Cell2Chem: mining explored and unexplored biosynthetic chemical spaces.

SUMMARY: Living cell strains have important applications in synthesizing their native compounds and potential for use in studies exploring the universal chemical space. Here, we present a web server named as Cell2Chem which accelerates the search for explored compounds in organisms, facilitating investigations of biosynthesis in unexplored chemical spaces. Cell2Chem uses co-occurrence networks and natural language processing to provide a systematic method for linking living organisms to biosynthesized compounds and the processes that produce these compounds. The Cell2Chem platform comprises 40 370 species and 125 212 compounds. Using reaction pathway and enzyme function in silico prediction methods, Cell2Chem reveals possible biosynthetic pathways of compounds and catalytic functions of proteins to expand unexplored biosynthetic chemical spaces. Cell2Chem can help improve biosynthesis research and enhance the efficiency of synthetic biology. AVAILABILITY AND IMPLEMENTATION: Cell2Chem is available at: http://www.rxnfinder.org/cell2chem/.

ChemHub: a knowledgebase of functional chemicals for synthetic biology studies.

SUMMARY: The field of synthetic biology lacks a comprehensive knowledgebase for selecting synthetic target molecules according to their functions, economic applications and known biosynthetic pathways. We implemented ChemHub, a knowledgebase containing >90 000 chemicals and their functions, along with related biosynthesis information for these chemicals that was manually extracted from >600 000 published studies by more than 100 people over the past 10 years. AVAILABILITY AND IMPLEMENTATION: Multiple algorithms were implemented to enable biosynthetic pathway design and precursor discovery, which can support investigation of the biosynthetic potential of these functional chemicals. ChemHub is freely available at: http://www.rxnfinder.org/chemhub/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

SARS2020: an integrated platform for identification of novel coronavirus by a consensus sequence-function model.

MOTIVATION: The 2019 novel coronavirus outbreak has significantly affected global health and society. Thus, predicting biological function from pathogen sequence is crucial and urgently needed. However, little work has been conducted to identify viruses by the enzymes that they encode, and which are key to pathogen propagation. RESULTS: We built a comprehensive scientific resource, SARS2020, which integrates coronavirus-related research, genomic sequences and results of anti-viral drug trials. In addition, we built a consensus sequence-catalytic function model from which we identified the novel coronavirus as encoding the same proteinase as the severe acute respiratory syndrome virus. This data-driven sequence-based strategy will enable rapid identification of agents responsible for future epidemics. AVAILABILITYAND IMPLEMENTATION: SARS2020 is available at http://design.rxnfinder.org/sars2020/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Local treatment improves survival in patients with stage IVB cervical cancer.

OBJECTIVE: To evaluate the value of local treatment in stage IVB cervical cancer (CC). METHODS: Patients diagnosed with stage IVB CC between 2010 and 2015 were included using the data from the Surveillance, Epidemiology, and End Results program. Propensity score matching (PSM) was used to balance the clinicopathological variables of patients. Multivariate Cox regression analyses were performed to analyze the risk factors associated with cause-specific survival (CSS). RESULTS: We identified 960 patients in this study, all patients had received chemotherapy. Of these patients, 818 patients were treated with local treatment (85.2%), including 724 (88.5%) and 94 (11.5%) patients receiving radiotherapy (RT) alone and surgery ± RT, respectively. Local treatment was the independent prognostic factor associated with better CSS. Before PSM, patients who received RT (hazard ratio [HR] 0.633, 95% confidence interval [CI] 0.517-0.775, P < 0.001) or surgery (HR 0.391, 95% CI 0.277-0.552, P < 0.001) were independently associated with a better CSS compared to those with no local treatment. The 3-years CSS rate was 14.4%, 32.4%, and 54.8% in no local treatment, RT alone, and surgery groups, respectively (P < 0.001). Similar results were found after PSM. Patients receiving RT (HR 0.643, 95% CI 0.436-0.947, P = 0.025) and surgery (HR 0.146, 95% CI 0.052-0.410, P < 0.001) had better CSS compared to patients with no local treatment after PSM. While similar CSS was shown between RT alone cohort and the surgery cohort (HR 0.756, 95% CI 0.454-1.260, P = 0.284). CONCLUSIONS: The addition of local surgery or RT to chemotherapy appears to confer improved survival outcomes in patients with stage IVB CC.

novoPathFinder: a webserver of designing novel-pathway with integrating GEM-model.

To increase the number of value-added chemicals that can be produced by metabolic engineering and synthetic biology, constructing metabolic space with novel reactions/pathways is crucial. However, with the large number of reactions that existed in the metabolic space and complicated metabolisms within hosts, identifying novel pathways linking two molecules or heterologous pathways when engineering a host to produce a target molecule is an arduous task. Hence, we built a user-friendly web server, novoPathFinder, which has several features: (i) enumerate novel pathways between two specified molecules without considering hosts; (ii) construct heterologous pathways with known or putative reactions for producing target molecule within Escherichia coli or yeast without giving precursor; (iii) estimate novel pathways with considering several categories, including enzyme promiscuity, Synthetic Complex Score (SCScore) and LD50 of intermediates, overall stoichiometric conversions, pathway length, theoretical yields and thermodynamic feasibility. According to the results, novoPathFinder is more capable to recover experimentally validated pathways when comparing other rule-based web server tools. Besides, more efficient pathways with novel reactions could also be retrieved for further experimental exploration. novoPathFinder is available at http://design.rxnfinder.org/novopathfinder/.

AddictedChem: A Data-Driven Integrated Platform for New Psychoactive Substance Identification.

The mechanisms underlying drug addiction remain nebulous. Furthermore, new psychoactive substances (NPS) are being developed to circumvent legal control; hence, rapid NPS identification is urgently needed. Here, we present the construction of the comprehensive database of controlled substances, AddictedChem. This database integrates the following information on controlled substances from the US Drug Enforcement Administration: physical and chemical characteristics; classified literature by Medical Subject Headings terms and target binding data; absorption, distribution, metabolism, excretion, and toxicity; and related genes, pathways, and bioassays. We created 29 predictive models for NPS identification using five machine learning algorithms and seven molecular descriptors. The best performing models achieved a balanced accuracy (BA) of 0.940 with an area under the curve (AUC) of 0.986 for the test set and a BA of 0.919 and an AUC of 0.968 for the external validation set, which were subsequently used to identify potential NPS with a consensus strategy. Concurrently, a chemical space that included the properties of vectorised addictive compounds was constructed and integrated with AddictedChem, illustrating the principle of diversely existing NPS from a macro perspective. Based on these potential applications, AddictedChem could be considered a highly promising tool for NPS identification and evaluation.

BCSExplorer: a customized biosynthetic chemical space explorer with multifunctional objective function analysis.

SUMMARY: The biosynthetic ability of living organisms has important applications in producing bulk chemicals, biofuels and natural products. Based on the most comprehensive biosynthesis knowledgebase, a computational system, BCSExplorer, is proposed to discover the unexplored chemical space using nature's biosynthetic potential. BCSExplorer first integrates the most comprehensive biosynthetic reaction database with 280 000 biochemical reactions and 60 000 chemicals biosynthesized globally over the past 130 years. Second, in this study, a biosynthesis tree is computed for a starting chemical molecule based on a comprehensive biotransformation rule library covering almost all biosynthetic possibilities, in which redundant rules are removed using a new algorithm. Moreover, biosynthesis feasibility, drug-likeness and toxicity analysis of a new generation of compounds will be pursued in further studies to meet various needs. BCSExplorer represents a novel method to explore biosynthetically available chemical space. AVAILABILITY AND IMPLEMENTATION: BCSExplorer is available at: http://www.rxnfinder.org/bcsexplorer/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PrecursorFinder: a customized biosynthetic precursor explorer.

SUMMARY: Synthetic biology has a great potential to produce high value pharmaceuticals, commodities or bulk chemicals. However, many biosynthetic target molecules have no defined or predicted biosynthetic pathways. Biosynthetic precursors are crucial to create biosynthetic pathways. Thus computer-assisted tools for precursor identification are urgently needed to develop novel metabolic pathways. To this end, we present PrecursorFinder, a computational tool that explores biosynthetic precursors for the query target molecules using chemical structure, similarity as well as MCS (maximum common substructure). This platform comprises more than 60 000 compounds biosynthesized for being promising precursors, which are extracted from >500 000 scientific literatures and manually curated by more than 100 people over the past 8 years. The PrecursorFinder could speed up the process of biosynthesis research and make synthetic biology or metabolic engineering more efficient. AVAILABILITY AND IMPLEMENTATION: PrecursorFinder is available at: http://www.rxnfinder.org/precursorfinder/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

An open-label, single-arm phase II clinical study of induction chemotherapy and sequential Nimotuzumab combined with concurrent chemoradiotherapy in N3M0 stage nasopharyngeal carcinoma.

INTRODUCTION: The purpose of this study was to analyze the efficacy and safety of induction chemotherapy and sequential Nimotuzumab combined with concurrent chemoradiotherapy in N3M0 stage nasopharyngeal carcinoma (NPC). METHODS: This study included 45 N3 stage NPC patients treated with induction chemotherapy, sequential Nimotuzumab plus concurrent chemoradiotherapy. The intensity modulated radiation therapy (IMRT) doses for planning target volume (PTV) were 70-72 Gy for gross disease in the nasopharynx, and 66-70 Gy for positive lymph nodes. The doses for high risk and low risk regions PTV were 60-62 Gy and 54-56 Gy in 31-33 fractions. Induction chemotherapy consisted of 3 cycles of docetaxel (75 mg/m2, day 1) plus lobaplatin (30 mg/m2, day 1). Concurrent with radiotherapy, patients received chemotherapy consisting of lobaplatin 50 mg/m2, day 1. Targeted drug therapy given on the first time of IMRT consisted of Nimotuzumab (200mg, iv weekly for 7 courses). Cycle repetition of chemotherapy was every 21 days. RESULTS: The efficacy of 3 cycles of induction chemotherapy before the start of concurrent chemoradiotherapy was 100%, and the overall efficacy after the end of chemoradiotherapy was also 100%. Three-year overall survival (OS), distant metastasis-free survival (DMFS), locoregional control (LRC) and progression-free survival (PFS) rates were 85.6, 81.9, 97.8 and 79.5%, respectively. The main adverse reactions were hematologic toxicity, particularly neutropenia (100%), anemia (88.9%) and thrombocytopenia (68.9%). Patients developed a relatively low degree of mucositis and vasculitis. Chronic toxicity was mainly grade I-II radiation-induced xerostomia (18 cases). There were 11 cases of hearing loss and 4 cases of neck skin fibrosis. No cases of treatment-related death and radiation-induced cranial nerve damage or trismus were observed. CONCLUSION: In N3 stage NPC, induction chemotherapy and sequential Nimotuzumab plus concurrent chemoradiotherapy yielded an excellent survival benefit, and the toxicities were tolerable. Distant metastasis was the main cause of treatment failure.

An open-label, single-arm phase II clinical study of docetaxel plus lobaplatin for Chinese patients with pulmonary and hepatic metastasis of nasopharyngeal carcinoma.

To evaluate the efficacy and safety of the chemotherapy program of docetaxel combined with lobaplatin for Chinese patients with pulmonary and hepatic metastasis of nasopharyngeal carcinoma (NPC). This study included 37 NPC patients with pulmonary and hepatic metastasis. The chemotherapy program included docetaxel (75 mg/m, day 1) plus lobaplatin (30 mg/m, day 1). Cycle repetition was every 21 days. Patients were monitored for 7-41 months, with a median follow-up duration of 18 months. The total efficiency of this group was 67.6% and the disease control rate was 81.1%. The median progression-free survival was 9.4 months (95% confidence interval, 6.8-14.3 months), the median overall survival was 18.3 months (95% confidence interval, 13.7-22.8 months), and the 2-year survival rate was 37.8%. The main hematological toxicities were leukopenia (91.9%), anemia (81.1%), and thrombocytopenia (70.3%); other adverse reactions were mild. Changes in Epstein-Barr-DNA levels can basically reflect the dynamic changes in the efficacy of chemotherapy. Docetaxel combined with lobaplatin has a favorable outcome for the treatment of pulmonary and hepatic metastatic NPC. It has been a convenient regimen with tolerable toxicity.

Case report: A case of rectal metastatic squamous cell carcinoma from the esophagus.

Esophageal cancer is prone to distant metastasis, and the prognosis is very poor; the occurrence of intestinal metastasis is extremely rare, with atypical clinical manifestations. We report a case of rectal metastasis after surgery for esophageal squamous cell carcinoma. The patient was a 63-year-old male who was admitted to the hospital due to progressive dysphagia. He was diagnosed with moderately differentiated esophageal squamous cell carcinoma after the surgery. He was not treated with chemoradiotherapy after surgery and had recurrent blood in his stool at 9 months post-surgery; rectal metastasis of esophageal squamous carcinoma was diagnosed based on postoperative pathology. Because the patient had a positive rectal margin, we used adjuvant chemoradiotherapy and carrelizumab immunotherapy, achieving very good short-term efficacy. The patient is currently in a state of tumor-free survival and is still being closely followed up and treated. Through this case report, we hope to deepen understanding of rare metastasis of esophageal squamous cell carcinoma and actively promote local radiotherapy plus chemotherapy and immunotherapy to improve survival.

The Survival Effect of Chest Wall With or Without Regional Lymphatic Radiotherapy for Breast Cancer Patients With T3~4N0M0.

BACKGROUND: Peripheral lymphatic radiotherapy in patients with pT3N0M0 and pT4N0M0 breast cancer has been a matter of considerable debate among radiation oncologists. This is the first report in a non-Caucasian population. PATIENTS AND METHODS: The study included 165 pT3N0M0 and pT4N0M0 patients. Univariate, multivariate, propensity score matching (PSM), and Kaplan-Meier analyses were conducted to evaluate the survival of patients. We also review all the literature about regional lymph nodes radiation in T3-4N0M0 patients and summarize them with tables to compare with the present study. RESULTS: The median follow-up duration was 58.7 months. Multivariate analyses showed that advance T stage and grade were dependent poor prognostic factors for OS, DMFS, LRFS, and DFS between group A (chest wall radiation) and group B (chest wall and regional lymph nodes radiation). The overall survival (OS), disease-free survival (DFS), local relapse-free survival (LRFS), and distant metastasis-free survival (DMFS) rates were not significantly different between group A and group B. The 5-year OS rate was 92.3% vs 89.7% for group A and group B, respectively (P=0.819). The 5-year LRFS rate was 94.9% vs 94.3% for group A and group B, respectively (P=0.852). Fifty-four pairs of patients were selected after propensity score matching (PSM) analysis was conducted. There was also no significant difference between group A and group B in regard to the OS, DFS, LRFS, and DMFS rates after PSM. The patients included in previous studies were all Caucasians, and our study was focused on non-Caucasians. The cases of previous studies were 10 to 20 years ago, but our study has more recent cases. The radiotherapy techniques of previous studies were conventional, and the techniques used in our study were three-dimensional conformal radiotherapy (3DCRT) or intensity modulated radiotherapy (IMRT). CONCLUSION: Both our study and previous studies suggested that regional lymph nodes radiation cannot improve the survival rate for breast cancer patients with T3-4N0M0 in non-Caucasian population. Advance T stage and grade were the dependent poor prognostic factors for T3-4N0M0 patients.

A data-driven integrative platform for computational prediction of toxin biotransformation with a case study.

Recently, biogenic toxins have received increasing attention owing to their high contamination levels in feed and food as well as in the environment. However, there is a lack of an integrative platform for seamless linking of data-driven computational methods with 'wet' experimental validations. To this end, we constructed a novel platform that integrates the technical aspects of toxin biotransformation methods. First, a biogenic toxin database termed ToxinDB (http://www.rxnfinder.org/toxindb/), containing multifaceted data on more than 4836 toxins, was built. Next, more than 8000 biotransformation reaction rules were extracted from over 300,000 biochemical reactions extracted from ~580,000 literature reports curated by more than 100 people over the past decade. Based on these reaction rules, a toxin biotransformation prediction model was constructed. Finally, the global chemical space of biogenic toxins was constructed, comprising ~550,000 toxins and putative toxin metabolites, of which 94.7% of the metabolites have not been previously reported. Additionally, we performed a case study to investigate citrinin metabolism in Trichoderma, and a novel metabolite was identified with the assistance of the biotransformation prediction tool of ToxinDB. This unique integrative platform will assist exploration of the 'dark matter' of a toxin's metabolome and promote the discovery of detoxification enzymes.

FRCD: A comprehensive food risk component database with molecular scaffold, chemical diversity, toxicity, and biodegradability analysis.

The presence of natural toxins, pesticide residues, and illegal additives in food products has been associated with a range of potential health hazards. However, no systematic database exists that comprehensively includes and integrates all research information on these compounds, and valuable information remains scattered across numerous databases and extensive literature reports. Thus, using natural language processing technology, we curated 12,018 food risk components from 152,737 literature reports, 12 authoritative databases, and numerous related regulatory documents. Data on molecular structures, physicochemical properties, chemical taxonomy, absorption, distribution, metabolism, excretion, toxicity properties, and physiological targets within the human body were integrated to afford the comprehensive food risk component database (FRCD, http://www.rxnfinder.org/frcd/). We also analyzed the molecular scaffold and chemical diversity, in addition to evaluating the toxicity and biodegradability of the food risk components. The FRCD could be considered a highly promising tool for future food safety studies.

The impact of the interval between the induction of chemotherapy and radiotherapy on the survival of patients with nasopharyngeal carcinoma.

BACKGROUND: There have been no reliable scientific studies examining whether the interval between induction chemotherapy (IC) and initiating radiotherapy is associated with poor outcomes of nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: In this retrospective study, we included a total of 239 local advanced NPC patients who underwent concurrent chemoradiotherapy and IC. Based on the interval between IC and intensity-modulated radiation therapy (IMRT), the patients were classified into three groups as follows: Group A (≤7 vs >7 days), Group B (≤14 vs >14 days), and Group C (≤ 21 vs >21 days). Univariate and multivariate regression analyses were performed to determine the prognostic factors of survival outcomes. The differences between the two groups were compared by the log-rank test. RESULTS: The median IC-IMRT interval was 9 days (range, 1-76 days). The median follow-up time was 40 months (range, 4-58 months). The IC-IMRT interval including Group A, Group B, and Group C was not significantly associated with overall survival (OS), distant metastasis-free survival (DMFS), locoregional relapse-free survival (LRFS), or disease-free survival (DFS). Multivariate analysis showed that the tumor stage was the independent significant predictor for OS, DMFS, LRFS, and DFS. But it appears that there was a trend toward improvement in the outcome of ≤7 days group in OS from the Kaplan-Meier curves. CONCLUSION: It is also feasible to postpone radiotherapy for 1-3 weeks if patients were unable to receive treatment immediately due to chemotherapy complications such as bone marrow suppression. However, we suggest that patients should start IMRT as soon as possible after IC.

CF-Targeter: A Rational Biological Cell Factory Targeting Platform for Biosynthetic Target Chemicals.

Biosynthesis is a promising method for chemical synthesis. However, due to varieties between different microorganism hosts, yield and heterologous pathways needed for production of target chemical may also vary from different strains. One of the main challenges in metabolic engineering is to select an appropriate chassis host for specified target chemical production. However, with thousands of microorganisms existing in nature and extremely complicated metabolism within them, it is still time-consuming and error-prone work to achieve such a goal only through experimental methods, even with some existing computational methods. Hence, more efficient methods should be proposed to assist in selecting appropriate chassis hosts. In this article, based on symbolic reaction repositories and a pathway search algorithm which performed 1 400 000 searches for per target compound, we established a biological reasoning system for appropriate chassis host selection by coupling with various GEM-models. By using a supercomputer to calculate the biosynthetic pathways for more than 1 month, nearly 50 000 000 biosynthetic pathways are computed for production of 6026 compounds within 70 microorganisms. With retrieved organisms for specified target production, several heterologous biosynthetic pathways can be shown in length order, and then the maximum theoretical yields and thermodynamic feasibility can be calculated in real time under customized growth conditions and physiological states. From the computation results, the system not only identifies experimentally validated pathways but also outputs more efficient solutions with less heterologous steps or higher maximum possible theoretical yield by engineering other organism hosts. CF-targeter is available at http://www.rxnfinder.org/cf_targeter/.

EcoSynther: A Customized Platform To Explore the Biosynthetic Potential in E. coli.

Developing computational tools for a chassis-centered biosynthetic pathway design is very important for a productive heterologous biosynthesis system by considering enormous foreign biosynthetic reactions. For many cases, a pathway to produce a target molecule consists of both native and heterologous reactions when utilizing a microbial organism as the host organism. Due to tens of thousands of biosynthetic reactions existing in nature, it is not trivial to identify which could be served as heterologous ones to produce the target molecule in a specific organism. In the present work, we integrate more than 10,000 E. coli non-native reactions and utilize a probability-based algorithm to search pathways. Moreover, we built a user-friendly Web server named EcoSynther. It is able to explore the precursors and heterologous reactions needed to produce a target molecule in Escherichia coli K12 MG1655 and then applies flux balance analysis to calculate theoretical yields of each candidate pathway. Compared with other chassis-centered biosynthetic pathway design tools, EcoSynther has two unique features: (1) allow for automatic search without knowing a precursor in E. coli and (2) evaluate the candidate pathways under constraints from E. coli physiological states and growth conditions. EcoSynther is available at http://www.rxnfinder.org/ecosynther/ .

Adenoid cystic carcinoma of the larynx: A report of two cases.

Laryngeal adenoid cystic carcinoma (ACC) is extremely rare, worldwide. From January 1994 to January 2014, all cases of laryngeal ACC that were diagnosed in the four largest hospitals in Hainan province, were reviewed. Only two such cases were identified. The first patient had a tumor in the subglottic region and the second patient, in the glottic region. The patient with subglottic ACC, who had experienced ongoing symptoms for 3 years, had previously been diagnosed with asthma, at a local hospital. Both presented at an advanced stage. The patient with subglottic disease received a total laryngectomy with a positive surgical margin, was treated with adjuvant radiotherapy, and later succumbed to a pleural effusion as a result of pulmonary metastases. The patient with glottic disease received a partial laryngectomy and declined adjuvant radiotherapy. Subsequently, she developed recurrent disease and passed away following an episode of asphyxia at 14 months post-surgery. Each of these cases had a poor prognosis at presentation. For patients with locoregionally advanced laryngeal ACC, more effective management strategies are required.