RESUMEN
Objective: The purpose of this study was to understand the relationship between the multiple chronic conditions (MCC), mental health and cognitive function of older adults in the community, and to propose a hypothesis that depressive symptom mediate the number of chronic diseases and cognitive impairment in older adults. Method: Participants aged 65 years and older from 35 communities in 14 cities in Guangxi, China were recruited. The residents' depressive symptom (PHQ-9) and cognitive status (AD-8) were evaluated, Chi-square test was used to explore the effects of different socio-demographic characteristics on depressive symptom and cognitive impairment. Pearson correlation analysis and the process model 4 were used to explore the relationship between the number of chronic diseases, depressive symptom and cognitive impairment. Result: A total of 11,582 older adults were included in our analysis. The rate of MCC reaching 26.53%. Hypertension combined with diabetes accounts for the highest proportion of two chronic diseases (13.2%). Among the combination of three chronic diseases, the highest incidence of coexisting hypertension combined with cervical/lumbar spondylosis, and rheumatoid arthritis (7.1%). In this study, depression symptoms accounted for 12.9% of older adults aged 65 and above, and cognitive impairment accounted for 27.4%. Female, older age, reside in urban areas, lower educational levels, no spouse, live alone, and MCC were risk factors for depressive symptom and cognitive impairment in older adults (P<0.05). Depressive symptom had a mediating effect in the number of chronic diseases and cognitive impairment, and the mediating effect (1.109) accounted for 44.13% of the total effect (0.247). Conclusion: The mental health of the older adult needs to be taken seriously, and improving depressive symptom can reduce the occurrence of cognitive impairment in older patients with MCC to a certain extent.
RESUMEN
Aristolochia contorta Bunge is an academically and medicinally important plant species. It belongs to the magnoliids, with an uncertain phylogenetic position, and is one of the few plant species lacking a whole-genome duplication (WGD) event after the angiosperm-wide WGD. A. contorta has been an important traditional Chinese medicine material. Since it contains aristolochic acids (AAs), chemical compounds with nephrotoxity and carcinogenicity, the utilization of this plant has attracted widespread attention. Great efforts are being made to increase its bioactive compounds and reduce or completely remove toxic compounds. MicroRNAs (miRNAs) and natural antisense transcripts (NATs) are two classes of regulators potentially involved in metabolism regulation. Here, we report the identification and characterization of 223 miRNAs and 363 miRNA targets. The identified miRNAs include 51 known miRNAs belonging to 20 families and 172 novel miRNAs belonging to 107 families. A negative correlation between the expression of miRNAs and their targets was observed. In addition, we identified 441 A. contorta NATs and 560 NAT-sense transcript (ST) pairs, of which 12 NATs were targets of 13 miRNAs, forming 18 miRNA-NAT-ST modules. Various miRNAs and NATs potentially regulated secondary metabolism through the modes of miRNA-target gene-enzyme genes, NAT-STs, and NAT-miRNA-target gene-enzyme genes, suggesting the complexity of gene regulatory networks in A. contorta. The results lay a solid foundation for further manipulating the production of its bioactive and toxic compounds.
Asunto(s)
Aristolochia , Regulación de la Expresión Génica de las Plantas , Redes Reguladoras de Genes , MicroARNs , Metabolismo Secundario , MicroARNs/genética , MicroARNs/metabolismo , Aristolochia/genética , Metabolismo Secundario/genética , ARN sin Sentido/genética , Genoma de Planta , ARN de Planta/genéticaAsunto(s)
Inmunoconjugados , Enfermedad de Paget Extramamaria , Receptor ErbB-2 , Humanos , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Enfermedad de Paget Extramamaria/tratamiento farmacológico , Enfermedad de Paget Extramamaria/metabolismo , Inmunoconjugados/uso terapéutico , Femenino , Masculino , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Persona de Mediana Edad , Antineoplásicos Inmunológicos/uso terapéutico , Anciano de 80 o más AñosRESUMEN
Prunella vulgaris is an important material for Chinese medicines with rosmarinic acid (RA) as its index component. Based on the chromosome-level genome assembly we obtained recently, 51 RA biosynthesis-related genes were identified. Sequence feature, gene expression pattern and phylogenetic relationship analyses showed that 17 of them could be involved in RA biosynthesis. In vitro enzymatic assay showed that PvRAS3 catalyzed the condensation of p-coumaroyl-CoA and caffeoyl-CoA with pHPL and DHPL. Its affinity toward p-coumaroyl-CoA was higher than caffeoyl-CoA. PvRAS4 catalyzed the condensation of p-coumaroyl-CoA with pHPL and DHPL. Its affinity toward p-coumaroyl-CoA was lower than PvRAS3. UPLC and LC-MS/MS analyses showed the existence of RA, 4-coumaroyl-3',4'-dihydroxyphenyllactic acid, 4-coumaroyl-4'-hydroxyphenyllactic acid and caffeoyl-4'-hydroxyphenyllactic acid in P. vulgaris. Generation and analysis of pvras3 homozygous mutants showed significant decrease of RA, 4-coumaroyl-3',4'-dihydroxyphenyllactic acid, 4-coumaroyl-4'-hydroxyphenyllactic acid and caffeoyl-4'-hydroxyphenyllactic acid and significant increase of DHPL and pHPL. It suggests that PvRAS3 is the main enzyme catalyzing the condensation of acyl donors and acceptors during RA biosynthesis. The role of PvRAS4 appears minor. The results provide significant information for quality control of P. vulgaris medicinal materials.
RESUMEN
MicroRNAs (miRNAs) are a group of endogenous small non-coding RNAs in plants. They play critical functions in various biological processes during plant growth and development. Salvia miltiorrhiza is a well-known traditional Chinese medicinal plant with significant medicinal, economic, and academic values. In order to elucidate the role of miRNAs in S. miltiorrhiza, six small RNA libraries from mature roots, young roots, stems, mature leaves, young leaves and flowers of S. miltiorrhiza and one degradome library from mixed tissues were constructed. A total of 184 miRNA precursors, generating 137 known and 49 novel miRNAs, were genome-widely identified. The identified miRNAs were predicted to play diversified regulatory roles in plants through regulating 891 genes. qRT-PCR and 5' RLM-RACE assays validated the negative regulatory role of smi-miR159a in SmMYB62, SmMYB78, and SmMYB80. To elucidate the function of smi-miR159a in bioactive compound biosynthesis, smi-miR159a transgenic hairy roots were generated and analyzed. The results showed that overexpression of smi-miR159a caused a significant decrease in rosmarinic acid and salvianolic acid B contents. qRT-PCR analysis showed that the targets of smi-miR159a, including SmMYB62, SmMYB78, and SmMYB80, were significantly down-regulated, accompanied by the down-regulation of SmPAL1, SmC4H1, Sm4CL1, SmTAT1, SmTAT3, SmHPPR1, SmRAS, and SmCYP98A14 genes involved in phenolic acid biosynthesis. It suggests that smi-miR159a is a significant negative regulator of phenolic acid biosynthesis in S. miltiorrhiza.
Asunto(s)
Regulación de la Expresión Génica de las Plantas , Hidroxibenzoatos , MicroARNs , Salvia miltiorrhiza , Salvia miltiorrhiza/genética , Salvia miltiorrhiza/metabolismo , MicroARNs/genética , Hidroxibenzoatos/metabolismo , Raíces de Plantas/genética , Raíces de Plantas/metabolismo , ARN de Planta/genética , Genoma de PlantaRESUMEN
Background: Anti-Program-Death-1 (PD-1) is a standard adjuvant therapy for patients with resected melanoma. We hypothesized that there are discrepancies in survival, recurrence pattern and toxicity to adjuvant PD-1 between different ethnicities and melanoma subtypes. Objective: We performed a multicenter cohort study incorporating 6 independent institutions in Australia, China, Japan, and the United States. The primary outcomes were recurrence free survival (RFS) and overall survival (OS). Secondary outcomes were disease recurrence patterns and toxicities. Results: In total 534 patients were included. East-Asian/Hispanic/African reported significantly poorer RFS/OS. Nonacral cutaneous or melanoma of unknown primary reported the best RFS/OS, followed by acral, and mucosal was the poorest. Within the nonacral cutaneous or melanoma of unknown primary subtypes, East-Asian/Hispanic/African reported significantly poorer RFS/OS than Caucasian. In the multivariate analysis incorporating ethnicity/melanoma-subtype/age/sex/stage/lactate dehydrogenase/BRAF (v-Raf murine sarcoma viral oncogene homolog B)-mutation/adjuvant radiotherapy, East-Asian/Hispanic/African had independently significantly poorer outcomes (RFS: HR, 1.71; 95% CI, 1.19-2.44 and OS: HR, 2.34; 95% CI, 1.39-3.95), as was mucosal subtype (RFS: HR, 3.25; 95% CI, 2.04-5.17 and OS: HR, 3.20; 95% CI, 1.68-6.08). Mucosal melanoma was an independent risk factor for distant metastasis, especially liver metastasis. East-Asian/Hispanic/African had significantly lower incidence of gastrointestinal/musculoskeletal/respiratory/other-rare-type-toxicities; but higher incidences of liver toxicities. Limitations: A retrospective study. Conclusions: Ethnicity and melanoma subtype are associated with survival and recurrence pattern in melanoma patients treated with adjuvant anti-PD-1. Toxicity profile differs by ethnicity and may require a precision toxicity surveillance strategy.
RESUMEN
Aporphine alkaloids are a large group of natural compounds with extensive pharmaceutical application prospects. The biosynthesis of aporphine alkaloids has been paid attentions in the past decades. Here, we determined the contents of four 1-benzylisoquinoline alkaloids and five aporphine alkaloids in root, stem, leaf, and flower of Aristolochia contorta Bunge, which belongs to magnoliids. Two CYP80 enzymes were identified and characterized from A. contorta. Both of them catalyze the unusual C-C phenol coupling reactions and directly form the aporphine alkaloid skeleton. AcCYP80G7 catalyzed the formation of hexacyclic aporphine corytuberine. AcCYP80Q8 catalyzed the formation of pentacyclic proaporphine glaziovine. Kingdom-wide phylogenetic analysis of the CYP80 family suggested that CYP80 first appeared in Nymphaeales. The functional divergence of hydroxylation and C-C (or C-O) phenol coupling preceded the divergence of magnoliids and eudicots. Probable crucial residues of AcCYP80Q8 were selected through sequence alignment and molecular docking. Site-directed mutagenesis revealed two crucial residues E284 and Y106 for the catalytic reaction. Identification and characterization of two aporphine skeleton-forming enzymes provide insights into the biosynthesis of aporphine alkaloids.
Asunto(s)
Alcaloides , Aporfinas , Aristolochia , Sistema Enzimático del Citocromo P-450 , Filogenia , Proteínas de Plantas , Aporfinas/metabolismo , Aristolochia/enzimología , Aristolochia/metabolismo , Aristolochia/genética , Aristolochia/química , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Alcaloides/metabolismo , Hojas de la Planta/metabolismo , Hojas de la Planta/genética , Hojas de la Planta/enzimología , Raíces de Plantas/metabolismo , Raíces de Plantas/enzimología , Raíces de Plantas/genética , Flores/enzimología , Flores/genética , Flores/metabolismo , Tallos de la Planta/metabolismo , Tallos de la Planta/enzimología , Tallos de la Planta/genéticaRESUMEN
BACKGROUND: Bone metastasis (BM) is considered a poor prognostic factor of renal cell carcinoma (RCC). Confusion exists regarding how to deal with RCC patients with bone-only metastasis. PATIENTS AND METHODS: The clinical data of consecutive RCC patients with bone-only metastasis at Peking University Cancer Hospital between 2006 and 2018 were retrospectively collected and analyzed. RESULTS: Fifty-four eligible patients were screened from an RCC database of 1,878 metastatic patients. After a median follow-up of 43.6 m, 61.1% of the patients were presented with progression of prior BM or new BM. The progression-free survival (PFS) and overall survival (OS) was 16.2 m (95%CI: 11.4-21.0) and 65.2 m, respectively. For the 30 patients with oligo-metastasis (≤3 loci) and 24 ones with multiple-metastasis (>3 loci), the median OS was not reached and 42.0m (95%CI: 12.7-71.2) with statistical difference (P < 0.001). In the oligo-metastasis group, the median PFS of the 15 patients treated with local therapy and of the 13 patients treated with systemic therapy was 14.2 m (95%CI: 5.3-23.3) and 18.0 m (95%CI:15.4-20.6), respectively. In the multiple-metastasis group, the median PFS and OS of the 18 patients treated with systemic therapy was 16.6 m (95%CI: 7.5-25.7) and 63.9 m (95%CI: 21.8-106.0), respectively. Univariate analysis and multivariate analysis showed that the number of metastatic sites (oligo/multiple) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score, RCC pathological subtype were significantly associated with prognosis (P < 0.05). CONCLUSION: RCC patients with bone-only metastases have a favorable prognosis. The number of metastatic sites, IMDC, RCC pathological subtype could serve as survival predictors, which might provide clue of treatment modality.
Asunto(s)
Neoplasias Óseas , Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Estudios Retrospectivos , Pronóstico , Neoplasias Óseas/secundarioRESUMEN
Prunella vulgaris is one of the bestselling and widely used medicinal herbs. It is recorded as an ace medicine for cleansing and protecting the liver in Chinese Pharmacopoeia and has been used as the main constitutions of many herbal tea formulas in China for centuries. It is also a traditional folk medicine in Europe and other countries of Asia. Pentacyclic triterpenoids are a major class of bioactive compounds produced in P. vulgaris. However, their biosynthetic mechanism remains to be elucidated. Here, we report a chromosome-level reference genome of P. vulgaris using an approach combining Illumina, ONT, and Hi-C technologies. It is 671.95 Mb in size with a scaffold N50 of 49.10 Mb and a complete BUSCO of 98.45%. About 98.31% of the sequence was anchored into 14 pseudochromosomes. Comparative genome analysis revealed a recent WGD in P. vulgaris. Genome-wide analysis identified 35 932 protein-coding genes (PCGs), of which 59 encode enzymes involved in 2,3-oxidosqualene biosynthesis. In addition, 10 PvOSC, 358 PvCYP, and 177 PvUGT genes were identified, of which five PvOSCs, 25 PvCYPs, and 9 PvUGTs were predicted to be involved in the biosynthesis of pentacyclic triterpenoids. Biochemical activity assay of PvOSC2, PvOSC4, and PvOSC6 recombinant proteins showed that they were mixed amyrin synthase (MAS), lupeol synthase (LUS), and ß-amyrin synthase (BAS), respectively. The results provide a solid foundation for further elucidating the biosynthetic mechanism of pentacyclic triterpenoids in P. vulgaris.
Asunto(s)
Cromosomas de las Plantas , Genoma de Planta , Triterpenos Pentacíclicos , Prunella , Prunella/genética , Prunella/metabolismo , Triterpenos Pentacíclicos/metabolismo , Genoma de Planta/genética , Cromosomas de las Plantas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Filogenia , Transferasas Intramoleculares/genética , Transferasas Intramoleculares/metabolismo , Triterpenos/metabolismoRESUMEN
Background: Both dabrafenib/trametinib (D/T) and anti-PD-1 monotherapy (PD-1) are approved adjuvant therapies for patients with stage III BRAF V600-mutant melanoma. However, there is still a lack of head-to-head comparative data. We aimed to describe efficacy and toxicity outcomes for these two standard therapies across melanoma centers. Methods: This multicenter, retrospective cohort study was conducted in 15 melanoma centers in Australia, China, Germany, Italy, Japan, UK, and US. We included adult patients with resected stage III BRAF V600-mutant melanoma who received either adjuvant D/T or PD-1 between Jul 2015 and Oct 2022. The primary endpoint was relapse-free survival (RFS). Secondary endpoints included overall survival (OS), recurrence pattern and toxicity. Findings: We included 598 patients with stage III BRAF V600-mutant melanoma who received either adjuvant D/T (n = 393 [66%]) or PD-1 (n = 205 [34%]) post definitive surgery between Jul 2015 and Oct 2022. At a median follow-up of 33 months (IQR 21-43), the median RFS was 51.0 months (95% CI 41.0-not reached [NR]) in the D/T group, significantly longer than PD-1 (44.8 months [95% CI 28.5-NR]) (univariate: HR 0.66, 95% CI 0.50-0.87, P = 0.003; multivariate: HR 0.58, 95% CI 0.39-0.86, P = 0.007), with comparable OS with PD-1 (multivariate, HR 0.90, 95% CI 0.48-1.70, P = 0.75). Similar findings were observed using a restricted-mean-survival-time model. Among those who experienced recurrence, the proportion of distant metastases was higher in the D/T cohort. D/T had a higher incidence of treatment modification due to adverse events (AEs) than PD-1, but fewer persistent AEs. Interpretation: In patients with stage III BRAF V600-mutant melanoma post definitive surgery, D/T yielded better RFS than PD-1, with higher transient but lower persistent toxicity, and comparable OS. D/T seems to provide a better outcome compared with PD-1, but a longer follow-up and ideally a large prospective trial are needed. Funding: Dr. Xue Bai was supported by the Beijing Hospitals Authority Youth Programme (QMS20211101) for her efforts devoted to this study. Dr. Keith T. Flaherty was funded by Adelson Medical Research Foundation for the efforts devoted to this study.
RESUMEN
IMPORTANCE: Betacoronaviruses, including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and mouse hepatitis virus (MHV), exploit the lysosomal exocytosis pathway for egress. However, whether all betacoronaviruses members use the same pathway to exit cells remains unknown. Here, we demonstrated that porcine hemagglutinating encephalomyelitis virus (PHEV) egress occurs by Arl8b-dependent lysosomal exocytosis, a cellular egress mechanism shared by SARS-CoV-2 and MHV. Notably, PHEV acidifies lysosomes and activates lysosomal degradative enzymes, while SARS-CoV-2 and MHV deacidify lysosomes and limit the activation of lysosomal degradative enzymes. In addition, PHEV release depends on V-ATPase-mediated lysosomal pH. Furthermore, this is the first study to evaluate ßCoV using lysosome for spreading through the body, and we have found that lysosome played a critical role in PHEV neural transmission and brain damage caused by virus infection in the central nervous system. Taken together, different betacoronaviruses could disrupt lysosomal function differently to exit cells.
Asunto(s)
Betacoronavirus 1 , Infecciones por Coronavirus , Exocitosis , Lisosomas , Neuronas , Animales , Ratones , Betacoronavirus 1/metabolismo , Lisosomas/enzimología , Lisosomas/metabolismo , Lisosomas/virología , Virus de la Hepatitis Murina/metabolismo , Neuronas/enzimología , Neuronas/metabolismo , Neuronas/patología , Neuronas/virología , SARS-CoV-2/metabolismo , Porcinos/virología , Concentración de Iones de Hidrógeno , ATPasas de Translocación de Protón Vacuolares/metabolismo , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/transmisión , Infecciones por Coronavirus/virologíaRESUMEN
Background: Our study aimed to build a risk stratification system predicting the progression-free survival (PFS) to classify patients into diverse prognostic subgroups for advanced non-small-cell lung cancer patients treated with PD-(L)1 inhibitor. Methods: 404 patients from our center were enrolled in this study and 70% patients (n = 282) were randomly assigned into the training cohort and other 30% patients (n = 122) into the validation cohort. A testing cohort contained 81 patients from other centers were used to assess the generalizability of model. Cox regression analyses were used to identify the most significant clinical parameters. The model's performance was assessed by using concordance index (C-index), calibration curves, Decision Curve Analyses (DCAs), net reclassification improvement (NRI), integrated discrimination improvement (IDI) analyses, and survival curve. Results: Five clinical parameters were identified as the most significant predictors by using cox regression. We then integrated them into a Nomogram to Evaluate the relative PFS of ICIs Treatment (NEPIT). The C-index of NEPIT in the training cohort, the validation cohort and testing cohort was 0.789 (95%CI: 0.750-0.828), 0.745 (95%CI: 0.706-0.784), and 0.766 (95%CI: 0.744-0.788), respectively. The calibration curves presented a good congruence between the predictions and actual observations. The Decision Curve Analyses (DCAs) reflected positive net benefits can be obtained for NEPIT. The results from NRI and IDI analyses showed that the NEPIT could improve predictive power of TPS. In addition, the further constructed risk stratification system could effectively categorize patients into different risk subgroups. Conclusion: The tools developed in this study would have value in guiding the optimal patient selection for precision care.
RESUMEN
Salvia miltiorrhiza is a model medicinal plant with significant economic and medicinal value. Its roots produce a group of diterpenoid lipophilic bioactive components, termed tanshinones. Biosynthesis and regulation of tanshinones has attracted widespread interest. However, the methylome of S. miltiorrhiza has not been analysed and the regulatory mechanism of DNA methylation in tanshinone production is largely unknown. Here we report single-base resolution DNA methylomes from roots and leaves. Comparative analysis revealed differential methylation patterns for CG, CHG, and CHH contexts and the association between DNA methylation and the expression of genes and small RNAs. Lowly methylated genes always had higher expression levels and 24-nucleotide sRNAs could be key players in the RdDM pathway in S. miltiorrhiza. DNA methylation variation analysis showed that CHH methylation contributed mostly to the difference. Go enrichment analysis showed that diterpenoid biosynthetic process was significantly enriched for genes with downstream overlapping with hypoCHHDMR in July_root when comparing with those in March_root. Tanshinone biosynthesis-related enzyme genes, such as DXS2, CMK, IDI1, HMGR2, DXR, MDS, CYP76AH1, 2OGD25, and CYP71D373, were less CHH methylated in gene promoters or downstream regions in roots collected in July than those collected in March. Consistently, gene expression was up-regulated in S. miltiorrhiza roots collected in July compared with March and the treatment of DNA methylation inhibitor 5-azacytidine significantly promoted tanshinone production. It suggests that DNA methylation plays a significant regulatory role in tanshinone biosynthesis in S. miltiorrhiza through changing the levels of CHH methylation in promoters or downstreams of key enzyme genes.
RESUMEN
BACKGROUND: The proliferation marker Ki67 is associated with the progression and prognosis of melanoma. However, its prognostic impact on acral melanoma (AM) remains unclear. METHODS: A total of 314 AM patients were enrolled from a cohort of 5758 patients with melanoma at Peking University Cancer Hospital between 2006 and 2018. The patients were divided into Ki67 high- and low-expressing groups using a cut-off value of 30%. The associations between Ki67 and clinicopathologic characteristics as well as survival were analyzed. Cox proportional regression analysis was used to establish a nomogram to predict the survival probabilities of AM. RESULTS: Among 314 patients, the Ki67-high group (Ki67 ≥ 30%) included 49.4% of patients at diagnosis. Patients in the Ki67-high group had lower median melanoma-specific survival (MSS) than those in the Ki67-low group (60.7 months vs. not reached, p < 0.001). In multivariate analyses, Ki67, lymph node metastasis and primary site were independent prognostic factors for MSS. The nomogram showed that Ki67 had the fourth greatest impact on survival, following Breslow thickness, lymph node metastasis and primary site. The C-index of the nomogram was 0.765 and 0.758 in the training and validation cohort, respectively. Area under the curve values were both near 0.8 in the training and validation cohorts. Net reclassification improvement and integrated discrimination improvement demonstrated that the predictive nomogram performed better than the traditional AJCC staging system. CONCLUSION: Ki67 expression is an independent prognostic factor for MSS in AM. A predictive model incorporating Ki67 and clinical factors was constructed to predict the prognosis of AM.
RESUMEN
Salvia miltiorrhiza is well known for its clinical practice in treating heart and cardiovascular diseases. Its roots, used for traditional Chinese medicine materials, are usually brick-red due to accumulation of red pigments, such as tanshinone IIA and tanshinone I. Here we report a S. miltiorrhiza line (shh) with orange roots. Compared with the red roots of normal S. miltiorrhiza plants, the contents of tanshinones with a single bond at C-15,16 were increased, whereas those with a double bond at C-15,16 were significantly decreased in shh. We assembled a high-quality chromosome-level genome of shh. Phylogenomic analysis showed that the relationship between two S. miltiorrhiza lines with red roots was closer than the relationship with shh. It indicates that shh could not be the mutant of an extant S. miltiorrhiza line with red roots. Comparative genomic and transcriptomic analyses showed that a 1.0 kb DNA fragment was deleted in shh Sm2OGD3m. Complementation assay showed that overexpression of intact Sm2OGD3 in shh hairy roots recovered furan D-ring tanshinone accumulation. Consistently, in vitro protein assay showed that Sm2OGD3 catalyzed the conversion of cyptotanshinone, 15,16-dihydrotanshinone I and 1,2,15,16-tetrahydrotanshinone I into tanshinone IIA, tanshinone I and 1,2-dihydrotanshinone I, respectively. Thus, Sm2OGD3 functions as tanshinone 15,16-dehydrogenase and is a key enzyme in tanshinone biosynthesis. The results provide novel insights into the metabolic network of medicinally important tanshinone compounds.
RESUMEN
Importance: Acral melanoma, known for low tumor mutation burden, responds poorly to immunotherapy. A standard therapy is still lacking. Objective: To investigate the activity and safety of camrelizumab (an anti-programmed cell death-1 antibody) plus apatinib (a vascular endothelial growth factor receptor 2 inhibitor) and temozolomide as first-line treatment in patients with advanced acral melanoma. Design, Setting, and Participants: In this single-arm, single-center, phase 2 nonrandomized clinical trial, patients with treatment-naive unresectable stage III or IV acral melanoma were enrolled at Peking University Cancer Hospital and Institute between June 4, 2020, and August 24, 2021. The data cutoff date was April 10, 2022. Interventions: Patients received 4-week cycles of intravenous camrelizumab, 200 mg, every 2 weeks; oral apatinib 250 mg, once daily; and intravenous temozolomide, 200 mg/m2, once daily on days 1 to 5 until disease progression or unacceptable toxic effects. Main Outcomes and Measures: The primary end point was objective response rate as assessed by investigators according to the Response Evaluation Criteria In Solid Tumors (version 1.1). Secondary end points included progression-free survival, time to response, duration of response, disease control rate, overall survival, and safety. Results: A total of 50 patients (32 men [64%]; median age, 57 years [IQR, 52-62 years]) were enrolled and received treatment. The median follow-up duration was 13.4 months (IQR, 9.6-16.2 months). The objective response rate was 64.0% (32 of 50; 95% CI, 49.2%-77.1%). The median time to response and duration of response were 2.7 months (IQR, 0.9-2.9 months) and 17.5 months (95% CI, 12.0 to not reached), respectively. The disease control rate was 88.0% (44 of 50; 95% CI, 75.7%-95.5%). The estimated median progression-free survival was 18.4 months (95% CI, 10.6 to not reached). The median overall survival was not reached. The most common grade 3 or 4 treatment-related adverse events were increased gamma-glutamyltransferase levels (15 [30%]), decreased neutrophil count (11 [22%]), increased conjugated bilirubin levels (10 [20%]), and increased aspartate aminotransferase levels (10 [20%]). No treatment-related deaths occurred. Conclusions and Relevance: The findings of this nonrandomized clinical trial suggest that camrelizumab plus apatinib and temozolomide may be a potential first-line treatment option for patients with advanced acral melanoma, which warrants further validation in a randomized clinical trial. Trial Registration: ClinicalTrials.gov Identifier: NCT04397770.
Asunto(s)
Melanoma , Factor A de Crecimiento Endotelial Vascular , Masculino , Humanos , Persona de Mediana Edad , Temozolomida/uso terapéutico , Melanoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Melanoma Cutáneo MalignoRESUMEN
Contamination of soil by petroleum is becoming increasingly serious in the world today. However, the research on gene functional characteristics, metabolites and distribution of microbial genomes in oil-contaminated soil is limited. Considering that, metagenomic and metabonomic were used to detect microbes and metabolites in oil-contaminated soil, and the changes of functional pathways were analyzed. We found that oil pollution significantly changed the composition of soil microorganisms and metabolites, and promoted the relative abundance of Pseudoxanthomonas, Pseudomonas, Mycobacterium, Immundisolibacter, etc. The degradation of toluene, xylene, polycyclic aromatic hydrocarbon and fluorobenzoate increased in Xenobiotics biodegradation and metabolism. Key monooxygenases and dioxygenase systems were regulated to promote ring opening and degradation of aromatic hydrocarbons. Metabolite contents of polycyclic aromatic hydrocarbons (PAHs) such as 9-fluoronone and gentisic acid increased significantly. The soil microbiome degraded petroleum pollutants into small molecular substances and promoted the bioremediation of petroleum-contaminated soil. Besides, we discovered the complete degradation pathway of petroleum-contaminated soil microorganisms to generate gentisic acid from the hydroxylation of naphthalene in PAHs by salicylic acid. This study offers important insights into bioremediation of oil-contaminated soil from the aspect of molecular regulation mechanism and provides a theoretical basis for the screening of new oil degrading bacteria.
Asunto(s)
Petróleo , Hidrocarburos Policíclicos Aromáticos , Contaminantes del Suelo , Petróleo/análisis , Metagenómica , Microbiología del Suelo , Biodegradación Ambiental , Hidrocarburos Policíclicos Aromáticos/metabolismo , Metabolómica , Suelo , Contaminantes del Suelo/metabolismo , Hidrocarburos/metabolismoRESUMEN
BACKGROUND: Patients with laryngeal cancer have more than five times the incidence of suicide compared with the general population. In this study, we aimed to develop an online risk stratification system, named Larysuicide, to identify patients at high risk of suicide after the laryngeal cancer diagnosis. METHODS: Forty-two thousand and sixty-six American patients from the SEER-18 database and 4207 Chinese patients from our center were included in this study. We randomly assigned American patients into the training set and validation set at a ratio of 7:3, and all Chinese patients remained as an independent external testing set. LASSO regression model was applied for data dimension reduction, feature selection, and Larysuicide building. The performance of model was evaluated and validated by C-index, AUC, calibration curves, decision curve analysis (DCA), and univariate regression analysis. RESULTS: The Larysuicide developed with seven selected features-age, race, cancer site, pathological subtype, grade, stage at presentation, and radiation. The model showed good discrimination, with a C-index of 0.745 (95% CI 0.723-0.767) in training set, 0.759 (95% CI 0.722-0.800) in validation set, and 0.749 (95% CI 0.730-0.769) in testing set. The AUC was 0.745 in training set, 0.759 in validation set, and 0.749 in testing set. The calibration curves showed good calibration. Decision curve analysis demonstrated that Larysuicide was clinically useful. The univariate regression analysis presented patients in the high-risk group identified by Larysuicide suffered a significantly higher risk of committing suicide after cancer diagnosis. CONCLUSION: We constructed an online risk stratification system which could help health-care professionals efficiently identify patients at high risk of suicide after the laryngeal cancer diagnosis. Larysuicide could be a useful tool for health-care professionals to implement an early and appropriate psychological intervention in context of precision medicine.