Discovery of 4-(phenoxymethyl)-1H-1,2,3-triazole derivatives as novel xanthine oxidase inhibitors.

A series of 4-(phenoxymethyl)-1H-1,2,3-triazole derivatives were designed, synthesized, and evaluated for their xanthine oxidase (XO) inhibitory activities. Among these compounds, 9m emerged as the most effective XO inhibitor with an IC50 value of 0.70 µM, which was approximately 14-fold more potent than allopurinol. Additionally, compound 9m displayed favorable drug-like properties with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.33 and 3.41, respectively. We further explored the binding mode of 9m in complex with XO by molecular docking and molecular dynamics studies. In vivo hypouricemic studies also suggested that 9m could effectively lower the serum uric acid levels of rat. In summary, compound 9m could be a promising lead for further development of XO inhibitors.

Design, synthesis and biological evaluation of N-(4-alkoxy-3-(1H-tetrazol-1-yl)phenyl) heterocyclic aromatic amide derivatives as xanthine oxidase inhibitors.

Xanthine oxidase (XO) is a flavoprotein that exists in various organisms and can catalyze the uric acid formation in the human body. Based on the amide framework of N-(4-((3-cyanobenzyl)oxy)-3-(1H-tetrazol-1-yl)phenyl)isonicotinamide (compound 1) reported in our previous work, a series of N-(4-alkoxy-3-(1H-tetrazol-1-yl)phenyl) heterocyclic aromatic amide derivatives were designed, synthesized and evaluated as novel amide-based XO inhibitors. Structure-activity relationship campaign identified the most promising compound g25 (IC50 = 0.022 µM), which possesses a special 1H-imidazole-5-carboxamide scaffold and presented comparable XO inhibitory potency to topiroxostat (IC50 = 0.017 µM). Enzyme kinetic studies revealed that compound g25 acted as a mixed-type XO inhibitor. Molecular docking and molecular dynamics indicated that imidazole NH of g25 formed two stable hydrogen bonds with Glu1261 residue of XO that provided a vital contribution for the binding affinity. In addition, in vivo activity evaluation demonstrated that compound g25 exhibited obviously hypouricemic effect on a potassium oxonate induced hyperuricemic rat model.

A possible covalent xanthine oxidase inhibitor TS10: Inhibition mechanism, metabolites identification and PDPK assessment.

Xanthine oxidase (XO) inhibitors are widely used in the control of serum uric acid levels in the clinical management of gout. Our continuous efforts in searching novel amide-based XO inhibitors culminated in the identification of N-(4-((3-cyanobenzyl)oxy)-3-(1H-tetrazol-1-yl)phenyl)isonicotinamide (TS10), which exhibited comparable in vitro inhibition to that of topiroxostat (TS10, IC50 = 0.031 µM; topiroxostat, IC50 = 0.020 µM). According to the molecular modeling, we speculated that, as well as topiroxostat, TS10 would be biotransformed by XO to yield TS10-2-OH. In this work, TS10-2-OH was successfully identified in XO targeted metabolism study, demonstrated that TS10 underwent a covalent binding with XO via a TS10-O-Mo intermediate after anchoring in the XO molybdenum cofactor pocket. Furthermore, TS10-2-OH is a weak active metabolite, and its potency was explained by the molecular docking. In metabolites identification, TS10 could be oxidized by CYP2C9, CYP3A4 and CYP3A5 to generate two mono-hydroxylated metabolites (not TS10-2-OH); and could occur degradation in plasma to mainly generate a hydrolytic metabolite (TS10-hydrolysate). In pharmacokinetic assessment, the low oral system exposure was observed (Cmax = 14.73 ± 2.66 ng/mL and AUClast = 9.17 ± 1.42 h⋅ng/mL), which could be explained by the poor oral absorption property found in excretion studies. Nonetheless, in pharmacodynamic evaluation, TS10 exhibited significant uric acid-lowering effect after oral administration in a dose-dependent manner. Briefly, in addition to allopurinol and topiroxostat, TS10 is possibly another explicitly mechanism-based XO inhibitor with powerful covalent inhibition.

N-(3-cyano-1H-indol-5-yl)isonicotinamide and N-(3-cyano-1H-indol-5-yl)-1H-benzo[d]imidazole-5-carboxamide derivatives: Novel amide-based xanthine oxidase inhibitors.

Our previous work demonstrated that amide is an efficient linker to explore chemical space of xanthine oxidase (XO) inhibitors that are entirely different from febuxostat and topiroxostat. In this effort, with 3-cyano-1H-indol-5-yl as a key moiety, two series of amide-based XO inhibitors, N-(3-cyano-1H-indol-5-yl)isonicotinamides (2a-w) and N-(3-cyano-1H-indol-5-yl)-1H-benzo[d]imidazole-5-carboxamides (3a-i), were designed and synthesized. The structure-activity relationship investigation identified N-(3-cyano-1-cyclopentyl-1H-indol-5-yl)-1H-benzo[d]imidazole-5-carboxamide (3i, IC50 = 0.62 µM) as the most promising compound, with 14.4-fold higher in vitro inhibitory potency than allopurinol (IC50 = 8.91 µM). Molecular simulations provided reasonable interaction modes for the representative compounds. Furthermore, in vivo activity evaluation demonstrated that compound 3i (oral dose of 12.8 mg/kg) has obviously hypouricemic effect on a potassium oxonate induced hyperuricemic rat model. Cytotoxicity assay and ADME prediction also supported that 3i is an excellent lead for further exploration of amide-based XO inhibitors.

Amide-based xanthine oxidase inhibitors bearing an N-(1-alkyl-3-cyano-1H-indol-5-yl) moiety: Design, synthesis and structure-activity relationship investigation.

Our previous work identified a promising isonicotinamide based xanthine oxidase (XO) inhibitor, N-(3-cyano-4-((2-cyanobenzyl)oxy)phenyl)isonicotinamide (1), and concluded that amide is an effective linker in exploring the XO inhibitor chemical space that is completely different from the five-membered ring framework of febuxostat and topiroxostat. Indole, an endogenous bioactive substance and a popular drug construction fragment, was involved in the structural optimization campaign of the present effort. After the installation of some functional groups, N-(1-alkyl-3-cyano-1H-indol-5-yl) was generated and employed to mend the missing H-bond interaction between the 3'-cyano of 1 and Asn768 residue of XO by shortening their distance. In this context, eight kinds of heterocyclic aromatic amide chemotypes were rationally designed and synthesized to investigate the structure-activity relationship (SAR) of amide-based XO inhibitors. The optimized compound a6 (IC50 = 0.018 µM) exhibits 17.2-fold improved potency than the initial compound 1 (IC50 = 0.31 µM). Its potency is comparable to that of topiroxostat (IC50 = 0.013 µM). Molecular docking and molecular dynamics studies proved the existence of the stable H-bond between the cyano group and the Asn768 residue. Moreover, oral administration of a6 (11.8 mg/kg) could effectively reduce serum uric acid levels in an acute hyperuricemia rat model. Liver microsomal stability assay illustrated that compound a6 possesses well metabolic stability in rat liver microsomes. However, the in vivo potency of a6 was much lower than that of topiroxostat, which may be explained by the poor absorption found in the parallel artificial membrane permeability assay (PAMPA). In addition, 6a has non-cytotoxicity against normal cell lines MCF10A and 16HBE. Taken together, this work culminated in the identification of compound 6a as an excellent lead for further exploration of amide-based XO inhibitors.

Identification of Novel Src Inhibitors: Pharmacophore-Based Virtual Screening, Molecular Docking and Molecular Dynamics Simulations.

Src plays a crucial role in many signaling pathways and contributes to a variety of cancers. Therefore, Src has long been considered an attractive drug target in oncology. However, the development of Src inhibitors with selectivity and novelty has been challenging. In the present study, pharmacophore-based virtual screening and molecular docking were carried out to identify potential Src inhibitors. A total of 891 molecules were obtained after pharmacophore-based virtual screening, and 10 molecules with high docking scores and strong interactions were selected as potential active molecules for further study. Absorption, distribution, metabolism, elimination and toxicity (ADMET) property evaluation was used to ascertain the drug-like properties of the obtained molecules. The proposed inhibitor-protein complexes were further subjected to molecular dynamics (MD) simulations involving root-mean-square deviation and root-mean-square fluctuation to explore the binding mode stability inside active pockets. Finally, two molecules (ZINC3214460 and ZINC1380384) were obtained as potential lead compounds against Src kinase. All these analyses provide a reference for the further development of novel Src inhibitors.

Small molecular CD73 inhibitors: Recent progress and future perspectives.

The occurrence and development of the tumor are very complex biological processes. In recent years, a large number of research data shows that CD73 is closely related to tumor growth and metastasis. It has been confirmed that the cascade hydrolysis of extracellular ATP to adenosine is one of the most important immunosuppressive regulatory pathways in the tumor microenvironment. The metabolite adenosine can mediate immunosuppression by activating adenosine receptor (such as A2A) on effector Immune cells and enable tumor cells to achieve immune escape. Therefore, attenuating or completely removing adenosine-mediated immunosuppression in the tumor microenvironment by inhibiting CD73 is a promising approach in the treatment of solid tumors. This paper focuses on the research progress of CD73 enzyme and CD73 small molecule inhibitors, and is expected to provide some insights into the development of small-molecule antitumor drugs targeting CD73.

Biological Characteristics, Domesticated Cultivation Protocol, Antioxidant Activity, and Protective Effects against Cellular Oxidative Stress of an Underutilized Medicinal Mushroom: Fomitopsis palustris.

Brown-rot fungus is one of the important medicinal mushrooms, which include some species within the genus Fomitopsis. This study identified wild macrofungi collected from a broad-leaved tree in Liaoning Province as Fomitopsis palustris using both morphological and molecular methods. To elucidate the potential medicinal and economic value of F. palustris, we conducted single-factor and orthogonal tests to optimize its mycelium culture conditions. Subsequently, we completed liquid culture and domestic cultivation based on these findings. Furthermore, crude polysaccharides were extracted from the cultivated fruiting bodies of F. palustris and their antioxidant activity was evaluated using chemical methods and cell-based models. The results showed that the optimal culture conditions for F. palustris mycelium were glucose as the carbon source, yeast extract powder as the nitrogen source, pH 6.0, and a temperature of 35 °C. Moreover, temperature was found to have the most significant impact on mycelial growth. The liquid strains were fermented for 6 days and then inoculated into a cultivation substrate composed of broadleaf sawdust, resulting in mature fruiting bodies in approximately 60 days. The crude polysaccharides extracted from the cultivated fruiting bodies of F. palustris (FPPs) possess in vitro scavenging abilities against DPPH radicals and OH radicals, as well as a certain ferric-reducing antioxidant power. Additionally, FPPs effectively mitigated H2O2-induced oxidative stress in RAW264.7cells by enhancing the intracellular activity of antioxidant enzymes such as SOD and CAT, scavenging excess ROS, and reducing MDA levels. This study provides preliminarily evidence of the potential medicinal and economic value of F. palustris and offers initial data for the future development and utilization of this species.

Effect of renal denervation for patients with isolated systolic hypertension: a systematic review and meta-analysis.

BACKGROUND: Renal denervation (RDN) is a promising treatment based on catheter intervention for patients with refractory hypertension. However, the effect in patients with isolated systolic hypertension (ISH) remains controversial. The aim of this meta-analysis was to determine the blood pressure lowing effect of RDN in patients with ISH compared with combined systolic/diastolic hypertension (CH) patients. METHODS: PubMed, Embase, Cochrane and ClinicalTrials.gov were searched for prospective clinical studies that included RDN. The outcomes of interest were the change of 24-hour ambulatory systolic blood pressure (SBP) from baseline. We used the fixed effects model to calculate weighted mean difference (WMD) with 95% confidence interval (CI). RESULTS: Six trials were included, with 1405 participants, including 597 patients with ISH and 808 patients with CH. Mean follow-up was five months. The reduction of 24-hour ambulatory SBP was significantly greater for the CH patients than the ISH patients (WMD = 3.89, 95% CI: 2.32-5.45, P < 0.0001). RDN also showed a greater reduction in office SBP in the CH patients compared to the ISH patients (WMD = 10.24, 95% CI: 4.24-15.74, P = 0.0003). And the effect was independent of age, length of follow-up, and ablation device. CONCLUSIONS: RDN provides superior blood pressure control in the CH patients compared with the ISH patients, and the CH patients may be the best suitable population for which RDN is indicated.

(E)-2-styrylanthracene-9,10-dione derivatives as novel fluorescent probes: synthesis, photophysical properties and application in mitochondria imaging.

Our previous work firstly reported that (E)-2-styrylanthracene-9,10-dione is a novel fluorescent core (EK01) with the ability of specific mitochondria imaging. In this effort, we mainly focused our attention on the structure-photophysical property relationship and application in cells imaging of this new fluorescent chemotype. A series of the structural derivatives (TZ series) were designed and synthesized by introducing some substituents onto the 2-styryl moiety. The structure-photophysical property relationship analysis suggested that TZ03 is an excellent fluorescent molecular building block with the property of fluorescent "turn-on" effect after the modification of acylation, and TZ07 is an excellent fluorescent dye with a series of advantages such as high fluorescence intensity (Fmax = 4049.0 in CH2Cl2, 25.80 µM), moderate molar extinction coefficients (3.77 × 103-5.93 × 103 mol-1∙L∙cm-1), strong fluorescence quantum yield (Φmax = 0.739 in CH2Cl2), large Stokes shift (99.0 nm-161.8 nm) and well biological tolerance. As a classical D-π-A structure, the ICT characteristic of TZ07 was analyzed through spectroscopy verification and DFT calculations. Furthermore, optimized compound TZ07 was successfully applied in the living cells imaging with the excellent selectivity to mitochondria in a green fluorescent form. It was also suggested that the mechanism of TZ07 targeting mitochondria is independent of mitochondrial membrane potential, but probably related to the mitochondrial complex I. These findings may provide some insights into the development of novel mitochondria-targeted fluorescent probes.

Boletaceae in China: Taxonomy and phylogeny reveal a new genus, two new species, and a new record.

Boletaceae, the largest family in Boletales, has been attracted by mycologists in the world due to its diverse morphology and complex history of evolution. Although considerable work has been done in the past decades, novel taxa are continually described. The current study aimed to introduce three new taxa and one new record of Boletaceae from China. The morphological descriptions, color photographs, phylogenetic trees to show the positions of the taxa, and comparisons with allied taxa are provided. The new genus Hemilanmaoa is unique in the Pulveroboletus group, and Hemilanmaoa retistipitatus was introduced as the type species. It can be distinguished by its bluing basidioma when injured, a decurrent hymenophore, a stipe covered with distinct reticulations, and a fertile stipitipellis. Porphyrellus pseudocyaneotinctus is characterized by its pileipellis consisting of broadly concatenated cells and thin-walled caulocystidia in Porphyrellus. In Phylloporus, Phylloporus biyangensis can be distinguished by its hymenophores that change to blue when injured and yellow basal mycelium. Lanmaoa angustispora, as a new record, is first reported in Northern China. Internal transcribed spacer (ITS), 28S rDNA (28S), translation elongation factor 1-alpha (tef1-α), RNA polymerase II subunit 1 (rpb1), and RNA polymerase II subunit 2 (rpb2) were employed to execute phylogenetic analyses.

A new species and new records species of Pluteus from Xinjiang Uygur Autonomous Region, China.

Xinjiang Uyghur Autonomous Region in China embraces a unique geographical and ecological environment, and the macrofungi represent a rich resource. However, few studies on the genus Pluteus have been reported from Xinjiang. In 2021, the macrofungal resources in Xinjiang were surveyed, and 10 specimens belonging to the genus Pluteus were collected. Based on the morphological study and molecular analysis, three species were recognized, P. aletaiensis, P. brunneidiscus, and P. hongoi. Pluteus aletaiensis is proposed as a new species. It is characterized by its bright yellow lamellae and stipe, brittle texture, subfusiform to vesicular pleurocystidia, with short pedicels to broadly lageniform to obtuse at apices, a hymeniderm pileipellis, containing dark brown intracellular pigment, and it grows on the ground. Pluteus brunneidiscus, a new record to China, is characterized by uneven, smooth, grayish brown to brown pileus, with an entire margin, and pointed or flatter apices intermediate cystidia, without apical hooks. Pluteus hongoi, a new record to Xinjiang Uyghur Autonomous Region, China, is characterized by the apical hook's structure (commonly bifid) of pleurocystidia. The nuclear internal transcribed spacer (nrITS) and translation elongation factor 1-alpha (TEF1-a) region were used for the molecular analysis. Phylogenetic trees were constructed using both the maximum likelihood analysis (ML) and Bayesian inference (BI). Detailed descriptions of the three species are presented herein. Finally, a key to the list of eight species of the genus Pluteus knew from Xinjiang is provided.

Exploring the Relationships between Four New Species of Boletoid Fungi from Northern China and Their Related Species.

The family Boletaceae primarily represents ectomycorrhizal fungi, which play an essential ecological role in forest ecosystems. Although the Boletaceae family has been subject to a relatively global and comprehensive history of work, novel species and genera are continually described. During this investigation in northern China, many specimens of boletoid fungi were collected. Based on the study of their morphology and phylogeny, four new species, Butyriboletus pseudoroseoflavus, Butyriboletus subregius, Tengioboletus subglutinosus, and Suillellus lacrymibasidiatus, are introduced. Morphological evidence and phylogenetic analyses of the single or combined dataset (ITS or 28S, rpb1, rpb2, and tef1) confirmed these to be four new species. The evidence and analyses indicated the new species' relationships with other species within their genera. Detailed descriptions, color photographs, and line drawings are provided. The species of Butyriboletus in China were compared in detail and the worldwide keys of Tengioboletus and Suillellus were given.

Morphology and molecular study of three new Cordycipitoid fungi and its related species collected from Jilin Province, northeast China.

Cordyceps species are notable medicinal fungi in China, which are pathogenic on insects and exhibit high biodiversity in tropical and subtropical regions. Recently, three new Cordyceps species, Cordycepschangchunensis and Cordycepsjingyuetanensis growing on pupae of Lepidoptera and Cordycepschangbaiensis growing on larvae of Lepidoptera, were found in Jilin Province, China and are described, based on morphological and ecological characteristics. These three new species are similar to the Cordycepsmilitaris group, but are distinctly distinguishable from the known species. Cordycepschangchunensis, characterised by its small and light yellow to orange stromata which is occasionally forked, covered with white mycelium at the base of stipe, globose to ovoid perithecia, is macroscopically similar to Cordycepsmilitaris. Cordycepschangbaiensis is clearly discriminated from other Cordyceps species by its white to orange and branched stromata, clavate to cylindrical fertile apical portion, immersed and globose to ovoid perithecia. Moreover, unbranched, clavate and orange to light red stromata, almond-shaped to ovoid and immersed perithecia separate Cordycepsjingyuetanensis from other Cordyceps species. nrITS, nrLSU and EF-1α sequences were undertaken and phylogenetic trees, based on Maximum Likelihood and Bayesian Inference analysis showed that the three new species clustered with Cordycepsmilitaris, but formed individual clades, as well as confirmed the results of our morphological study.

2-((1-Phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[3.2.1]octan-3-one derivatives: Simplification and modification of aconitine scaffold for the discovery of novel anticancer agents.

The molecular chaperone heat shock protein 90 (Hsp90) is a promising target for cancer therapy. Natural product aconitine is a potential Hsp90 inhibitor reported in our previous work. In this study, we designed and synthesized a series of 2-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[3.2.1]octan-3-one derivatives as potent Hsp90 inhibitors by simplifying and modifying aconitine scaffold. Among these compounds, 14t exhibited an excellent antiproliferative activity against LoVo cells with an IC50 value of 0.02 µM and a significant Hsp90α inhibitory activity with an IC50 value of 0.71 nM. Molecular docking studies provided a rational binding model of 14t in complex with Hsp90α. The following cell cycle and apoptosis assays revealed that compound 14t could arrest cell cycle at G1/S phase and induce cell apoptosis via up-regulation of bax and cleaved-caspase 3 protein expressions while inhibiting the expressions of bcl-2. Moreover, 14t could inhibit cell migration in LoVo and SW620 cell lines. Consistent with in vitro results, 14t significantly repressed tumor growth in the SW620 xenograft mouse model.

[Clinical and Pathological Characteristics of Blastic Plasmacytoid Dendritic Cell Neoplasm].

OBJECTIVE: To explore the clinical manifestation, pathological features and treatment regimen of blastic plasmacytoid dendritic cell neoplasm (BPDCN). METHODS: The clinical and pathologic features, diagnosis, treatment and prognosis of 5 BPDCN patients were analyzed retrospectively. RESULTS: 5 patients had skin lesions, and bone marrow involvement. The immunohistochemical staining showed that the CD56 expression was observed in 5 patients, CD4 and CD123 in 4 patients, and CD43 expressed in 3 patients. After initial treatment, 3 patients achieved complete remission and 1 patient did not. One patient showed disease progression after partial remission for 1 month. Two young patients underwent sibling allo-PBHSCT, and then achieved long-term survival. CONCLUSION: BPDCN often presents skin lesions as the first symptom, moreover, soft tissues, lymph nodes and bone marrow were involved, which suggested the disease progresses. There is currently no uniform treatment protocol for this disease. Active allogeneic peripheral blood hematopoietic stem cell transplantation in the CR1 phase for appropriate patients may increase their chances for long-term survival.

[Detection of BCR/ABL Fusion Gene and ASS1 Gene Deletion by Using Tricolor Dual-fusion Probe].

OBJECTIVE: To analyze the significance of various abnormal signal patterns appreared in CML and B-ALL patients by using BCR/ABL/ASS1 tricolor dual-fusion probe, and to explore its application value in detecting BCR/ABL fusion gene and ASS1 gene deletion. METHODS: 50 newly diagnosed CML patients and 50 newly diagnosed B-ALL patients were detected by fluorescence in situ hybridization (FISH) with BCR/ABL/ASS1 tricolor dual-fusion probe. Meanwhile, karyotype analysis was performed on all the patients using the 24 hours short-term culture and R-banding. RESULTS: Among the 50 CML patients, Ph+ was found in 49 cases, 5 normal interphase karyotype was observed in 1 case. FISH detection showed that BCR/ABL fusion gene existed in all patients (100%), while the positive signal pathway showed that 1R1G2B2F was observed in 39 cases (78%), 2R1G2B1F in 2 cases (4%) and 1R1G2B1F in 6 cases (12%), simultaneous existence of 1R1G1B1F and 1R1G2B3F in 1 case (2%), 2R1G1B1F in 1 case (2%) 1R1G3B3F in 1 case (2%). FISH detection also showed that the karyotype of 6 case at ASS1 gene deletion (1R1G1B1F) all were simple t (9; 22) translocation, and other abnormalities not were observed. Among 50 cases of B-ALL, Ph+ was found in 13 cases, the numerical aberration and structural aberration of non t (9; 22) in 16 cases, normal karyotype in 20 cases, absence of mitotic phase in 1 case. FISH detection showed that 16 cases (32%) had BCR/ABL fusion gene including 13 cases (26%) of 1R1G2B2F, 1 case (2%) of stimultaneous exitance of 1R1G2B2F and 1R1G3B3F 1 case (2%) of 2R1G1B1F, 1 case (2%) of 1R1G3B2F. FISH detection also showed that 3 cases had BCR/ABL fusion gene, including 1 case with ASS1 gene deletion (2R1G1B1F), 1 case with classical t (9; 22) translocation (1R1G2B2F) and 1 case with BCR/ABL fusion gene and increase of ASS1 gene copy (1R1G3B3F). CONCLUSION: Tricolor dual-fusion FISH probe for detecting BCR/ABL fusion gene and ASS1 gene deletion is simple, rapid, sensitive and stable. It can detect various forms of molecular fusion and avoid the false positive results due to coincidental overlap of signals generated by D-FISH probe and ES-FISH probe. In addition, this detection method not only can directly observe the presence or absence of ASS1 gene deletion, but also improve the reliability of the positive results of newly diagnosed BCR/ABL fusion gene and accuracy of monitoring results of minimal residual disease for the subsequent visit.

[Clinical Efficacy of Allo-HSCT on FLT3-ITD Positive AML Patients].

OBJECTIVE: To detect the expression levels of FAM19A5 in patients with mantle cell lymphoma (MCL), and to determine the relationship between FAM19A5 and the prognosis of MCL patients. METHODS: Twenty-five MCL patients were choosen in the study, cytometric bead assay was used to detected the concentration of FAM19A5 in serum and immunohistochemical analysis were used to detect the expression levels of FAM19A5 in lymph nodes. The relationship of the FAM19A5 expression in serum and tissue were analyzed, the relationship of FAM19A5 and clinical characteristics of MCL patients, treatment and prognosis of MCL patients was analyzed. RESULTS: The average serum concentration of FAM19A5 in MCL patients was 90.55±38.24 (ng/ml), which was significantly higher than that in control (P=0.0461). The proportion of high, medium, and low expression of FAM19A5 in lymph nodes was 32%, 36% and 32%, respectively, which showed significant difference from that in control group (P=0.001). The expression of FAM19A5 in serum and lymph nodes showed significant correlation (r=0.8683，P=0.001). The serum concentration of FAM19A5 showed positive correlation with the proportion of Ki67 (P=0.0222, r=0.4554). The mean survival time without relapse/death of MCL patients with high, middle and low expression of FAM19A5 was 17, 27 and 37.5 months, respectively，which showed significant statistical difference (P=0.0360). ROC curve analysis showed that serum concentration of FAM19A5 could predict the therapeutic effect in MCL patients, the cut-off value was 91.49 ng/ml. The proportion of recurrent/death in AML patients with FAM19A5 ＞91.49 ng/ml was significantly higher than that in patients with FAM19A5＜91.49 ng/ml (P=0.0156). CONCLUSION: The expression level of FAM19A5 is increased in MCL patient, and patients with high expression of FAM19A5 are more likely to relapse or die. FAM19A5 may be a new prognostic marker and potential therapeutic target for MCL.

Coexistence of recurrent chromosomal abnormalities and the Philadelphia chromosome in acute and chronic myeloid leukemias: report of five cases and review of literature.

Progression of chronic myelogenous leukemia (CML) is frequently accompanied by cytogenetic evolution. Additional genetic abnormalities are seen in 10-20% of CML cases at the time of diagnosis, and in 60-80% of cases of advanced disease. Unbalanced chromosomal changes such as an extra copy of the Philadelphia chromosome (Ph), trisomy 8, and i(17)(q10) are common. Balanced chromosomal translocations, such as t(3;3), t(8;21), t(15;17), and inv(16) are typically found in acute myeloid leukemia, but rarely occur in CML. Translocations involving 11q23, t(8;21), and inv(16) are relatively common genetic abnormalities in acute leukemia, but are extremely rare in CML. In the literature to date, there are at least 76 Ph+ cases with t(3;21), 47 Ph+ cases with inv(16), 16 Ph+ cases with t(8;21), and 9 Ph+ cases with t(9;11). But most of what has been published is now over 30 years old, without the benefit of modern immunophenotyping to confirm diagnosis, and before the introduction of treatment regimes such as TKI. In this study, we explored the rare concomitant occurrence of coexistence current chromosomal translocation and t(9;22) in CML or acute myeloid leukemia (AML).

Design, synthesis and biological evaluation of N-(3-(1H-tetrazol-1-yl)phenyl)isonicotinamide derivatives as novel xanthine oxidase inhibitors.

In our previous study, we reported a series of N-phenylisonicotinamide derivatives as novel xanthine oxidase (XO) inhibitors and identified N-(3-cyano-4-((2-cyanobenzyl)oxy)phenyl)isonicotinamide (compound 1) as the most potent one with an IC50 value of 0.312 µM. To further optimize the structure and improve the potency, a structure-based drug design (SBDD) strategy was performed to construct the missing H-bond between the small molecule and the Asn768 residue of XO. We introduced a tetrazole moiety at the 3'-position of the phenyl to serve as an H-bond acceptor and obtained a series of N-(3-(1H-tetrazol-1-yl)phenyl)isonicotinamide derivatives (2a-t and 6-8). Besides, to investigate the influence of the amide-reversal, some N-(pyridin-4-yl)-3-(1H-tetrazol-1-yl)benzamide derivatives (3c, 3e, 3i, 3k and 3u) were also synthesized and evaluated. Biological evaluation and structure-activity relationship analysis demonstrated that the 3'-(1H-tetrazol-1-yl) moiety was an excellent fragment for the N-phenylisonicotinamide scaffold; a substituted benzyloxy, especially, an m-cyanobenzyloxy (e.g., 2s), linking at the 4'-position was welcome for the potency; and the amide-reversal could damage the potency, so maintenance of the N-phenylisonicotinamide scaffold was essential. In summary, starting from compound 1, the SBDD effort successfully identified a promising XO inhibitor 2s (IC50 = 0.031 µM), with a 10-fold gain in potency. Its potency was very close to the positive control topiroxostat (IC50 = 0.021 µM). A Lineweaver-Burk plot indicated that compound 2s acted as a mixed-type XO inhibitor. Molecular docking and molecular dynamics simulations revealed that the tetrazole moiety could occupy the Asn768-sub-pocket with N-4 atom accepting an H-bond from the Asn768 residue, as expected.