Activation of the stimulator of interferon gene (STING) pathway within the tumor microenvironment has been shown to generate a strong antitumor response. Although local administration of STING agonists has promise for cancer immunotherapy, the dosing regimen needed to achieve efficacy requires frequent intratumoral injections over months. Frequent dosing for cancer treatment is associated with poor patient adherence, with as high as 48% of patients failing to comply. Multiple intratumoral injections also disrupt the tumor microenvironment and vascular networks and therefore increase the risk of metastasis. Here, we developed microfabricated polylactic-co-glycolic acid (PLGA) particles that remain at the site of injection and release encapsulated STING agonist as a programmable sequence of pulses at predetermined time points that mimic multiple injections over days to weeks. A single intratumoral injection of STING agonist–loaded microparticles triggered potent local and systemic antitumor immune responses, inhibited tumor growth, and prolonged survival as effectively as multiple soluble doses, but with reduced metastasis in several mouse tumor models. STING agonist–loaded microparticles improved the response to immune checkpoint blockade therapy and substantially decreased the tumor recurrence rate from 100 to 25% in mouse models of melanoma when administered during surgical resection. In addition, we demonstrated the therapeutic efficacy of STING microparticles on an orthotopic pancreatic cancer model in mice that does not allow multiple intratumoral injections. These findings could directly benefit current STING agonist therapy by decreasing the number of injections, reducing risk of metastasis, and expanding its applicability to hard-to-reach cancers.

Accurate medical recordkeeping is a major challenge in many low-resource settings where well-maintained centralized databases do not exist, contributing to 1.5 million vaccine-preventable deaths annually. Here, we present an approach to encode medical history on a patient using the spatial distribution of biocompatible, near-infrared quantum dots (NIR QDs) in the dermis. QDs are invisible to the naked eye yet detectable when exposed to NIR light. QDs with a copper indium selenide core and aluminum-doped zinc sulfide shell were tuned to emit in the NIR spectrum by controlling stoichiometry and shelling time. The formulation showing the greatest resistance to photobleaching after simulated sunlight exposure (5-year equivalence) through pigmented human skin was encapsulated in microparticles for use in vivo. In parallel, microneedle geometry was optimized in silico and validated ex vivo using porcine and synthetic human skin. QD-containing microparticles were then embedded in dissolvable microneedles and administered to rats with or without a vaccine. Longitudinal in vivo imaging using a smartphone adapted to detect NIR light demonstrated that microneedle-delivered QD patterns remained bright and could be accurately identified using a machine learning algorithm 9 months after application. In addition, codelivery with inactivated poliovirus vaccine produced neutralizing antibody titers above the threshold considered protective. These findings suggest that intradermal QDs can be used to reliably encode information and can be delivered with a vaccine, which may be particularly valuable in the developing world and open up new avenues for decentralized data storage and biosensing.

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SUMMARY The train formation plan (TFP) determines the train services and their frequencies and assigns the demands. The TFP models are often formulated as a capacitated service network design problem, and the optimal solution is normally difficult to find. In this paper, a hybrid algorithm of the Simplex method and simulated annealing is proposed for the TFP problem. The basic idea of the proposed algorithm is to use a simulated annealing algorithm to explore the solution space, where the revised Simplex method evaluates, selects, and implements the moves. In the proposed algorithm, the neighborhood structure is based on the pivoting rules of the Simplex method that provides an efficient method to reach the neighbors of the current solution. A state‐of‐the‐art method is applied for parameters tuning by using the design of experiments approach. To evaluate the proposed model and the solution method, 25 test problems have been simulated and solved. The results show the efficiency and the effectiveness of the proposed approach. The proposed approach is implemented to develop the TFP in the Iranian railway as a case study. It is possible to save significant time and cost through solving the TFP problem by using the proposed algorithm and developing the efficient TFP plan in the railway networks. Copyright © 2012 John Wiley & Sons, Ltd.

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Nowadays, the demand for achieving cars with higher strength, lower fuel consumption, and better safety considerations propels automakers to produce parts with extremely high strength-to-weight ratios. This criterion is done through the hot-stamping process considered as a novel technology employed for producing high-strength steel parts with low springback, particularly appropriate for the vehicle body. In this paper, firstly, numerical simulation of the hot-stamping process of a blank consisted of boron-alloyed steel 22MnB5 (with commercial name of Usibor 1500) is performed. Secondly, effects of different design parameters including blank holder force, die radius, gap between the punch and die, and forming time on the final temperature distributions as well as springback of the part is investigated. Consequently, optimization has been performed using Taguchi L16 orthogonal array to obtain the parameters which minimize abovementioned parameters as two objective functions. Obtained results are verified based on performing numerical simulation and comparison to a similar work in the literature. Accuracy of the results is also assessed via the technique of plotting normal probability graphs of both objective functions. Finally, via evaluation of contribution percentage associated with analysis of variance considering each design parameter, a discussion is done by proposing the optimum design.

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