Short-term efficacy observation of venetoclax combined with azacitidine in treatment of patients with acute myeloid leukemia / 白血病·淋巴瘤

Objective:To explore the clinical short-term efficacy of venetoclax (Ven) combined with azacitidine (AZA) in treatment of newly treated and relapsed/refractory patients with acute myeloid leukemia (AML).Methods:The data of 18 newly treated and relapsed/refractory patients with AML who received Ven+AZA treatment in Suzhou Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine from April 2020 to June 2022 were retrospectively analyzed. The complete remission or complete remission with incomplete recovery of blood cell count (CR/CRi) and objective remission rate (ORR) [calculated as CR/CRi+partial remission (PR)] were analyzed in newly treated and relapsed/refractory patients or patients with different gene mutations. The patients were followed up until June 30, 2022, and the overall survival (OS) of relapsed/refractory patients was analyzed. The occurrence of adverse reactions was summarized.Results:The median age of the 18 patients was 58 years old (23-81 years old), 8 were males and 10 were females; 6 were newly treated and 12 were relapsed/refractory; the median follow-up time was 3 months (1-15 months). In 6 newly treated patients, after the first cycle of Ven+AZA, 5 cases achieved CR/CRi, and the ORR was 83.3% (5/6). In 12 relapsed/refractory patients, after the first cycle of Ven+AZA, 5 cases achieved CR/CRi, 3 achieved PR, and the ORR was 66.7% (8/12). Among the 18 patients, 7 cases had FLT3-ITD/TKD mutation, after the first cycle of Ven+AZA, 1 case achieved CR/CRi, 1 case achieved PR, and the ORR was 28.6% (2/7); 3 cases had NPM1 mutation combined with FLT3-ITD/TKD mutation, 1 case achieved CR/CRi, and the ORR was 33.3% (1/3); 4 cases had IDH1/2 mutation, and 3 cases of them combined with FLT3-ITD/TKD mutation, all of which were non-remission, and the other 1 relapsed/refractory patient combined with K/NRAS mutation achieved CR/CRi; among the 4 cases with K/NRAS mutation, 2 cases combined with FLT3-ITD/TKD mutation, including 1 case of NR and 1 case of PR, and the other 2 cases achieved CR/CRi, the ORR was 75.0% (3/4). Of the 12 relapsed/refractory patients, 6 died by the end of follow-up, with a median OS time of 2.6 months (1- 8 months), including 4 cases of disease progression and 2 cases of disease relapse; the 6 surviving patients had stable disease. All the 18 patients had ≥grade 3 hematologic adverse reactions, and non-hematologic adverse reactions included lung infection, nausea, vomiting and diarrhea.Conclusions:Ven+AZA treatment for newly treated and relapsed/refractory AML patients results in a high response rate with tolerable adverse reactions, but it is not effective in AML patients with FLT3-ITD/TKD mutation.

Equol and its enantiomers inhibited urethane-induced lung cancer in mice / 北京大学学报(医学版)

OBJECTIVE@#To investigate the effects and mechanisms of equol and its enantiomers on urethane-induced lung cancer in mice.@*METHODS@#A total of 120 5-week-old male C57BL/6 mice were randomly divided into 8 groups: lung cancer tumor control group (CG), genistein control group (GCG), low dose racemic equol group (LEG), high dose racemic equol group (HEG), low dose R-equol group (LRE), high dose R-equol group (HRE), low dose S-equol group (LSE) and high dose S-equol group (HSE). Urethane was injected subcutaneously twice a week for 4 weeks to induce lung cancer and then the mice were fed for 4 months. The body weight and food intake of each group were measured and recorded weekly. After the mice were sacrificed, the blood, livers and lungs of the mice were collected. The incidence of lung cancer in each group was recorded. The concentration of serum superoxide dismutase (SOD), malondialdehyde (MDA) and 8-hydroxydeoxygunosine (8-OHdG) were detected by the corresponding kits. Western blotting was used to detect the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in the livers. Between-group differences in body weight and food intake of the mice were compared using repeated measures ANOVA, and ANOVA for the differences between non-repeated measurements, with post hoc analysis using Tukey's method if there were between-group differences. Comparisons of categorical data were performed by chi-square test, and if there were differences between the groups, the Bonferroni method was used for pairwise comparison.@*RESULTS@#A total of 49 in the 120 mice developed lung cancer. The overall incidence of lung cancer was 40.8%. Compared with the control group, the incidence of lung cancers in each experimental group was lower, and the difference was statistically significant. The incidence of lung cancer in the high-dose experimental group was significantly lower than that in the low-dose experimental group. However, the incidence of lung cancer was similar in the three equol groups and the genistein group at the same dose. Compared with the control group, the high-dose experimental group had higher serum SOD concentration, lower MDA and 8-OHdG concentrations, and the differences were statistically significant. Western blotting analysis showed that the expression levels of Nrf2 protein in the experimental groups were higher than those in the control group except the low-dose racemic equol group, and the Nrf2 protein expression level in the high-dose equol groups was higher than that in the low-dose equol groups.@*CONCLUSION@#Racemic equol and its enantiomers mayinhibit lung carcinogenesis through antioxidant effects.

Correlation of Serum Concentration of Nilotinib with Clinical Efficacy in Patients with Chronic Myeloid Leukemia / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To investigate the correlation of the serum minimal concentrations (Cmins) of nilotinib(NIL) with the clinical efficacy and adverse events (AEs) in CML patients.</p><p><b>METHODS</b>A total of 54 patients were divided into two groups according to the dosage of nilotinib. 44 cases received dose of 600-800 mg/d were classified as group A; while 10 cases received dose of 400 mg/d as group B. The Cmins of nilotinib were determmined by liquid chromatography-tandem mass spectrometry.</p><p><b>RESULTS</b>Median Cmins of nilotinib in 54 patients was 1.71 (0.52-5.93) µg/ml. Cmins of nilotinib in group A and group B were 2.09± 1.21 µg/ml and 0.94± 0.27 µg/ml respectively, Cmins of group A was significantly higher than that of group B (P=0.001). In group A, 24 out of 44 cases obtained major molecular response (MMR) in 12 months, while 20 cases did not reach MMR in 12 months; the serum drug concentrations were 1.70± 0.75 µg/ml and 2.03± 0.82 µg/ml respectively, without statistically significant differences between these 2 subgroups(P=0.154). However, Cmins of nilotinib in patients with III-IV grade of adverse events were significantly higher than those in patients with 0-II grade of adverse events (3.09± 1.76 µg/ml vs 1.76± 0.68 µg/ml)(P=0.018). There was no statistic diffence in Cmins of nilotinib with MMR in 12 months of group A MMR 1.15± 0.27 µg/ml vs no MMR 0.83± 0.24 µg/ml(P=0.051). The MMR rate at 12 months in group A was 54.5%(24/44) and that in group B was 40%(4/10) (P=0.494). But the incidence of grade III-IV adverse events in group A was 29.5%(13/44), which was significantly higher than that of group B[0/10(0%)].</p><p><b>CONCLUSION</b>Cmins of nilotinib shows significant individual differences. The Cmins of nilotinib relate with the dosage and grade III-IV of adverse events. The lower dose of nilotinib may maintain a good therapeutic effect and significantly reduce the adverse events.</p>

Key technologies in synthetic biology of natural products / 中国中药杂志

Natural products with complex and diverse structures are the major sources of new drugs. The biosynthesis of natural products is considered to be one of the best ways to solve the problems of complex and scarce natural products. DNA assembly technology and genome editing technology are two key technologies in the emerging interdisciplinary field of synthetic biology. A number of novel DNA assembly methods developed in the last few years have paved the way for the engineering of high molecular weight DNA molecules, including whole genomes, hence, it can realize the reconstruction of the metabolic pathways and speed up optimization process. A wide variety of new tools for microbial genome editing will be applied widely to modify the chassis genome to increase its adaptation with the exogenetic pathways. This article summarized the latest advance with respect to DNA assembly and genome editing, which aims to provide help for reconstruction and optimization of the synthetic biological systems of natural products.

Strategies of elucidation of biosynthetic pathways of natural products / 中国中药杂志

Elucidation of the biosynthetic pathways of natural products is not only the major goal of herb genomics, but also the solid foundation of synthetic biology of natural products. Here, this paper reviewed recent advance in this field and put forward strategies to elucidate the biosynthetic pathway of natural products. Firstly, a proposed biosynthetic pathway should be set up based on well-known knowledge about chemical reactions and information on the identified compounds, as well as studies with isotope tracer. Secondly, candidate genes possibly involved in the biosynthetic pathway were screened out by co-expression analysis and/or gene cluster mining. Lastly, all the candidate genes were heterologously expressed in the host and then the enzyme involved in the biosynthetic pathway was characterized by activity assay. Sometimes, the function of the enzyme in the original plant could be further studied by RNAi or VIGS technology. Understanding the biosynthetic pathways of natural products will contribute to supply of new leading compounds by synthetic biology and provide "functional marker" for herbal molecular breeding, thus but boosting the development of traditional Chinese medicine agriculture.

Advance in flavonoids biosynthetic pathway and synthetic biology / 中国中药杂志

Flavonoids are the valuable components in medicinal plants, which possess a variety of pharmacological activities, including anti-tumor, antioxidant and anti-inflammatory activities. There is an unambiguous understanding about flavonoids biosynthetic pathway, that is,2S-flavanones including naringenin and pinocembrin are the skeleton of other flavonoids and they can transform to other flavonoids through branched metabolic pathway. Elucidation of the flavonoids biosynthetic pathway lays a solid foundation for their synthetic biology. A few flavonoids have been produced in Escherichia coli or yeast with synthetic biological technologies, such as naringenin, pinocembrin and fisetin. Synthetic biology will provide a new way to get valuable flavonoids and promote the research and development of flavonoid drugs and health products, making flavonoids play more important roles in human diet and health.

Advance in biosynthesis of terpenoid indole alkaloids and its regulation in Catharanthus roseus / 中国中药杂志

Catharanthus roseus can produce a variety of terpenoid indole alkaloids (TIA), most of which exhibit strong pharmacological activities. Hence, biosynthesis and regulation of TIA have received recent attention. 3α (S)-strictosidine is an important node in TIA biosynthesis, which is a condensation product of secologanin and tryptamine. The former is produced in iridoid pathway, and the latter is produced in indole pathway. Vindoline and catharanthine, which are produced respectively by 3α (S)-strictosidine via multi-step enzymatic reaction, can form α-3, 4-anhydrovinblastine by the condensation reaction. Then, vinblastine and vincristine are generated from α-3, 4-anhydrovinblastine. Many transcription factors are involved in the regulation of TIA synthesis, such as AP2/ERF and WRKY. Illumination of biosynthetic pathway has laid a foundation for the study of synthetic biology. Today, 3α (S)-strictosidine and vindoline have been synthesized in heterologous hosts Saccharomyces cerevisiae.Research about synthetic biology and the regulation mechanisms will provide a guidance for the production and development of TIA drugs in C. roseus.

Advance in transcriptomic studies of ginseng species / 中国中药杂志

There are many valuable medicinal plants in Ginseng genus belonging to Araliaceae. Among them, Panax ginseng, P. quinquefolium and P. notoginseng are the most famous species. With the development of next-generation sequencing (NGS) technologies, sequencing and analysis of transcriptomes have become powerful tools for discovery of novel genes, screening molecular markers and elucidation of specific biosynthetic pathway of secondary metabolites. Their transcriptomes provided abundant genes for further study on functional genomics. Here this paper summarized the recent advances in the transcriptomic studies of these three medicinal plants, including discovery of novel genes and elucidation of metabolic regulation, which will contribute to functional genomics in ginseng species.

Recent advances in biosynthetic pathway and synthetic biology of taxol / 中国中药杂志

Taxol, a kind of terpenoid secondary metabolite produced by Taxus brevifolia, is an effective anticancer drug that manufacture relies mainly on the extraction form plants. In order to solve the resource shortage, a lot of work has been done to develop the alternative method. Recently, using synthetic biology to realize heterologous biosynthesis of the precursors of taxol has become a hotspot. Now, the basic framework of taxol biosynthetic pathways has been confirmed, and most enzyme genes involved in taxol biosynthesis have been cloned and identified. The two taxol precursors, taxa-4(5),11(12)-diene and taxa-4(20),11(12)-dien-5α-ol, have been synthesized in Escherichia coli and Saccharomyces cerevisiae. Here this paper reviewed the recent advances in the biosynthetic pathway of taxol and the latest developments of synthetic biology, which aims to provide a guidance for the heterologous biosynthesis of taxol.

Advances in Transcriptomic Studies and Ginsenoside Biosynthesis of American Ginseng / 中草药·英文版

American ginseng (. Panax quinquefolius L.), belonging to the Araliaceae family, is one of the most widely used traditional herbs in the world. Its major bioactive constituents are triterpene saponins known as ginsenosides. Up to date, it is still a big challenge to sequence and assemble the large and repeat-enriched genome of tetraploid American ginseng, using whole genome shotgun (WGS) sequencing strategy. The lack of American ginseng genome information has significantly impeded its genetic and functional genomic studies. With the development of next-generation sequencing (NGS) technologies, sequencing and analysis of transcriptomes have become powerful tools for the discovery of novel genes and elucidation of specific biosynthetic pathways of secondary metabolites. Here we summarized the recent advances in the transcriptomic studies of American ginseng, including high-throughput transcriptome sequencing, assembly, and functional gene annotation and classification. Based on the results of transcriptomic data mining and co-expression analyses, many candidate genes possibly involved in the biosynthetic pathway of ginsenosides have been found, thereby providing an unparalleled opportunity to fully understand the mechanism of ginsenoside biosynthesis and its regulations in American ginseng. Advances in transcriptomic studies will contribute to the molecular breeding and planting management of American ginseng and to the development of novel ginsenoside-type drugs.

Comparison of magnetic resonance elastography and diffusion-weighted imaging for staging hepatic fibrosis / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>To compare the diagnostic values of magnetic resonance elastography (MRE) and diffusion-weighted imaging (DWI) in staging hepatic fibrosis (HF) in an animal model.</p><p><b>METHODS</b>This study consisted of 44 rabbits served as HF group and 9 normal rabbits. HF group was divided into two subgroups: Group A (n = 32) and Group B (n = 12). Rabbits in Group B were served as a complementary group when rabbits in Group A suddenly died during the study. Rabbits from control and Group A underwent abdominal MR imaging (MRI), MRE, and DWI. In Group A, random eight rabbits underwent MRI examinations at 4, 5, 6, 10 weeks after carbon tetrachloride oil subcutaneous injection. Liver stiffness (LS) and apparent diffusion coefficient (ADC) values of liver parenchyma were measured. The diagnostic performance of MRE and DWI for staging HF was compared using the receiver operating characteristic curve analysis on the basis of the histopathological analysis of HF.</p><p><b>RESULTS</b>Significant differences of LS and DWI values were present among HF stages (P < 0.005). The LS values measured on MRE (r = 0.838, P < 0.001) were more strongly correlated with the HF stages than with ADC values (r = -0.527, P < 0.001). The area under the receiver operating characteristic curve values of LS were significantly larger than those of DWI were for discriminating two stages of HF (0.979 vs. 0.712 for ≥ S1, 0.922 vs. 0.699 for ≥ S2). MRE showed higher specificity for predicting all stages of HF compared to DWI.</p><p><b>CONCLUSIONS</b>MRE more strongly correlated with the HF stages than DWI and is more specific in predicting all HF stages.</p>

Triple-phase helical CT in the differential diagnosis between small hepatocellular carcinoma and small hepatic cavernous hemangioma / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To scrutinize the enhancement pattern at hepatic arterial phase (HAP), portal venous phase (PVP) and delayed phase (DP) by helical CT examination in order to differentiate small hepatocellular carcinoma (SHCC) from small hepatic cavernous hemangioma (SHCH).</p><p><b>METHODS</b>In 38 patients (41 lesions) with SHCC and 35 patients (45 lesions) with SHCH, the images at HAP, PVP and DP were recorded as to the characteristic of enhancements with the average CT value at the HAP monitored and compared.</p><p><b>RESULTS</b>The enhancement patterns of SHCC at the HAP, PVP, and DP were assessed as hyper-hypo-hypodense in 20 lesions, hyper-iso-hypodense in 6 lesions, hyper-hyper-hypodense in 3 lesions, hyper-iso-isodense in 5 lesions, iso-hypo-hypodense in 3 lesions, and hypo-hypo-hypodense in 4 lesions. The enhancement patterns of the SHCH were assessed as a peripheral hyperdense nodular at HAP, then progressively enlarged at PVP and turned into a isodense or homogeneous hyperdense nodular at DP in 27 lesions, hyper-hyper-iso or hyperdense in 9 lesions, hyper-iso-isodense in 3 lesions, hypo-hypo-hypodense in 6 lesions. The enhancement CT values at the HAP of homogeneous hyperdense SHCC and SHCH were (40.4 +/- 15.5) Hounsfield Unit (HU) and (102.8 +/- 18.9) HU respectively (P < 0.01).</p><p><b>CONCLUSION</b>Most of the small hepatocellular carcinoma and small hepatic cavernous hemangioma have typical appearance by triple-phase helical CT examination, and can easily and properly be diagnosed. But it is difficult to distinguish SHCC from SHCH with atypical appearance in isolated cases. Hence differentiation may be difficult. Therefore, further examinations such as MRI, ultra-sonography or isotope scintigraphy are helpful in the differential diagnosis.</p>