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Abstract Background: Lung cancer is currently the most prevalent malignancy and the leading cause of cancer deaths worldwide. Although the early stage non-small cell lung cancer (NSCLC) presents a relatively good prognosis, a considerable number of lung cancer cases are still detected and diagnosed at locally advanced or late stages. Surgical treatment combined with perioperative multimodality treatment is the mainstay of treatment for locally advanced NSCLC and has been shown to improve patient survival. Following the standard methods of neoadjuvant therapy, perioperative management, postoperative adjuvant therapy, and other therapeutic strategies are important for improving patients’ prognosis and quality of life. However, controversies remain over the perioperative management of NSCLC and presently consensus and standardized guidelines are lacking for addressing critical clinical issues in multimodality treatment. Methods: The working group consisted of 91 multidisciplinary experts from thoracic surgery, medical oncology, radiotherapy, epidemiology, and psychology. This guideline was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The clinical questions were collected and selected based on preliminary open-ended questionnaires and subsequent discussions during the Guideline Working Group meetings. PubMed, Web of Science, Cochrane Library, Scopus, and China National Knowledge Infrastructure (CNKI) were searched for available evidence. The GRADE system was used to evaluate the quality of evidence and grade the strengths of recommendations. Finally, the recommendations were developed through a structured consensus-building process. Results: The Guideline Development Group initially collected a total of 62 important clinical questions. After a series of consensus-building conferences, 24 clinical questions were identified and corresponding recommendation were ultimately developed, focusing on neoadjuvant therapy, perioperative management, adjuvant therapy, postoperative psychological rehabilitation, prognosis assement, and follow-up protocols for NSCLC. Conclusions: This guideline puts forward reasonable recommendations focusing on neoadjuvant therapy, perioperative management, adjuvant therapy, postoperative psychological rehabilitation, prognosis assessment, and follow-up protocol of NSCLC. It standardizes perioperative multimodality treatment and provides guidance for clinical practice among thoracic surgeons, medical oncologists, and radiotherapists, aiming to reduce postoperative recurrence, improve patient survival, accelerate recovery, and minimize postoperative complications such as atelectasis.

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ABSTRACT Anaerobic degradation of polycyclic aromatic hydrocarbons (PAHs) with three or more aromatic rings is extremely slow because the compounds are very poorly soluble in water and chemically stable. Phenanthrene is the only three-ring PAH where the anaerobic degradation has been partially elucidated. Phenanthrene is first activated via carboxylation producing 2-phenanthroate, which is further converted to 2-phenanthroyl-coenzyme A (CoA) via the enzyme 2-phenanthroate:CoA ligase. In this study, we elucidated the next degradation step, the reduction of 2-phenanthroyl-CoA to dihydro-2-phenanthroyl-CoA. We cloned the putative gene from the genome of culture TRIP_1 and heterologously expressed and purified the 2-phenanthroyl-CoA reductase enzyme from Escherichia coli . The identified monomeric flavo-enzyme belongs to the novel group of type III aryl-CoA reductases in the old-yellow enzyme family and has a molecular mass of 72 kDa. 2-Phenanthroyl-CoA reductase contains one FMN, one FAD, and one [4Fe-4S] iron-sulfur cluster as cofactors. The enzyme has a specific activity of 17.6 ± 0.4 nmol/min/mg, a K m value of 1.8 µM, and a Vmax of 7.9 µmol/min/mg at pH 7.5, when reduced methyl viologen was used as electron donor. 2-Phenanthroyl-CoA reductase catalyzed a two-electron reduction step producing one of five possible isomers. Quantum mechanical calculations and nuclear magnetic resonance analysis of the reaction product suggested 9,10-dihydro-2-phenanthroyl-CoA as the most stable isomer. However, our experimental evidence suggests 7,8-dihydro-2-phenanthroyl-CoA (International Union of Pure and Applied Chemistry [IUPAC]: 1,2-dihydro-7-phenanthroyl-CoA) or 5,6-dihydro-2-phenanthroyl-CoA (IUPAC: 3,4-dihydro-7-phenanthroyl-CoA) as the most likely reduced product with a saturated bond in ring 3 of the substrate 2-phenanthroyl-CoA, before undergoing isomerization changes to reach the more stable structure of 9,10-dihydro-2-phenanthroyl-CoA. IMPORTANCE PAHs are a group of highly toxic and persistent environmental pollutants. The anaerobic degradation of three-ring PAHs like phenanthrene is still poorly understood. Phenanthrene degradation starts with a carboxylation reaction to form 2-phenanthroic acid followed by a CoA-thioesterification reaction catalyzed by 2-phenanthroate:CoA ligase to produce 2-phenanthroyl-CoA. The next degradation step is the reduction of 2-phenanthroyl-CoA to dihydro-2-phenanthroyl-CoA to overcome the resonance energy of the aromatic ring system. Herein, we elucidated that the reduction reaction is catalyzed by the enzyme 2-phenanthroyl-CoA reductase. Furthermore, we provided biochemical and structural properties of the heterologously expressed and purified 2-phenanthroyl-CoA reductase, which confirmed that the enzyme belongs to the novel group of type III aryl-CoA reductases in the old-yellow enzyme family.

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