins PS1 (λmax = 630 nm). The singlet oxygen generation rates of I1-6 and II1-4 were significantly higher than PS1 and HMME. All PSs mediated PDT showed obvious cytotoxic effect against Eca-109 cells compared to HMME in vitro and in vivo. Among these PSs, II4 exhibited appropriate absorption in the phototherapeutic window, higher 1O2 generation rate (k = 0.0061 s-1), the strongest phototoxicity (IC50 = 0.4 μM), lower dark toxicity in vitro on Eca-109 cells and excellent photodynamic anti-tumor efficacy in vivo. Besides, cell necrosis was induced by compound II4 mediated PDT.Conclusion All new compounds have obvious photodynamic anti-esophageal cancer effects. Among them, the photosensitizer II4 showed excellent efficacy in vitro and in vivo, which has the potential to become a photodynamic anti-tumor drug.

We study integrated production- and delivery-scheduling problems that arise in practical make-to-order settings in several industries. In these problems, make-to-order products are first processed in a plant and then delivered to customer sites through two stages of shipping: first, from the plant to a pool point (e.g., a port, a distribution, or a consolidation center) and, second, from the pool point to customer sites. The objective is to obtain a joint schedule of job processing at the plant and two-stage shipping of completed jobs to customer sites to optimize a performance measure that takes into account both delivery timeliness and total transportation costs. We consider two problems in which delivery timeliness is measured by total or maximum lead time of the jobs and study both offline and online versions of these problems. For the offline problems involving a single production line at the plant, we provide optimal dynamic programming algorithms. For the more general offline problems involving multiple production lines at the plant, we propose fast heuristics and analyze their worst-case and asymptotic performances. For the online problems, we propose online algorithms and analyze their competitive ratios. By comparing our offline heuristics with lower bounds using randomly generated test instances, it is shown that these heuristics are capable of generating near-optimal solutions quickly. Using real data from Baosteel’s Meishan plant, we also show that our corresponding offline heuristic generates significantly better solutions than Baosteel’s rule-based approach. In addition, our computational results on the performance of the online algorithms relative to the offline heuristics generate important methodological insights that can be used by practitioners in choosing a specific solution approach.

Carbon based polymer dots have piqued attention of researchers because of excellent biocompatibility, and good solubility. Most of the p-dots are able to generate ROS which is effective for photodynamic therapy for the treatment of cancer while some photosensitizers such as porphyrins possess some drawbacks such as hydrophobicity, and dark toxicity. Therefore in this study we conjugated red emission carbon based polymer with pyropheophorbide-α through amide condensation and π–π stacking. One pot synthesis of the conjugate was successfully achieved. Their photophysiological properties were studied and structures were characterized by FT-IR, TEM and 1HNMR. pH- sensitivity of the conjugates was confirmed using fluorescence and UV–vis spectroscopy. Photo toxicity and dark toxicity of the prepared conjugates were evaluated in human esophageal cancer cell line (Eca-109). Hemocompatibility of the synthesized conjugates was evaluated and proved that the conjugates are safe to use for the treatment of tumor. Our results showed the PS doped p-dots had less dark toxicity and increased light toxicity as well as ROS generation was high as compared to precursor drug. Therefore, incorporation of p-dots to porphyrin improved biocompatibility and enhanced the photodynamic effect.

A photosensitizer with high phototoxicity, suitable amphipathy and low dark toxicity could play a pivotal role in photodynamic therapy (PDT). In this study, a facile and versatile approach was adopted to synthesize a series of novel fluorinated hematoporphyrin ether derivatives (I1-I5 and II1-II4), and the photodynamic activities of these compounds were studied. Compared to hematoporphyrin monomethyl ether (HMME), all PSs showed preferable photodynamic activity against A549 lung tumor cells. The longest visible absorption wavelength of these compounds was approximately 622 nm. Among them, II3 revealed the highest singlet oxygen yield (0.0957 min−1), the strongest phototoxicity (IC50 = 1.24 μM), the lowest dark toxicity in vitro, and exhibited excellent anti-tumor effects in vivo. So compound II3 could act as new drug candidate for photodynamic therapy.

We study an integrated production and transportation problem for a make-to-order manufacturing company that operates under the commit-to-delivery mode and uses third-party logistics service provide...

It is challenging to achieve selective off to on modulation of the emissive state of a fluorophore within a complex and heterogeneous cellular environment. Herein we show that the dis-assembly of a non-fluorescent aggregate to produce individual fluorescent molecules, termed disaggregation induced emission (DIE), can be utilised to achieve this goal with an amphiphilic BF 2 -azadipyrromethene (NIR-AZA) probe. Optical near-infrared properties of the NIR-AZA probe used in this study include absorption and emission maxima at 700 and 726 nm respectively when in the emissive non-aggregated state. Key to the success of the probe is the bis-sulfonic acid substitution of the NIR-AZA fluorophore, which is atypical for membrane probes as it does not contain zwitterionic lipid substituents. The aggregation/disaggregation properties of the NIR-fluorophore have been investigated in model surfactant and synthetic liposomal systems and shown to be emissive responsive to both. Real-time live cell imaging experiments in HeLa Kyoto and MC3T3 cells showed a rapid switch on of emission specific to the plasma membrane of viable and apoptotic cells attributable to a disaggregation-induced emission of the probe. Image analysis software confirmed localisation of fluorescence to the plasma membrane. Cell membrane staining was also effective for formaldehyde fixed cells, with staining possible either before or after fixation. This study adds new and important findings to recent developments of DIE responsive probes and further applications of this controllable emission-switching event are anticipated.

We consider a practical dynamic pricing problem with two substitutable products involving a number of business rules commonly seen in practice. Demand substitution exists between the two products (interproduct substitution) and may also exist across different time periods (intertemporal substitution). However, there is limited demand information such that the underlying probability distributions of the demand cannot be characterized precisely. We use an interval to represent, respectively, the demand for each individual product in each period, the aggregate demand for the two products in each period, and the total aggregate demand for the two products across multiple time periods. We propose a robust optimization model for this problem to maximize the worst-case total revenue. For the problem with interproduct demand substitution only, we develop a dynamic programming algorithm and show that the search spaces in the DP can be reduced greatly, which enables the algorithm to generate optimal solutions in a reasonable amount of time. For the problem with both interproduct and intertemporal demand substitutions, we develop a more complex dynamic programming algorithm and design a fully polynomial time approximation scheme that guarantees a proven, near optimal solution in a manageable computation time for practically sized problems. Our computational results show that, compared to a risk-neutral approach, our robust optimization approach can decrease the variance of the revenue at a small expense of the average revenue. We also generate a number of managerial insights: (i) none of the key structural properties commonly studied in the pricing literature hold for our problem; (ii) the revenue impact of ignoring intertemporal demand substitution when such substitution exists can be quite significant; and (iii) under- or overestimating the bounds of the demand intervals or imposing moderate business rules leads to relatively small revenue loss, typically less than 3%. The online appendix is available at https://doi.org/10.1287/msom.2017.0639 .

Photodynamic therapy (PDT) is emerging as a promising method for the treatment of various cancer diseases. However, the clinical application of PDT is limited due to the lack of effective photosensitizers. In this study, a novel chlorophyll derivative, N,N-bis(2-carboxyethyl)pyropheophorbide a (BPPA), had been synthesized and characterized. BPPA had a characteristic long wavelength absorption peak at 669nm and a singlet oxygen quantum yield of 0.54. To investigate the photodynamic ability of BPPA against cholangiocarcinoma (CCA), cellular uptake, subcellular location and bio-distribution, in vitro and in vivo PDT efficacy of BPPA were studied. The results showed that BPPA could rapidly accumulate in QBC-939 cells and localize in the cytoplasm. BPPA- PDT was effective in reducing the cell viability in a drug dose- and light dose-dependent manner in vitro. In CCA xenograft nude mouse model, the concentration of BPPA in the plasma lowered rapidly, and the fluorescence signal peaked at 0.5h and 2h after injection in the skin and tumor, respectively. Significant quantities could be observed in the tumor. BPPA followed by irradiation could significantly inhibit growth of tumors, and histological examination revealed necrotic damage in PDT-treated tumors. These results suggested that BPPA could be a promising drug candidate for photodynamic therapy in cholangiocarcinoma.

We consider several integrated production, inventory, and delivery problems that arise in a number of practical settings where customer orders have pre-specified delivery time windows. These orders are first processed in a plant and then delivered to the customers by transporters (such as trains and air flights) which have fixed delivery departure times. If an order is completed but not immediately delivered by a transporter, the order is kept temporarily in inventory, which incurs an inventory cost. There is a delivery cost for delivering an order, which varies with the departure time. Given a set of orders, the objective is to find an integrated schedule for processing the orders, keeping finished orders in inventory if necessary, and delivering them to the customers such that the total inventory and delivery cost is minimum. We consider two classes of problems: where order delivery is splittable and where order delivery is nonsplittable. For each of the problems considered, we study its computational complexity by either showing that the problem is NP-hard or proposing an algorithm that can find an optimal solution. For the two most general problems, we show that any polynomial time algorithm has an arbitrarily bad worst-case performance bound, and propose combined column generation and tabu search heuristic algorithms that can find near optimal solutions for them in a reasonable computational time. The online appendix is available at https://doi.org/10.1287/ijoc.2016.0726 .

Photodynamic therapy (PDT) has been demonstrated to be an effective and safe treatment for subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). The photosensitizer is crucial factor in the efficacy of PDT. In this study, the physicochemical properties and the biological activity of a pyropheophorbide-a derivative, 2-(1-methoxyethyl)-2-devinylpyropheophorbide-a (MEP) had been evaluated in vivo and in vitro . MEP had a characteristic long wavelength absorption peak at 664 nm and the singlet oxygen quantum yield was determined as 0.38. In vitro , MEP showed low dark cytotoxicity and high photocytotoxicity, reducing the cell viability in a drug dose – dependent and light dose – dependent manner. In vivo , MEP could selectively localize to experimental CNV in BN rats, resulting in occlusion of CNV with minimal damage to retina tissues. The results indicate that MEP has the perspective to be developed as a safe and effective photosensitizer in PDT for AMD.

Photodynamic therapy (PDT) is an emerging non-invasive treatment based on a combination of photochemistry and photophysics. PDT has more advantages compared with traditional...

Negative regulation of immunoreceptor signaling is required for preventing hyperimmune activation and maintaining immune homeostasis. The roles of p38IP in immunoreceptor signaling remain unclear. Here, we show that p38IP suppresses T-cell receptor (TCR)/LPS-activated NF-κB and p38 by targeting TAK1 kinase and that p38IP protein levels are downregulated in human PBMCs from rheumatoid arthritis (RA) patients, inversely correlating with the enhanced activity of NF-κB and p38. Mechanistically, p38IP interacts with TAK1 to disassemble the TAK1-TAB (TAK1-binding protein) complex. p38IP overexpression decreases TCR-induced binding of K63-linked polyubiquitin (polyUb) chains to TAK1 but increases that to TAB2, and p38IP knockdown shows the opposite effects, indicating unanchored K63-linked polyUb chain transfer from TAB2 to TAK1. p38IP dynamically interacts with TAK1 upon stimulation, because of the polyUb chain transfer and the higher binding affinity of TAK1 and p38IP for polyUb-bound TAB2 and TAK1, respectively. Moreover, p38IP scaffolds the deubiquitinase USP4 to deubiquitinate TAK1 once TAK1 is activated. These findings reveal a novel role and the mechanisms of p38IP in controlling TCR/LPS signaling and suggest that p38IP might participate in RA pathogenesis.

A series of novel angiotensin II receptor 1 antagonists (1a–f, 2a–f) were designed, synthesized and evaluated. Radioligand binding assays showed that all these prepared compounds displayed nanomolar affinity for angiotensin II type 1 receptor, among which compound 1f was more affinitive than telmisartan at the same order of magnitude with an IC50 value of 1.13 ± 1.68 nM. The antihypertensive effects showed that all these compounds could decrease blood pressure in a dose dependent manner on spontaneously hypertensive rats. And compound 2-(4-((2-butyl-4-methyl-6-(oxazolo[4,5-b]pyridine-2-yl)benzimidazole-1-yl)methyl)-1H-indol-1-yl) benzoic acid (1f), showed efficient and long-lasting effects in reducing blood pressure, with a maximal response lowered 55.98 ± 4.74 mmHg at 10 mg kg−1 and 35.82 ± 6.20 mmHg at 5 mg kg−1, the antihypertensive effect of it lasted beyond 24 h which was better than telmisartan. In the single-dose pharmacokinetic experiments, compound 1f was absorbed efficiently and metabolized smoothly in Wistar rats. The values of Cmax, Tmax, AUC0–72, MRT0–72 and T1/2 were 17.92 ± 10.85 ng mL−1, 2.60 ± 3.05 h, 252.85 ± 144.59 ng mL−1 h, 18.75 ± 0.43 h and 17.16 ± 4.24 h respectively. Compound 1f was distributed into tissues rapidly and extensively after oral administration and the level of it was the highest in the liver, followed by in the kidney, and the lowest in brain. The acute toxicity assays in ICR rats of 1f showed that it had low acute toxicity with an LD50 value of 1459.89 mg kg−1. These encouraging results make 1f an efficient, long-acting and safe antihypertensive drug candidate and deserving of further investigation.

This study aimed to investigate the effect of hematoporphyrin dimethylether (HDME)-mediated photodynamic therapy for laser-induced choroidal neovascularization (CNV) in adult Brown Norway rats. HDME was administered via tail vein at 14 d after the laser photocoagulation, and the rats received irradiance with a laser light at 570 nm at 15 min after injection. CNV was evaluated by fundus photography, fundus fluorescein angiography, optical coherence tomography, and hematoxylin and eosin staining. We found that CNV was occurred at 7 d after photocoagulation and reaching peak activity at 14 d after photocoagulation. There is a significant reduction in the total area of the fluorescein leakage and the number of strong fluorescein leakage spots on 7 d after HDME-mediated photodynamic therapy (PDT). The results suggest that HDME-mediated PDT inhibits laser-induced CNV in rats, representing a promising therapy for wet age-related macular degeneration.

We consider a dynamic pricing problem that involves selling a given inventory of a single product over a short, two-period selling season. There is insufficient time to replenish inventory during this season, hence sales are made entirely from inventory. The demand for the product is a stochastic, nonincreasing function of price. We assume interval uncertainty for demand, that is, knowledge of upper and lower bounds but not a probability distribution, with no correlation between the two periods. We minimize the maximum total regret over the two periods that results from the pricing decisions. We consider a dynamic model where the decision maker chooses the price for each period contingent on the remaining inventory at the beginning of the period, and a static model where the decision maker chooses the prices for both periods at the beginning of the first period. Both models can be solved by a polynomial time algorithm that solves systems of linear inequalities. Our computational study demonstrates that the prices generated by both our models are insensitive to errors in estimating the demand intervals. Our dynamic model outperforms our static model and two classical approaches that do not use demand probability distributions, when evaluated by maximum regret, average relative regret, variability, and risk measures. Further, our dynamic model generates a total expected revenue which closely approximates that of a maximum expected revenue approach which requires demand probability distributions.

This paper investigates a practical batching decision problem that arises in the batch annealing operations in the cold rolling stage of steel production faced by most large iron and steel companies in the world. The problem is to select steel coils from a set of waiting coils to form batches to be annealed in available batch annealing furnaces and choose a median coil for each furnace. The objective is to maximize the total reward of the selected coils less the total coil–coil and coil–furnace mismatching cost. For a special case of the problem that arises frequently in practical settings where the coils are all similar and there is only one type of furnace available, we develop a polynomial-time dynamic programming algorithm to obtain an optimal solution. For the general case of the problem, which is strongly NP-hard, an exact branch-and-price-and-cut solution algorithm is developed using a column and row generation framework. A variable reduction strategy is also proposed to accelerate the algorithm. The algorithm is capable of solving medium-size instances to optimality within a reasonable computation time. In addition, a tabu search heuristic is proposed for solving larger instances. Three simple search neighborhoods, as well as a sophisticated variable-depth neighborhood, are developed. This heuristic can generate near-optimal solutions for large instances within a short computation time. Using both randomly generated and real-world production data sets, we show that our algorithms are superior to the typical rule-based planning approach used by many steel plants. A decision support system that embeds our algorithms was developed and implemented at Baosteel to replace their rule-based planning method. The use of the system brings significant benefits to Baosteel, including an annual net profit increase of at least 1.76 million U.S. dollars and a large reduction of standard coal consumption and carbon dioxide emissions.

In this paper, we consider a pricing problem faced by a seller that sells a given inventory of some product over a short selling horizon with limited demand information. The seller knows only that the demand is a linear function of the price, but does not know the parameters involved in the demand function. However, the seller knows that each parameter involved in the demand function belongs to a known interval. The seller’s objective is to determine the optimal price for the entire selling season to minimize the maximum regret, where the maximum regret is defined as the maximum possible loss of revenue due to not knowing the precise values of the parameters. We derive closed-form optimal solutions for the problem under all possible cases of input parameters and identify some structural properties of the solution. We conduct computational tests to compare our modeling approach with several benchmark approaches and report related insights.

A series of new fluoro-substituted benzimidazole derivatives were designed, synthesized and pharmacologically evaluated. All the target compounds were characterized by 1HNMR, 13CNMR, mass spectra and elemental analysis. The biological evaluation showed that most of the synthesized compounds displayed nanomolar affinity to the angiotensin II type 1 (AT1) receptor and could decrease blood pressure efficiently in spontaneously hypertensive rats. The maximal response of mean blood pressure (MBP) lowered 74.5 ± 3.5 mmHg (1g) and 69.2 ± 0.9 mmHg (2a) at 10 g/kg after oral administration, and the antihypertensive effect lasted beyond 24 h, which performed better than both losartan and telmisartan. So, compounds 1g and 2a may be considered as potential antihypertension drug candidates.

Effective photosensitizers are particularly important factor in clinical photodynamic therapy (PDT). However, there is a scarcity of photosensitizers for simultaneous cancer photo-diagnosis and targeted PDT. Herein, two novel dimethyl 2-(guanidinyl)ethylamino chlorin e6 photosensitizers were synthesized and their efficacy in PDT in A549 tumor was investigated. It was shown that compounds 3 and 4 have a long absorption wavelength in the near infrared region and strong fluorescence emission with slow photo-bleaching rate and markedly strong ability of 1O2 generation. They exhibited lower cytotoxicity and higher photo-cytotoxicity in vitro compared to the known anticancer drug m-THPC in MTT assay in A549 lung cancer cell lines. Compound 4 exhibit better inhibition effect than compound 3 and the IC50 value of compound 4 was 0.197 μM/L under 2 J/cm2 laser irradiation, while compound 3 showed better anti-tumor effects compared to compound 4 in vivo. Intracellular ROS generation was found to be responsible for apoptotic cell death in DCFDA assay. Subcellular localization confirmed the damage site of compounds 3 and 4 in PDT. These findings suggest that the two novel photosensitizers might serve as potential photosensitizers for improved therapeutic efficiency of PDT.

[Image: see text] A series of new angiotensin II receptor 1 antagonists were prepared. They displayed nanomolar affinity to AT(1) receptor and could decrease blood pressure efficiently in spontaneously hypertensive rats. Among them, compounds 1b and 2b could reduce the blood pressure with more or equal potency compared to Losartan. So, compounds 1b and 2b could be considered as potential antihypertension drug candidates.

A novel photosensitizer trans-2,3-dihydro-2,3-bis(carboxymethyl)-5,10,15,20-tetraphenylchlorin (BCTC) was synthesized. Its photophysical and photochemical properties, intracellular localization, photocytotoxicity in vitro and vivo were also investigated. BCTC displays a characteristic long wavelength absorption peak at 652 nm and shows a singlet oxygen quantum yield of 0.68 in DMF. Without light activation, BCTC was nontoxic to human esophageal cancer cells. However, upon light activation, BCTC exhibited significant photocytotoxicity. After PDT treatment, the growth of Eca-109 tumor in nude mice was significantly inhibited. This study suggests that BCTC is an effective photosensitizer for PDT to tumors.

The contribution of imaging with near infrared (NIR) fluorophores to the elucidation of complex biological processes continues to rapidly expand. New tools for mild selective bioconjugation are strongly desirable for the construction of NIR labelled biomolecules. This work presents the synthesis and evaluation of a strained alkyne substituted NIR BF2-azadipyrromethene (NIR-AZA) which can conjugate in water with azido-homoalanine and cRGD peptide within 30 min at rt. Imaging analysis of the NIR-AZA–cRGD conjugate in vitro and in vivo showed efficient cellular uptake and good in vivo tumor targeting properties, illustrating the potential for translation to clinical imaging.

Photodynamic therapy (PDT) does well in both curing early stage tumors and improving patients’ quality of life. However, the limited selectivity of photosensitizers (PSs) to tumors has become an urgent issue during the application of PDT clinically, which would exhibit a poor therapeutic outcome and induce skin phototoxicity. To solve this problem, PS-loaded D-α-tocopheryl polyethylene glycol succinate (vitamin E TPGS, or simply TPGS) nanoparticles with tumor homing and penetrating peptide tLyp-1 decoration (t-NP) were constructed for PDT of tumors in this study. Verteporfin (VP), as an effective PS, was encapsulated in the core of t-NP, and tLyp-1 was functionalized on the surface as a functional ligand to increase vascular permeability and target the tumor cells. These nanoparticles were spherical in shape and exhibited a narrow size distribution of 23.3 ± 0.80 nm, and had a high encapsulation efficiency and loading capacity of hydrophobic VP. Compared with unmodified nanoparticles (NP), t-NP exhibited enhanced cellular uptake in both primary human umbilical vein endothelial cells (HUVECs) and drug-resistant human colon adenocarcinoma cells (HCT15); and t-NP showed higher selectivity to HCT15 tumors in vivo after intravenous administration of the same dose of VP. The anti-tumor experiment in vivo strongly indicated that nanoparticles with tLyp-1 peptide modification can enhance the selectivity of the PS, and improve the PDT effect.

In this paper, the antitumor activity of a novel porphyrin-based photosensitizer 5, 10, 15, 20-tetrakis[(5-diethylamino)pentyl] porphyrin (TDPP) was reported in vitro and in vivo. The photophysical and cellular properties of TDPP were investigated. The singlet oxygen generation quantum yield of TDPP was detected ; it showed a high singlet oxygen quantum yield of 0.52. The intracellular distribution of photosensitizer was detected with laser scanning confocal microscopy. The efficiency of TDPP-photodynamic therapy (PDT) in vitro was analyzed by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5- diphenyl-2H-tetrazolium bromide (MTT) assay and in situ trypan blue exclusion test. Treated with a 630-nm laser, TDPP can kill cultured human esophageal cancer cell line (Eca-109) cells and reduce the growth of Eca-109 xenograft tumors significantly in BABL/c nude mice. And histopathological study was also used to confirm the antitumor effect. It has the perspective to be developed as a new antitumor drug in photodynamic therapy and deserves further investigation.

Chlorin derivatives are promising photosensitive agents for photodynamic therapy (PDT) of tumors. The aim of the current study is to investigate the PDT therapeutic effects of a novel chlorin-based photosensitizer, meso-tetra[3-(N,N-diethyl)aminomethyl-4-methoxy]phenyl chlorin (TMPC) for gliomas in vitro and in vivo. Physicochemical characteristics of TMPC were recorded by ultraviolet visible spectrophotometer and fluorescence spectrometer. The rate of singlet oxygen generation of TMPC upon photo-excitation was detected by using 1,3-diphenylisobenzofuran (DPBF). The accumulation of TMPC in gliomas U87 MG cells was measured by fluorescence spectrometer. The efficiency of TMPC-PDT in vitro was analyzed by MTT assay and clonogenic assay. The biodistribution and clearance of TMPC were determined by fluorescence measuring. Human gliomas U87 MG tumor-bearing mice model was used to evaluate the antitumor effects of TMPC-PDT. TMPC shows a singlet oxygen generation rate of 0.05 and displays a characteristic long wavelength absorption peak at 653 nm (ε = 15,400). The accumulation of TMPC increased with the increase of incubation time. In vitro, PDT using TMPC and laser showed laser dose- and concentration-dependent cytotoxicity to U87 MG cells. In U87 MG tumor-bearing mice, TMPC-PDT significantly reduced the growth of the tumors. Both in vitro and in vivo, TMPC showed little dark toxicity. In vitro and in vivo studies, it found that TMPC has excellent antitumor activities. It suggests that TMPC is a potential photosensitizer of photodynamic therapy for cancer.

There are a variety of joint job production and transportation scheduling problems that arise in modern manufacturing systems. In this paper, we study two such problems that arise in a flowshop environment where there are two processing stages and a single transporter that is available to deliver the finished jobs from the first stage to the second. In the first problem, there is a single machine in each of the two flowshop stages and jobs have different sizes when loaded onto the transporter. In the second problem, there are two parallel machines in the first stage and a single machine in the second stage, and the transporter can carry only one job in each shipment. The objective of both problems is to minimize the makespan, i.e., the completion time of the last job in the second stage. The two problems are both strongly NP-hard. For each problem, we propose a fast heuristic and show that the heuristic has a tight worst-case bound of 2.

Dynamic pricing enables a firm to increase revenue by better matching supply with demand, responding to shifting demand patterns, and achieving customer segmentation. In the last 20 years, numerous success stories of dynamic pricing applications have motivated a rapidly growing research interest in a variety of dynamic pricing problems in the academic literature. A large class of problems that arise in various revenue management applications involve selling a given amount of inventory over a finite time horizon without inventory replenishment. In this study, we identify most recent trends in dynamic pricing research involving such problems. We review existing research on three new classes of problems that have attracted a rapidly growing interest in the last several years, namely, problems with multiple products, problems with competition, and problems with limited demand information. We also identify a number of possible directions for future research.

We study an integrated charge batching and casting width selection problem arising in the continuous casting operation of the steelmaking process at Shanghai, China based Baosteel. This decision-making problem is not unique to Baosteel; it exists in every large iron and steel company in the world. We collaborated with Baosteel on this problem from 2006 to 2008 by developing and implementing a decision support system (DSS) that replaced their manual planning method. The DSS is still in active use at Baosteel. This paper describes the solution algorithms we developed and imbedded in the DSS. For the general problem that is strongly NP-hard, a column generation-based branch-and-price (B&P) solution approach is developed to obtain optimal solutions. By exploiting the problem structure, efficient dynamic programming algorithms are designed to solve the subproblems involved in the column generation procedure. Branching strategies are designed in a way that ensures that after every stage of branching the structure of the subproblems is preserved such that they can still be solved efficiently. We also consider a frequently occurring case of the problem where each steel grade is incompatible with any other grade. For this special case, a two-level polynomial-time algorithm is developed to obtain optimal solutions. Computational tests on a set of real production data as well as on a more diverse set of randomly generated problem instances show that our algorithms outperform the manual planning method that Baosteel used to use by a significant margin both in terms of tundish utilization for almost every case, and in terms of total cost for most cases. Consequently, by replacing their manual method with our DSS, the estimated benefits to Baosteel include an annual cost saving of about US $1.6 million and an annual revenue increase of about US $3.25 million.

Shanghai Baoshan Iron and Steel Complex (Baosteel) is China’s largest and the world’s third-largest steel company. In 2005, our research team was tasked with developing advanced operations research-based planning tools to improve the operational efficiency of Baosteel’s Shanghai plant. In the following six years, we developed novel optimization algorithms and tailored metaheuristics, and implemented four decision support systems (DSSs) to replace the manual planning methods at the Shanghai plant. The DSSs have brought scientific operations management to Baosteel and transformed the plant’s production and final-product delivery operations. Baosteel estimates that from 2007 to 2012, they provided a cumulative economic benefit of 77 million. Based on their current usage at this plant, they also estimate that these DSSs will continue to provide an annual economic benefit of 20 million, which represents a 17 percent improvement of Baosteel’s information technology and operations management capability. They have also reduced Baosteel’s carbon dioxide emissions by 585,770 tons annually.

A series of 2-morpholinetetraphenylporphyrins functionalized with various substituents (Cl, Me, MeO group) at 4-phenyl position were prepared via nucleophilic substitution of 2-nitroporphyrin copper derivatives with morpholine by refluxing under a nitrogen atmosphere and then demetalization. Their basic photophysical properties, intracellular localization, cytotoxicities in vitro and in vivo were also investigated. All synthesized photosensitizers exhibited longer maxima absorption wavelengths than Hematoporphyrin monomethyl ether (HMME). They showed low dark cytotoxicity compared with that of HMME and were more phototoxic than HMME against Eca-109 cells in vitro. M3 also exhibited better photodynamic antitumor efficacy on BALB/c nude mice at a lower concentration. Therefore, M3 is a promising antitumor photosensitizer in photodynamic therapy application.

Kise, Ibaraki and Mine (Operations Research 26:121---126, 1978) give an O(n 2) time algorithm to find an optimal schedule for the single-machine number of late jobs problem with agreeable job release dates and due dates. Li, Chen and Tang (Operations Research 58:508---509, 2010) point out that their proof of optimality for their algorithm is incorrect by giving a counter-example. In this paper we give a correct proof of optimality for their algorithm.

This paper considers the coordination of pricing and scheduling decisions in a make-to-order environment. Following common industry practice, we assume knowledge of a deterministic demand function that is nonincreasing in price. We consider three alternative measures of scheduling cost: total work-in-process inventory cost of orders, total penalty for orders delivered late to customers, and total capacity usage. The objective is to maximize the total net profit, i.e., revenue less scheduling cost, resulting from the pricing and scheduling decisions. We develop computationally efficient optimal algorithms for solving the three pricing and scheduling problems. Because these problems are formally intractable, much faster algorithms are not possible. We develop a fully polynomial time approximation scheme for each problem. We also estimate the value of coordinating pricing and production scheduling decisions by comparing solutions delivered by (a) an uncoordinated approach where pricing and scheduling decisions are made independently, (b) a partially coordinated approach that uses only general information about scheduling that a marketing department typically knows, (c) a simple heuristic approach for solving the coordinated problem, and (d) our optimal algorithm for solving the coordinated problem. Our main managerial insight is that there is a significant benefit even if pricing and scheduling are only heuristically or partially coordinated. Moreover, heuristic and partial coordination are simple to achieve.

We consider an integrated production–distribution scheduling model in a make-to-order supply chain consisting of one supplier and one customer. The supplier receives a set of orders from the customer at the beginning of a planning horizon. The supplier needs to process all the orders at a single production line, pack the completed orders to form delivery batches, and deliver the batches to the customer. Each order has a weight, and the total weight of the orders packed in a batch must not exceed the capacity of the delivery batch. Each delivery batch incurs a fixed distribution cost. The problem is to find jointly a schedule for order processing and a way of packing completed orders to form delivery batches such that the total distribution cost (or equivalently, the number of delivery batches) is minimized subject to the constraint that a given customer service level is guaranteed. We consider two customer service constraints—meeting the given deadlines of the orders; or requiring the average delivery lead time of the orders to be within a given threshold. Several problems of the model with each of those constraints are considered. We clarify the complexity of each problem and develop fast heuristics for the NP-hard problems and analyze their worst-case performance bounds. Our computational results indicate that all the heuristics are capable of generating near optimal solutions quickly for the respective problems.

We study an integrated production and distribution scheduling model in a two-stage supply chain consisting of one or more suppliers, a warehouse, and a customer. Each supplier produces a different product at a constant rate. There is a setup time and a setup cost per production run for each supplier. Completed products are first delivered from the suppliers to the warehouse and are then sent from the warehouse to the customer. The customer's demand for each product is constant over time. The problem is to find jointly a cyclic production schedule for each supplier, a cyclic delivery schedule from each supplier to the warehouse, and a cyclic delivery schedule from the warehouse to the customer so that the customer demand for each product is satisfied without backlog at the least total production, inventory and distribution cost. We consider two production and delivery scheduling policies. We derive either an exact or a heuristic solution algorithm for the problem under each policy. Heuristics are evaluated computationally. We also evaluate the value of the warehouse by comparing our model with a model that does not have the warehouse in the supply chain (i.e. the products are delivered directly from the suppliers to the customer). Various managerial insights based on an extensive set of computational tests are reported, including how the value of warehouse and the delivery frequency from the suppliers to the warehouse are influenced by various problem parameters including production rates of the suppliers, unit inventory costs, delivery costs, and the warehouse location.

Polyaniline coated silica/maghemite nanoparticles (PANI/SiO2/γ-Fe2O3 composites) were synthesized by the combination of a sol–gel process and an in-situ polymerization method, in which ferrous and ferric salts as well as tetraethyl orthosilica (TEOS) acted as the precursor for γ-Fe2O3 and silica, respectively. As a result, the SiO2/γ-Fe2O3 particle showed a core-shell structure, with γ-Fe2O3 as the magnetic core and silica as the shell of the particle. The shell thickness can be controlled by changing the TEOS concentration. The PANI/SiO2/γ-Fe2O3 composites revealed a multilayer core-shell structure, where PANI is the outer shell of the composite. The doping level and the conductivity of PANI/SiO2/γ-Fe2O3 composites decreased with increasing the TEOS content due to the presence of the less coated PANI on the SiO2/γ-Fe2O3 core at higher TEOS content. For a SQUID analysis at room temperature, all γ-Fe2O3 containing composites showed a typical superparamagnetic behavior. The saturation magnetization of SiO2/γ-Fe2O3 nanoparticles decreased with increasing the TEOS content due to the increase in silica shell thickness, while the saturation magnetization of PANI/SiO2/γ-Fe2O3 composites also decreased with increasing the TEOS content, which is attributed to the lower conductivity of PANI in the composites at higher TEOS content.

Cadmium hydroxide-deposited cadmium selenide nanoparticles were prepared by the addition of cadmium sulfate solution to cadmium selenide nanoparticles in a weak alkaline solution at room temperature. The photoluminescence measurements displayed that the luminescence intensity was greatly increased by the addition of cadmium ions due to the formation of cadmium hydroxide on the surfaces of the cadmium selenide nanoparticles. Then, CdSe/Cd(OH)2/SiO2 nanocomposite particles were synthesized using 3-mercatopropyl trimethoxysilane by Stober method. After the formation of CdSe/Cd(OH)2/SiO2 nanocomposite particles, the emission ability was mostly stabilized. Additionally, the stabilization of the composite particles against dilution with the physiological saline was checked. The results showed that the photoluminescence stability was promoted after the deposition of silica on the surfaces of the CdSe/Cd(OH)2 nanoparticles. Comparison of the stability of CdSe/SiO2 nanoparticles with that of CdSe/Cd(OH)2/SiO2 ones showed that Cd(OH)2 shell could enhance the photoluminescence effectively.

The classical scheduling literature considers many problems where a given set of jobs must be processed at minimum cost, subject to various resource constraints. The literature only considers the issue of revenue generation in a very limited way, by allowing a job to remain unprocessed and its revenue contribution to be lost. By contrast, we consider three diverse practical situations where efficient scheduling affects revenue in much more general and realistic ways. First, we study two make-to-order environments where efficient scheduling increases customer goodwill, thus stimulating demand in different ways. Second, we study two make-to-stock environments where efficient scheduling creates inventory, thus also stimulating demand in different ways. Third, we study new product markets where efficient scheduling leads to a company becoming the first mover, and thus acquiring a larger market share. In each case, we provide both a computationally efficient algorithm for scheduling and a proof that a much more efficient algorithm is unlikely to exist. For both the make-to-stock and make-to-order problems, we also describe heuristic approaches that are easy to implement, and we study their average performance. The results show that substantial benefits arise from considering the implications of efficient scheduling for revenue and net profit. The practical impact of our work is to demonstrate the importance of efficient scheduling, not only in controlling cost, but also in increasing revenue and net profit.