Deep learning-based de novo drug design: principles, tools and practice / 药学学报

Design of structurally-novel drug molecules with deep learning can overcome the technical bottleneck of classical computer-aided drug design. It has become the frontier of new technique research on drug design, and has shown great potential in drug research and development practice. This review starts from the basic principles of deep learning-driven de novo drug design, goes on with the brief introduction to deep molecular generation techniques as well as computational tools and the analysis on representative successful cases, and eventually provides our perspective for future direction and application prospect about this technique. This review will provide ideas on new technique research and references for new drug research and development practice to which this technique is applied.

Clinicopathological characteristics and endoscopic treatment efficacy of de novo early colorectal cancer / 中华消化内镜杂志

Objective:To analyze the clinicopathological features of de novo early colorectal cancer and to evaluate the efficacy of endoscopic treatment.Methods:Patients with de novo early colorectal cancer who underwent endoscopic resection in Beijing Friendship Hospital, Capital Medical University from June 2020 to May 2022 were enrolled. The baseline data, endoscopic manifestations, treatment methods, postoperative pathological results and prognosis of the patients were collected retrospectively.Results:A total of 33 patients with de novo early colorectal cancer were enrolled with the age of 62.67 ± 8.62 years, and the male to female ratio was 7.25∶1. The long diameter of lesions was 0.96 ± 0.36 cm. The lesion morphology was mainly superficial phenotype (type 0-Ⅱ), accounting for 72.7% (24/33). Endoscopic submucosal dissection (ESD) was performed in 29 cases and endoscopic mucosal resection (EMR) was performed in 4 cases. Postoperative pathology showed that 11 cases (33.3%) were well differentiated tubular adenocarcinoma, of which the superficial submucosal layer was invaded in 2 cases. Twenty cases (60.6%) were moderately differentiated tubular adenocarcinoma, of which the superficial submucosa layer was invaded in 5 cases and the deep submucosa layer in 15 cases. Two cases (6.1%) were moderately-poorly differentiated tubular adenocarcinoma, where the deep submucosa layer was invaded in both. There was significant correlation between the depth of invasion and the degree of differentiation ( P<0.001), and moderately and moderately-poorly differentiated lesions were more likely to invade the deep submucosa layer. The en bloc resection rate was 100.0% (33/33), the complete resection rate was 97.0% (32/33), and the curative resection rate was 42.4% (14/33). Among the 19 patients who did not achieve curative resection, 13 patients received supplementary surgical treatment. No tumor residue or lymph node metastasis was found in the postoperative pathology. All patients were followed up for 3-25 months, and no signs of local recurrence or metastasis were found. Conclusion:Most de novo early colorectal cancers are superficial phenotype under endoscopy. The pathology is mainly moderately differentiated tubular adenocarcinoma. Endoscopic resection of de novo early colorectal cancer shows encouraging short-term efficacy.

A case of developmental epileptic encephalopathy type 67 caused by CUX2 gene mutation and literature review / 中华神经科杂志

Objective:To summarize the clinical phenotype and CUX2 gene variation characteristics of developmental epileptic encephalopathy type 67 confirmed by whole exome sequencing. Methods:Clinical data of 1 case diagnosed as CUX2 gene mutations related developmental epileptic encephalopathy type 67 in the Children′s Hospital Affiliated to Zhengzhou University in January 2021 were collected, the patient′s clinical characteristics, genetic testing, head imaging, electroencephalogram results and treatment were summarized, and the patient was regularly followed-up every 3 months. At the same time, the domestic and foreign literatures on epileptic encephalopathy caused by CUX2 gene mutation were reviewed. Results:The proband was a 6 years and 4 months old girl. The main clinical manifestations included focal origin progression to bilateral tonic-clonic seizures, retardation of intellectual, language, and motor development, autistic behavior, hyperactivity disorder, and involuntary hand clapping. The video electroencephalogram showed extensive spiny slow wave and multi-spiny slow wave emission in waking and sleeping stages, and spiny slow wave and spiky slow wave emission in bilateral anterior head in sleeping stage. Brain magnetic resonance imaging (MRI) plain scan and T 2-fluid attenuated inversion recovery (T 2-FLAIR) thin layer scan showed that the signal of the left hippocampus was higher than that of the right, and the left hippocampus was slightly swollen. One month later, the brain MRI and T 2-FLAIR were reexamined. The left hippocampal signal was still slightly higher and decreased, and the hippocampal volume was slightly reduced. Whole exome sequencing showed the CUX2 gene with c.1768G>A(p.Glu590Lys) heterozygous missense variant, which was a reported de novo pathogenic variant and both of her parents were wild-type. A total of 10 cases of new heterozygous missense variants in CUX2 gene [c.1768G>A (p.Gelu590Lys)] were reported in 4 literatures. No relevant cases have been reported in China. Conclusions:Developmental epileptic encephalopathy type 67 is relatively rare. The main clinical features are seizures, global developmental delay, movement disorders, athetosis, autism and hyperactivity disorder. The heterozygous missense variant c.1768G>A (Glu590Lys) of CUX2 gene maybe the genetic cause of this case.

Anemoside B4 regulates fatty acid metabolism reprogramming in mice with colitis-associated cancer / 中国中药杂志

The study aimed to investigate the effect of anemoside B4(B4) on fatty acid metabolism in mice with colitis-associated cancer(CAC). The CAC model was established by azoxymethane(AOM)/dextran sodium sulfate(DSS) in mice. Mice were randomly divided into a normal group, a model group, and low-, medium-, and high-dose anemoside B4 groups. After the experiment, the length of the mouse colon and the size of the tumor were measured, and the pathological alterations in the mouse colon were observed using hematoxylin-eosin(HE) staining. The slices of the colon tumor were obtained for spatial metabolome analysis to analyze the distribution of fatty acid metabolism-related substances in the tumor. The mRNA levels of SREBP-1, FAS, ACCα, SCD-1, PPARα, ACOX, UCP-2, and CPT-1 were determined by real-time quantitative PCR(RT-qPCR). The results revealed that the model group showed decreased body weight(P<0.05) and colon length(P<0.001), increased number of tumors, and increased pathological score(P<0.01). Spatial metabolome analysis revealed that the content of fatty acids and their derivatives, carnitine, and phospholipid in the colon tumor was increased. RT-qPCR results indicated that fatty acid de novo synthesis and β-oxidation-related genes, such as SREBP-1, FASN, ACCα, SCD-1, ACOX, UCP-2, and CPT-1 mRNA expression levels increased considerably(P<0.05, P<0.001). After anemoside B4 administration, the colon length increased(P<0.01), and the number of tumors decreased in the high-dose anemoside B4 group(P<0.05). Additionally, spatial metabolome analysis showed that anemoside B4 could decrease the content of fatty acids and their derivatives, carnitine, and phospholipids in colon tumors. Meanwhile, anemoside B4 could also down-regulate the expression of FASN, ACCα, SCD-1, PPARα, ACOX, UCP-2, and CPT-1 in the colon(P<0.05, P<0.01, P<0.001). The findings of this study show that anemoside B4 may inhibit CAC via regulating fatty acid metabolism reprogramming.

Dedifferentiated chordoma: A rare tumor with diagnostic challenge

Chordomas are rare locally invasive malignant bone tumors arising from remnants of embryonic notochord. Dedifferentiated chordoma (DC), a rare subtype, is characterized by the presence of a sarcomatous component in conventional chordoma (CC) which may arise de novo or as a malignant transformation of previously treated chordoma. The presence of dedifferentiation warrants a poor prognosis due to distant metastasis and recurrences. De novo DCs pose a diagnostic challenge especially in small biopsies and at metastatic sites. Here, we report the case of a 45-year-old female presenting with a long history of backache and constipation, finally diagnosed as DC. Radiological as well as histomorphological pictures of the tumor posed diagnostic challenges because they can mimic other tumors occurring in a similar location. We found this case worth reporting as de novo DC is rarely reported in the literature and it has the potential to pose diagnostic as well as therapeutic challenges.

De-novo Histoid Leprosy: A Series of Four Cases

Histoid leprosy, an unusual variant of lepromatous leprosy, originally thought to manifest following dapsone monotherapy, is being increasingly reported ‘de-novo’. We hereby report four de-novo cases; one mimicking lupus pernio presenting with an uncommon lesion (plaque) at an extremely rare site (nose). Of the remaining three classical cases, one exhibited a not-so-frequent development of erythema nodosum leprosum (ENL) reaction that needed modified multidrug therapy for two years, other three responded well to standard multibacillary multidrug therapy which was also given for two years.

The role of lipids and fatty acid metabolism in the development of prostate cancer

The reprogramming of lipid metabolism and signaling pathways is the central aspect of cancer biology. It is hypothesized that tumor cells can alter the lipid spectrum in order to fulfill their metabolic requirements. Furthermore, they can alter potential tumors and suppressive mechanisms in which lipids' involvement is essential. Recently, more attentions have been given on the alteration of lipid metabolism during prostate cancer development, and investigations have shown unique regulation of "de novo" lipid synthesis in cancer cells. Cancer cells often use newer pathways and enzymes to simplify the synthesis of fatty acids, and the newly synthesized lipids affect cellular processes, which impacts cancer cell proliferation and survival outcomes. Herein, we aimed to study the influence of lipid profile alterations on the development of prostate cancer. We found that the total amounts of lipids and phospholipids were increased within tissues from men with the malignant prostate tumor as compared with the benign prostate tissue. Significant changes were also observed in the composition of saturated and unsaturated fatty acids within the malignant tumor tissues. Intensification of lipid peroxidation has also been observed in malignant prostate tumors compared to benign prostate tumors. Collectively, these findings further highlights the fact that lipid and fatty acids play unique regulatory roles in the cellular development of prostate malignant transformation.

Insuficiencia cardíaca de novo: Un reto diagnóstico / Di novo heart failure: A diagnostic challenge

Introducción: El término insuficiencia cardíaca de novo hace referencia a pacientes sin diagnóstico previo de dicha enfermedad. La revisión de este tema deviene de un problema real, pues muchos pacientes acuden a la atención secundaria sin diagnóstico previo de insuficiencia cardíaca y además en estadios avanzados. Objetivo: Describir los elementos claves para el diagnóstico precoz de insuficiencia Cardíacas. Métodos: Se llevó a cabo una búsqueda bibliográfica en las siguientes bases de datos: Pubmed, SciELO, ESBCO, Cochrane y BVS, así como en diferentes webs médicas durante tres meses entre febrero de 2021 al 31 de mayo de 2021. Conclusiones: El diagnóstico precoz de insuficiencia cardíaca permitió disminuir el número de pacientes que llegan a la Atención Secundaria sin diagnóstico previo. Existen clasificaciones que identifican estadios tempranos de la enfermedad y la de la ACC/AHA es relevante para lograr este objetivo. En atención primaria esto es un reto si no se emplean pruebas diagnósticas como el ecocardiograma. Es importante la determinación de las concentraciones circulantes del péptido natriurético tipo B (BNP) y del fragmento N-terminal de su protohormona (N-terminal BNP). Este biomarcador debería estar accesible en las consultas ambulatorias para pacientes que presentan sospecha clínica de insuficiencia cardíaca «de novo»(AU)

Introduction: The term di novo heart failure refers to patients without a previous diagnosis of this disease. The review of this issue comes from a real problem, since a group of patients attend secondary care without a previous diagnosis of heart failure and also have in advanced stages. Objective: The objective is to provide a clue that facilitates the early diagnosis of heart failure. Methods: A bibliographic search was carried out in the following databases: Pubmed, SciELO, ESBCO, Cochrane and BVS, as well as in different medical websites for three months (February 1, 2021 to May 31, 2021). Conclusions: The early diagnosis of heart failure will allow us to reduce the number of patients who arrive at Secondary Care without a previous diagnosis. There are classifications that identify early stages of the disease, being in our opinion the ACC / AHA classification the one that should carry the most weight. In primary care this can be a challenge if diagnostic tests such as echocardiography are not used. Dosification of serum levels of type B natriuretic peptide (BNP) and the N-terminal fragment of its protohormone (N-terminal BNP) is very useful. This biomarker should be accessible in outpatient clinics for patients with clinical suspicion of di novo heart failure(AU)

Exploring the association between de novo mutations and non-syndromic cleft lip with or without palate based on whole exome sequencing of case-parent trios / 北京大学学报(医学版)

OBJECTIVE@#To explore the association between de novo mutations (DNM) and non-syndromic cleft lip with or without palate (NSCL/P) using case-parent trio design.@*METHODS@#Whole-exome sequencing was conducted for twenty-two NSCL/P trios and Genome Analysis ToolKit (GATK) was used to identify DNM by comparing the alleles of the cases and their parents. Information of predictable functions was annotated to the locus with SnpEff. Enrichment analysis for DNM was conducted to test the difference between the actual number and the expected number of DNM, and to explore whether there were genes with more DNM than expected. NSCL/P-related genes indicated by previous studies with solid evidence were selected by literature reviewing. Protein-protein interactions analysis was conducted among the genes with protein-altering DNM and NSCL/P-related genes. R package "denovolyzeR" was used for the enrichment analysis (Bonferroni correction: P=0.05/n, n is the number of genes in the whole genome range). Protein-protein interactions among genes with DNM and genes with solid evidence on the risk factors of NSCL/P were predicted depending on the information provided by STRING database.@*RESULTS@#A total of 339 908 SNPs were qualified for the subsequent analysis after quality control. The number of high confident DNM identified by GATK was 345. Among those DNM, forty-four DNM were missense mutations, one DNM was nonsense mutation, two DNM were splicing site mutations, twenty DNM were synonymous mutations and others were located in intron or intergenic regions. The results of enrichment analysis showed that the number of protein-altering DNM on the exome regions was larger than expected (P < 0.05), and five genes (KRTCAP2, HMCN2, ANKRD36C, ADGRL2 and DIPK2A) had more DNM than expected (P < 0.05/(2×19 618)). Protein-protein interaction analysis was conducted among forty-six genes with protein-altering DNM and thirteen genes associated with NSCL/P selected by literature reviewing. Six pairs of interactions occurred between the genes with DNM and known NSCL/P-related genes. The score measuring the confidence level of the predicted interaction between RGPD4 and SUMO1 was 0.868, which was higher than the scores for other pairs of genes.@*CONCLUSION@#Our study provided novel insights into the development of NSCL/P and demonstrated that functional analyses of genes carrying DNM were warranted to understand the genetic architecture of complex diseases.

A novel mutation in PAX6 gene causing congenital iris coloboma with congenital cataract in a pedigree / 中华实验眼科杂志

Objective:To identify the pathogenic gene and inheritance pattern in a pedigree of congenital iris coloboma with congenital cataract.Methods:The method of pedigree investigation was adopted.A pedigree of congenital iris coloboma with congenital cataract was collected by Yunnan Disabled Rehabilitation Center and the 2nd Afliated Hospital of Kunming Medical University in February 2020.Ophthalmic examinations were carried out on the female proband, her parents, her children and her husband, and the clinical diagnosis was made.Genomic DNA was extracted from peripheral blood samples collected from the family members.The suspected pathogenic gene in the proband and her husband was screened by whole exome sequencing and was identified by bioinformatics analysis.The amino acid conservation was analyzed by UGENE software.The impact of the mutation on protein translation was predicted using MutationTaster software.The pathogenicity of the mutation was assessed according to the American College of Medical Genetics (ACMG) Standards and Guidelines.Pathogenic gene and mutations were verified by Sanger sequencing.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of the 2nd Afliated Hospital of Kunming Medical University (No.PJ-2020-61).Written informed consent was obtained from each subject or custodian.Results:The proband showed large iris defects in both eyes with only a small amount of observable iris tissue in the periphery, lens cortical opacity and posterior capsule opacification, accompanied by nystagmus.A novel heterozygous frameshift variation c. 415dupA (p.R139fs) was located in exon 8 of PAX6 gene, and the variation was conservative across multiple species.The variation was in the highly conserved region of PAX6 gene and caused the dysfunction of PAX6 protein.The variation was graded as PVS1+ PM2+ PP1, a pathogenic variation, based on ACMG guidelines.The pedigree was consistent with co-segregation, indicating that the novel variation was pathogenic.The proband and her children were diagnosed, but her parents were phenotypically normal, in accordance with autosomal dominant inheritance. Conclusions:The novel frameshift variation c.415dupA (p.R139fs) on the exon 8 of PAX6 gene is responsible for congenital iris coloboma with congenital cataract in the pedigree.This is the first report of this novel variation in PAX6 gene.

Congenital disorder of glycosylation caused by de novo variant of SLC35A2 gene: a case report / 中华神经科杂志

Congenital disorder of glycosylation (CDG) is a group of genetic metabolic diseases involving multiple organs. A case of CDG caused by SLC35A2 gene mutation was diagnosed. The clinical characteristics included spasms, developmental retardation and multiple malformations. Video-electroencephalogram showed dysrhythmia. A de novo heterozygous missense mutation of SLC35A2 gene was detected by whole exome sequencing: c.844G>A (p.Gly282Arg). It was predicted to be likely pathogenic according to American College of Medical Genetics and Genomics guidelines which had not been reported in China.

Compound Kushen injection induces immediate hypersensitivity reaction through promoting the production of platelet-activating factor via de novo pathway / 中国药理学与毒理学杂志

OBJECTIVE Compound Kushen injection (CKI) is a bis-herbal formulation extracted from Kushen (Radix Sophorae Flavescentis) and Baituling (Rhizoma Heterosmilacis Japonicae). Clinically, it is used as the adjuvant treat?ment of cancer. However, with the increased application, the cases of immediate hypersensitivity reactions (IHRs) also gradually rise. In this study, we investigated the underlying mechanism(s) and active constituent(s) for CKI-induced IHRs in experimental models. METHODS T helper 2 (Th2) immunity-amplified mice were prepared by aluminum adjuvant. Anaphylactic shock was detected by measuring rectal thermometry in propranolol pretreated mice. For evaluating micro?vascular permeability, Evans blue extravasation assay was used. Platelet-activating factor (PAF), serum total IgE (tIgE) and mouse mast cell protease 1 (MMCP1) were measured by ELISA. RESULTS The obtained results showed that CKI did not elevate serum tIgE and MMCP1 after consecutive immunization for five weeks, but could induce Evans blue extravasation (local) and cause obvious hypothermia (systemic) after a single injection. Further study showed that alka?loids in Kushen, especially matrine, were responsible for CKI-induced IHRs. Mechanism study showed that various PAF receptor antagonists could significantly counter CKI-induced IHRs locally or systemically. In cell system, CKI was able to promote PAF production in a non-cell-selective manner. In cell lysate, the effect of CKI on PAF production became stron?ger and could be abolished by blocking de novo pathway. CONCLUSION In conclusion, our study identifies, for the first time, that CKI is a PAF inducer. It causes non-immunologic IHRs, rather than IgE-dependent IHRs, by promoting PAF production through de novo pathway. Alkaloids in Kushen, especially matrine, are the prime culprits for IHRs. Our find?ings may provide a potential approach for preventing and treating CKI-induced IHRs.

Endogenous HMGB1 Modulates Fatty Acid Metabolism of Hypoxic and Nutrient-poor Pancreatic Cancer Cells and Related Mechanism / 肿瘤防治研究

Objective To explore the role and mechanism of HMGB1 in the fatty acid metabolism reprogramming and mitochondrial fusion/fission of hypoxic and nutrient-poor pancreatic cancer cells. Methods The correlation between the expression level of HMGB1 in pancreatic cancer tissue and the survival rate of pancreatic cancer patients were analyzed by GEPIA database. CCK-8 assay was used to measure cell proliferation rate, and scratch test and Transwell chamber method were carried out to detect the effects of endogenous HMGB1 on the invasion and migration abilities of human pancreatic cancer cell line Patu8988 after hypoxic and nutrient-poor treatment. Laser confocal microscope was used to observe the changes of mitochondrial morphology of Patu8988 cells. Western blot was used to detect the expression levels of mitochondrial fusion/fission and de novo fatty acid synthesis-related proteins. Results GEPIA database analysis results showed that HMGB1 was highly expressed in pancreatic cancer tissues (P < 0.01), and the expression level was negatively correlated with the survival time of pancreatic cancer patients (P=0.00097). Knockdown of HMGB1 expression could inhibit the proliferation, invasion and migration abilities of Patu8988 cells under hypoxic and nutrient-poor conditions. However, mitochondrial fission in patu8988 cells was increased. Knockdown of HMGB1 in Patu8988 cells increased the expression of fission-related protein FIS1 while decreased the expression of p-DRP1(Ser637) and fusion-related protein MFN1 and MFN2 in hypoxic and nutrient-poor environment; ACLY, p-ACLY and FASN protein expression levels were down-regulated. Conclusion Endogenous HMGB1 can promote the fusion and inhibit the fission of mitochondria in hypoxic and nutrient-poor Patu8988 cells, maintain mitochondrial morphology and function, and thereby up-regulate ACLY protein expression and phosphorylation level, promote FA synthesis, and maintain the proliferation, invasion and migration abilities of pancreatic cancer cells.

Fructosa, un factor clave modificable en la patogenia del síndrome metabólico, la esteatosis hepática y la obesidad / Fructose, a modifiable key factor in the pathogenic basis of metabolic syndrome, NAFLD and obesity / Frutose, um fator chave modificável na patogênese da síndrome metabólica, esteatose hepática e obesidade

Resumen: En esta revisión se resume el rol específico que el exceso de consumo de fructosa más allá de sus calorías puede tener en el desarrollo del síndrome metabólico, la esteatosis hepática no alcohólica y su asociación con la obesidad. Se desglosan los efectos de la fructosa (en comparación con la glucosa) en la esteatosis hepática, lo que genera la insulino-resistencia y la hipertrigliceridemia. Por su metabolismo hepático mayoritario y la falta de regulación, los flujos altos de fructosa consumen ATP generando ácido úrico, producen metabolitos tóxicos, como ceramidas y metilglioxal, y activan la síntesis de lípidos. Además, se analizan los efectos en el tejido adiposo, la activación del cortisol y las hormonas involucradas en el control de la saciedad, todas las cuales se ven afectadas por el consumo de fructosa. La insulino-resistencia hepática inicial se complica con insulino-resistencia sistémica, que genera leptino-resistencia y un ciclo de hiperfagia. Estos resultados subrayan la necesidad de intervenciones clínicas y educativas dentro de la población para regular o reducir el consumo de fructosa, especialmente en niños y adolescentes, sus principales consumidores.

Summary: This review summarizes the specific role that excess fructose consumption (beyond its calories) may have in the development of MetS, NAFLD and its association with obesity. The effects of fructose (compared to glucose) on hepatic steatosis are discussed as well as their consequence: insulin resistance and hypertriglyceridemia. Unlike glucose, more than 80% ingested fructose stays in the liver, and due to lack of fine metabolic regulation, high fructose flows consume ATP generating uric acid, produce toxic metabolites such as ceramides and methylglyoxal and activate lipid synthesis. In addition, the study analyzes the effects of fructose on adipose tissue, cortisol activation and hormones involved in satiety control, all of which are affected by fructose consumption. The initial hepatic insulin resistance is complicated by systemic insulin resistance, which generates leptin resistance and a hyperphagia cycle. These results underscore the need for clinical and educational interventions within the population to regulate / reduce fructose consumption, especially in children and adolescents, their main consumers.

Resumo: No momento vivemos uma pandemia causada pelo vírus SARS-CoV-2, COVID-19, sendo o mais recomendado ficar em casa para reduzir o contágio e que este seja reduzido ao mínimo possível. No século 21, a tecnologia está mais presente do que nunca e faz parte do nosso dia a dia. Tendo em vista que há significativo abuso da mesma, principalmente por adolescentes, na nossa perspectiva que promove o movimento e a redução do comportamento sedentário, propomos o uso de videogames ativos em substituição aos videogames convencionais. Para isso, fizemos uma revisão dos principais benefícios que estas podem trazer, tanto para a população mais jovem como para os idosos. Esta última faixa etária é uma das mais afetadas pela pandemia e, portanto, há uma forte recomendação para que fiquem em casa. No entanto, é recomendável usá-lo com responsabilidade e não investir tempo excessivo que possa causar danos.

De novo transcriptome assembly and mining of EST-SSR markers in Gloriosa superba

Gloriosa superba is an economical source of pharmaceutical colchicine, which is a mitotic poison used to treat gout, cancer and inflammatory diseases. It is important to study the genetic variations in this plant, but the progress is impeded due to limited number of molecular markers. In this study, we developed the expressed sequence tag-derived simple sequence repeat (EST-SSR) markers from the transcriptome sequence of the leaf samples of three different ecotypes of G. superba. De novo assembly was performed on these sequencing data to generate a total of 65,579 unigenes and 38,200 coding sequences (CDSs). These CDSs were annotated using NCBI Nr protein database, gene ontology terms and KEGG pathways. Differential gene expression was studied to yield differences in these ecotypes at the molecular level. Finally, a total of 14,672 potential EST-SSRs were identified from these unigenes, among which the dinucleotide (5754, 39.22%) and trinucleotide (5421, 36.95%) repeats were most abundant types followed by mononucleotides (3213, 21.83%). The most frequent motifs were CT/GA (1392, 9.48%), AG/TC (1219, 8.31%), and GA/CT (1146, 7.82%) among the dinucleotide repeats and CCG/ CGG (1487, 10.13%), AGG/CCT (1421, 9.68%), AGC/CTG (697, 4.75%) and AAG/CTT (621, 4.23%) among the trinucleotide repeats. Polymorphism study using a random set of 20 newly developed EST-SSRs revealed polymorphic information content value ranging from 0 to 0.5926 with an average of 0.4021. The large-scale ESTs developed in the current study will be useful as a genomic resource for further investigation of the genetic variations in this species

Ranolazina en cardiopatía isquémica crónica: un factor protector frente a la fibrilación auricular de novo / Ranolazine in chronic ischaemic heart disease: a protective factor against de novo atrial fibrillation

Resumen Introducción: en pacientes con cardiopatía isquémica crónica, ranolazina se ha mostrado eficaz ante casos de angina. Estudios recientes la valoran como fármaco para prevenir la fibrilación auricular poscardioversión eléctrica, posquirúrgica o posinfarto. Objetivos: valorar la presencia a largo plazo de episodios de fibrilación auricular de novo en pacientes con cardiopatía isquémica crónica y nuevo episodio de angina inestable que inician ranolazina 350 o 500 mg/12 h, en comparación con el tratamiento habitual. Métodos: estudio observacional retrospectivo que compara la incidencia de fibrilación auricular de novo en 77 pacientes consecutivos, con diagnóstico de cardiopatía isquémica no revascularizable y nuevo ingreso por síndrome coronario agudo durante el año 2013, en comparación con los que iniciaron ranolazina frente a tratamiento convencional, en los 12 meses siguientes al evento. La detección de fibrilación auricular se basó en su presencia en un primer registro electrocardiográfico. Resultados: de 77 pacientes, 38 iniciaron ranolazina, sin diferencias en cuanto a las características basales de las dos poblaciones, con similares tasas de factores de riesgo cardiovascular clásicos, datos ecocardiográficos como tamaño auricular, o tratamiento previo empleado. Se observó una tasa de fibrilación auricular de novo del 5,3% en los pacientes tratados con ranolazina, frente al 23,1% en el grupo sin ranolazina (p<0,001). Al analizar el subgrupo de pacientes que presentó fibrilación auricular en su seguimiento, únicamente es significativa la no toma de ranolazina (p<0,001). Conclusión: el uso de ranolazina en pacientes con cardiopatía isquémica crónica no revascularizable podría suponer un efecto protector para el desarrollo de fibrilación auricular durante un seguimiento de al menos doce meses.

Abstract Introduction: Ranolazine has shown to be effective in cases of angina in patients with chronic ischaemic heart disease. Recent studies have evaluated it as a drug to prevent electrical post-cardioversion, post-surgical or post-infarction atrial fibrillation. Objectives: To perform a long-term evaluation of de novo atrial fibrillation episodes in patients with chronic ischaemic heart disease and a new episode of unstable angina that are taking 350 or 500 mg/12 h of ranolazine, in comparison with usual treatment. Methods: An observational, retrospective study was performed to compare the incidence of de novo atrial fibrillation in 77 consecutive patients with a diagnosis of non-revascularisable ischaemic heart disease and a new hospital admission due to acute coronary syndrome during the year 2013. These were compared with those that started with ranolazine and those on conventional treatment in the 12 months following the event. The detection of atrial fibrillation was based on its presence in a first electrocardiographic register. Results: Of the 77 patients, 38 were started on ranolazine, with no differences as regards the baseline characteristics of the two populations. They had similar rates of classic cardiovascular risk factors, echocardiographic data, such as atrial size, or previous treatment employed. A de novo atrial fibrillation rate of 5.3% was observed in the patients treated with ranolazine, compared to 23.1% in the non-ranolazine group (P<.001). On analysing the sub-group of patients that had an atrial fibrillation in their follow-up, only not taking of ranolazine was significant (P<.001). Conclusion: The use of ranolazine in patients with non-revascularisable ischaemic heart disease could have a protective effect against the development of atrial fibrillation during a 12 months follow-up.

Literature analysis report of de novo malignant tumors of digestive system after liver transplantation in China / 器官移植

Objective To investigate the incidence of de novo malignant tumors of the digestive system after liver transplantation (LT) in China. Methods Relevant literature review was performed from Wanfang data, China National Knowledge Infrastructure (CNKI) and Chongqing VIP. The retrieval time started from the establishment of each database to May 9, 2019. The Chinese search terms were liver transplantation+ postoperative/de novo+ malignant tumor/cancer. The age distribution, sex composition, time of diagnosis, involved organs, treatment and clinical prognosis of recipients with de novo malignant tumors of the digestive system after LT in China were retrospectively analyzed. Results After literature screening, 16 articles were eventually selected including 47 cases of de novo malignant tumors of the digestive system after LT. A majority of them were male recipients. The age of the recipients was 51 (23-65) years old, most of them were middle age (45-59 years old). The average time of diagnosis of de novo malignant tumors of the digestive system after operation was 43 (2-156) months, with the highest number of cases within postoperative 1-3 years. Colon and stomach were the most common tumor sites. Surgery combined with radiotherapy and chemotherapy remained the main treatment option. However, the overall clinical prognosis of patients with de novo malignant tumors of the digestive system after LT was poor with a mortality rate of 51%. Conclusions In China, colon cancer and gastric cancer are the main de novo malignant tumors of the digestive system after LT. The overall clinical prognosis of patients with de novo malignant tumors of the digestive system is poor. Sufficient attention should be paid to postoperative monitoring and prevention.

Pretransplant Hepatic Malignancy Increases Risk of De Novo Malignancy after Liver Transplantation

BACKGROUND: Hepatocellular carcinoma (HCC) recurrence and development of de novo malignancy (DNM) after liver transplantation (LT) are the major causes of late recipient death.METHODS: We analyzed the incidence of extrahepatic DNM following living donor LT according to the status of pretransplant hepatic malignancy. We selected 2,076 adult patients who underwent primary LDLT during 7 years from January 2010 to December 2016.RESULTS: The pretransplant hepatic malignancy group (n = 1,012) showed 45 cases (4.4%) of the following extrahepatic DNMs: posttransplant lymphoproliferative disease (PTLD) in 10; lung cancer in 10; stomach cancer in 6; colorectal cancer in 5; urinary bladder cancer in 3; and other cancers in 11. The pretransplant no hepatic malignancy group (n = 1,064) showed 25 cases (2.3%) of the following extrahepatic DNMs: colorectal cancer in 3; stomach cancer in 3; leukemia in 3; lung cancer in 3; PTLD in 2; prostate cancer in 2; and other cancers in 9. Incidences of extrahepatic DNM in the pretransplant hepatic malignancy and no hepatic malignancy groups were as follows: 1.1% and 0.5% at 1 year, 3.2% and 2.0% at 3 years, 4.6% and 2.5% at 5 years, and 5.4% and 2.8% at 8 years, respectively (P = 0.006). Their overall patient survival rates were as follows: 97.3% and 97.2% at 1 year, 91.6% and 95.9% at 3 years, 89.8% and 95.4% at 5 years, and 89.2% and 95.4% at 8 years, respectively (P < 0.001). Pretransplant hepatic malignancy was the only significant risk factor for posttransplant extrahepatic DNM.CONCLUSION: Our results suggest that patients who had pretransplant hepatic malignancy be followed up more strictly because they have a potential risk of primary hepatic malignancy recurrence as well as a higher risk of extrahepatic DNM than patients without pretransplant hepatic malignancy.

Research progress on risk factors of de novo malignancy after liver transplantation / 器官移植

De novo malignancy after liver transplantation is an important factor that affecting the long-term survival of recipient. The main risk factors for de novo malignancy include immunosuppression and many factors of recipients, such as age, gender, race, primary disease, preoperative tumor history and precancerous lesion, carcinogenic virus infection, smoking and drinking, etc. Currently, there is no standardized monitoring scheme after liver transplantation, but planned monitoring is required for high-risk recipients, thus to achieve early diagnosis and improve the survival rate. This article summarized the incidence, prognosis and related risk factors of de novo malignancy after liver transplantation, which provided reference for improving long-term survival rate of recipients after liver transplantation.

Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.