Dietary composition and calorie intake are major determinants of health and disease. Calorie restriction promotes metabolic changes that favor tissue regeneration and is arguably the most successful ...and best-conserved antiaging intervention. Obesity, in contrast, impairs tissue homeostasis and is a major risk factor for the development of diseases including cancer. Stem cells, the central mediators of tissue regeneration, integrate dietary and energy cues via nutrient-sensing pathways to maintain growth or respond to stress. We discuss emerging data on the effects of diet and nutrient-sensing pathways on intestinal stem cells, as well as their potential application in the development of regenerative and therapeutic interventions.
Metabolism and Colorectal Cancer Sedlak, Joseph C; Yilmaz, Ömer H; Roper, Jatin
Annual review of pathology,
01/2023, Letnik:
18, Številka:
1
Journal Article
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Reprogrammed metabolism is a hallmark of colorectal cancer (CRC). CRC cells are geared toward rapid proliferation, requiring nutrients and the removal of cellular waste in nutrient-poor environments. ...Intestinal stem cells (ISCs), the primary cell of origin for CRCs, must adapt their metabolism along the adenoma-carcinoma sequence to the unique features of their complex microenvironment that include interactions with intestinal epithelial cells, immune cells, stromal cells, commensal microbes, and dietary components. Emerging evidence implicates modifiable risk factors related to the environment, such as diet, as important in CRC pathogenesis. Here, we focus on describing the metabolism of ISCs, diets that influence CRC initiation, CRC genetics and metabolism, and the tumor microenvironment. The mechanistic links between environmental factors, metabolic adaptations, and the tumor microenvironment in enhancing or supporting CRC tumorigenesis are becoming better understood. Thus, greater knowledge of CRC metabolism holds promise for improved prevention and treatment.
•Additive manufacturing in supply chain context is examined.•An optimization model is developed to formulate the problem.•Several structural properties and a lower bound are presented for the ...problem.•Best-fit heuristic based algorithms are employed.•BFCUBS algorithm is suggested for solving the problem.
This study explores the problem of integrated jobs and vehicles scheduling in a two-stage supply chain, where parts are processed on additive manufacturing (AM) machines and then distributed to customers. In this study, we develop an optimization model for the problem with the objective of makespan minimization. Besides, several structural properties and lower bound formulation are provided to explain the main characteristics of the problem. In this regard, this study also contributes to the existing academic literature by investigating the two-stage supply chain scheduling problem with the additive manufacturing technology. Because the addressed problem belongs to non-deterministic polynomial-time hardness (NP-hard) problem class, a best-fit heuristic-based approach and several selection rules are developed to solve the problem. Each selection rule is designed by considering a distinct structural property of the problem and, thus, each of which is considered to be a different algorithm. A comprehensive experimental study is conducted through random instances, which are generated for small- and large-sized problems by considering real-production data. According to the computational results, the best-fit capacity utilization based selection (BFCUBS) algorithm is superior to others and yields a substantial improvement in the makespan. The reason behind this fact is that the high utilization of capacity enables a large number of jobs to be completed in a short time. Besides, as the number of jobs decreases and the capacity utilization rates increases all algorithms provide better results.
The heterogeneity of cellular states in cancer has been linked to drug resistance, cancer progression and the presence of cancer cells with properties of normal tissue stem cells. Secreted Wnt ...signals maintain stem cells in various epithelial tissues, including in lung development and regeneration. Here we show that mouse and human lung adenocarcinomas display hierarchical features with two distinct subpopulations, one with high Wnt signalling activity and another forming a niche that provides the Wnt ligand. The Wnt responder cells showed increased tumour propagation ability, suggesting that these cells have features of normal tissue stem cells. Genetic perturbation of Wnt production or signalling suppressed tumour progression. Small-molecule inhibitors targeting essential posttranslational modification of Wnt reduced tumour growth and markedly decreased the proliferative potential of lung cancer cells, leading to improved survival of tumour-bearing mice. These results indicate that strategies for disrupting pathways that maintain stem-like and niche cell phenotypes can translate into effective anti-cancer therapies.
The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and immune-based strategies to ...combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high-affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using multiple preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, resembling those in tumor-infiltrating lymphocytes of PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote immune evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical in maintaining immune evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.
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•A subset of neoantigen-expressing pancreas cancer evades immune surveillance•Markers of T cell exhaustion typify pancreas cancer tumor-infiltrating lymphocytes•The CD155/TIGIT axis promotes immune evasion in pancreas cancer•TIGIT/PD-1 co-blockade plus CD40 agonism reinvigorates tumor-reactive T cells
Freed-Pastor et al. identify the CD155/TIGIT axis as a key driver of immune evasion in pancreas cancer. Neoepitope prediction reveals a subset of human pancreas cancer patients with predicted high-affinity neoepitopes and functional interrogation using preclinical models identifies a combination immunotherapy approach (TIGIT/PD-1 co-blockade plus CD40 agonism) capable of eliciting profound anti-tumor responses.
In recent years, the interest in seru production system (SPS) has increased to enhance the flexibility of production systems. Because the worker resource in an SPS is critical for adapting to changes ...in demand, this study focuses on workforce-related operational strategies rarely considered for SPS. To this end, for the first time in the literature, a bi-objective workforce scheduling problem is addressed by considering the interseru worker transfer in SPS. A novel optimisation model is proposed to achieve two objectives, that of minimising makespan and reducing workload imbalance among workers. Because it is proved that the problem falls within a non-deterministic polynomial-time hardness (NP-hard) class, non-dominated sorting genetic algorithm-II (NSGA-II) is employed to solve large-sized problems. For small-sized problems, the second version of the augmented ε-constrained (AUGMECON2) method is implemented and Pareto-optimal solutions are obtained. A set of evaluation metrics is considered to compare two different operational strategies in terms of the desired objectives. The computational results indicate that allowing worker transfer leads to better results for all metrics. The main contribution of the present study is to provide a novel optimisation model for the addressed problem to compare two operational strategies by considering the heterogeneity inherent of workers.
Stem-cell-based therapies can potentially reverse organ dysfunction and diseases, but the removal of impaired tissue and activation of a program leading to organ regeneration pose major challenges. ...In mice, a 4-day fasting mimicking diet (FMD) induces a stepwise expression of Sox17 and Pdx-1, followed by Ngn3-driven generation of insulin-producing β cells, resembling that observed during pancreatic development. FMD cycles restore insulin secretion and glucose homeostasis in both type 2 and type 1 diabetes mouse models. In human type 1 diabetes pancreatic islets, fasting conditions reduce PKA and mTOR activity and induce Sox2 and Ngn3 expression and insulin production. The effects of the FMD are reversed by IGF-1 treatment and recapitulated by PKA and mTOR inhibition. These results indicate that a FMD promotes the reprogramming of pancreatic cells to restore insulin generation in islets from T1D patients and reverse both T1D and T2D phenotypes in mouse models.
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•Fasting mimicking diet induces prenatal-development gene expression in adult pancreas•FMD promotes Ngn3 expression to generate insulin-producing β cells•Cycles of FMD reverse β-cell failure and rescue mice from T1D and T2D•Inhibition of PKA or mTOR promotes Ngn3-driven β-cell regeneration in human T1D islets
A periodic short-term diet that mimics fasting modulates β-cell regeneration and promotes insulin secretion and glucose homeostasis with potential to treat both type 1 and type 2 diabetes.
In this study, an integrated bi-objective objective U-shaped assembly line balancing and parts feeding problem is explored by considering the heterogeneity inherent of workers. An optimization model ...is developed to formulate the addressed problem. Since the problem includes two different objectives, namely the minimizing the operational cost and maximum workload imbalance, the Pareto-optimal solutions are found by employing the second version of the augmented ε-constrained (AUGMECON2) method. To investigate the impact of qualification of workers on the system performance, a set of scenarios is constructed based on the worker skill levels. Each scenario is determined based on the nature of the worker pool in which workers are assigned to the stations. The optimization model and implemented method are validated through data taken from water-meter and elevator producers. The computational results reveal that the scenarios have a great impact on system performance. In particular, it is revealed that as the skill levels of workers increases, the quality of the Pareto-optimal solutions increase by up to 30% in terms of the comparison metrics. Therefore, an order release mechanism and worker training activities are suggested to be performed to enhance system performance.
Tumors display increased uptake and processing of nutrients to fulfill the demands of rapidly proliferating cancer cells. Seminal studies have shown that the proto-oncogene MYC promotes metabolic ...reprogramming by altering glutamine uptake and metabolism in cancer cells. How MYC regulates the metabolism of other amino acids in cancer is not fully understood. Using high-performance liquid chromatography (HPLC)-tandem mass spectrometry (LC-MS/MS), we found that MYC increased intracellular levels of tryptophan and tryptophan metabolites in the kynurenine pathway. MYC induced the expression of the tryptophan transporters SLC7A5 and SLC1A5 and the enzyme arylformamidase (AFMID), involved in the conversion of tryptophan into kynurenine. SLC7A5, SLC1A5, and AFMID were elevated in colon cancer cells and tissues, and kynurenine was significantly greater in tumor samples than in the respective adjacent normal tissue from patients with colon cancer. Compared with normal human colonic epithelial cells, colon cancer cells were more sensitive to the depletion of tryptophan. Blocking enzymes in the kynurenine pathway caused preferential death of established colon cancer cells and transformed colonic organoids. We found that only kynurenine and no other tryptophan metabolite promotes the nuclear translocation of the transcription factor aryl hydrocarbon receptor (AHR). Blocking the interaction between AHR and kynurenine with CH223191 reduced the proliferation of colon cancer cells. Therefore, we propose that limiting cellular kynurenine or its downstream targets could present a new strategy to reduce the proliferation of MYC-dependent cancer cells.
The metastatic process of colorectal cancer (CRC) is not fully understood and effective therapies are lacking. We show that activation of NOTCH1 signaling in the murine intestinal epithelium leads to ...highly penetrant metastasis (100% metastasis; with >80% liver metastases) in KrasG12D-driven serrated cancer. Transcriptional profiling reveals that epithelial NOTCH1 signaling creates a tumor microenvironment (TME) reminiscent of poorly prognostic human CRC subtypes (CMS4 and CRIS-B), and drives metastasis through transforming growth factor (TGF) β-dependent neutrophil recruitment. Importantly, inhibition of this recruitment with clinically relevant therapeutic agents blocks metastasis. We propose that NOTCH1 signaling is key to CRC progression and should be exploited clinically.
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•Epithelial NOTCH1 signaling drives metastasis in serrated CRC•Poor-prognosis CRC subtypes CMS4/CRIS-B are controlled by NOTCH1•TGF-β-mediated neutrophil infiltration is critical for NOTCH1-driven metastasis•Neutrophil targeting provides therapeutic opportunity in metastatic CRC
In a genetically engineered mouse model, Jackstadt et al. show that NOTCH1 activation drives metastasis in KRASG12D-driven serrated colorectal cancer (CRC) through TGFβ-dependent neutrophil recruitment. Thus, targeting neutrophil recruitment is a potential therapeutic approach in metastatic CRC.
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