RESUMEN
Bioprocess development benefits from kinetic models in many aspects, including scale-up, optimization, and process understanding. However, current models are unable to simulate the production process of a coxsackievirus A6 (CVA6) virus-like particle (VLP) vaccine using Chinese hamster ovary cell culture. In this study, a novel kinetic model was constructed, correlating (1) cell growth, death, and lysis kinetics, (2) metabolism of major metabolites, and (3) CVA6 VLP production. To construct the model, two batches of a laboratory-scale 2 L bioreactor cell culture were prepared and various pH shift strategies were applied to examine the effect of pH shift. The proposed model described the experimental data under various conditions with high accuracy and quantified the effect of pH shift. Next, cell culture performance with various pH shift timings was predicted by the calibrated model. A trade-off relationship was found between product yield and quality. Consequently, multiple objective optimization was performed by integrating desirability methodology with model simulation. Finally, the optimal operating conditions that balanced product yield and quality were predicted. In general, the proposed model improved the process understanding and enabled in silico process development of a CVA6 VLP vaccine. Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-023-00598-8.
RESUMEN
Nasopharyngeal carcinoma (NPC) is amongst the most common malignancies of head and neck cancers. Most patients are admitted to the hospital with advanced disease. NPC has a tendency toward early metastatic spread to cervical lymph nodes, and levels II and III are most commonly involved. A few reports have indicated specific metastatic sites of nasopharyngeal cancer, including lymph node metastasis and distant metastasis. Evidence of histopathology and immunohistochemistry is required to prove NPC origin. In many cases, surgery can be performed to obtain accurate evidence of the pathology. However, surgery can also affect the overall treatment plan and strategy for NPC and should be considered in the specific circumstances of the disease. Multidisciplinary consultation is required for these uncommonly specific metastases. Paying attention to the specific lymph node metastasis sites of NPC plays an important role in accurately diagnosing the stage, thereby giving an appropriate treatment strategy. It is also important in determining radiotherapy volumes because radiotherapy is the standard therapy for this disease. Herein, we are reporting 2 cases of NPC with clinical metastasis to unusual lymph node sites such as the parotid salivary gland and the cheek. Histological analyses from the resected specimens confirmed its nasopharyngeal origin. Lymph node metastases in the parotid gland and the cheek are unusual. In diagnosis and follow-up, it is necessary to evaluate carefully to make an accurate diagnosis and appropriate treatment plans for patients as well as early detect recurrent metastases at uncommon sites of lymph nodes.
RESUMEN
In streptomycetes, autoregulators are important signaling compounds that trigger secondary metabolism, and they are regarded as Streptomyces hormones based on their extremely low effective concentrations (nM) and the involvement of specific receptor proteins. Our previous distribution study revealed that butenolide-type Streptomyces hormones, including avenolide, are a general class of signaling molecules in streptomycetes and that Streptomyces albus strain J1074 may produce butenolide-type Streptomyces hormones. Here, we describe metabolite profiling of a disruptant of the S. albusaco gene, which encodes a key biosynthetic enzyme for butenolide-type Streptomyces hormones, and identify four butenolide compounds from S. albus J1074 that show avenolide activity. The compounds structurally resemble avenolide and show different levels of avenolide activity. A dual-culture assay with imaging mass spectrometry (IMS) analysis for in vivo metabolic profiling demonstrated that the butenolide compounds of S. albus J1074 stimulate avermectin production in another Streptomyces species, Streptomyces avermitilis, illustrating the complex chemical interactions through interspecies signals in streptomycetes.IMPORTANCE Microorganisms produce external and internal signaling molecules to control their complex physiological traits. In actinomycetes, Streptomyces hormones are low-molecular-weight signals that are key to our understanding of the regulatory mechanisms of Streptomyces secondary metabolism. This study reveals that acyl coenzyme A (acyl-CoA) oxidase is a common and essential biosynthetic enzyme for butenolide-type Streptomyces hormones. Moreover, the diffusible butenolide compounds from a donor Streptomyces strain were recognized by the recipient Streptomyces strain of a different species, resulting in the initiation of secondary metabolism in the recipient. This is an interesting report on the chemical interaction between two different streptomycetes via Streptomyces hormones. Information on the metabolite network may provide useful hints not only to clarification of the regulatory mechanism of secondary metabolism, but also to understanding of the chemical communication among streptomycetes to control their physiological traits.
