Investigations of the prognostic value of RUNX1 mutation in acute myeloid leukemia patients: Data from a real-world study.

RUNX1 is one of the recurrent mutated genes in newly diagnosed acute myeloid leukemia (AML). Although historically recognized as a provisional distinct entity, the AML subtype with RUNX1 mutations (AML-RUNX1mut) was eliminated from the 2022 WHO classification system. To gain more insight into the characteristics of AML-RUNX1mut, we retrospectively analyzed 1065 newly diagnosed adult AML patients from the First Affiliated Hospital of Soochow University between January 2017 and December 2021. RUNX1 mutations were identified in 112 patients (10.5%). The presence of RUNX1 mutation (RUNX1mut) conferred a lower composite complete remission (CRc) rate (40.2% vs. 58.4%, P＜0.001), but no significant difference was observed in the 5-year overall survival (OS) rate (50.2% vs. 53.9%; HR=1.293; P=0.115) and event-free survival (EFS) rate (51.5% vs. 49.4%; HR=1.487, P=0.089), even within the same risk stratification. Multivariate analysis showed that RUNX1mut was not an independent prognostic factor for OS (HR=1.352, P=0.068) or EFS (HR=1.129, P=0.513). When patients were stratified according to induction regimen, RUNX1mut was an unfavorable factor for CRc both on univariate and multivariate analysis in patients receiving conventional chemotherapy, and higher risk stratification predicted worse OS. In those who received venetoclax plus hypomethylating agents, RUNX1mut was not predictive of CRc and comparable OS and EFS were seen between intermediate-risk and adverse-risk groups. The results of this study revealed that the impact of RUNX1mut is limited. Its prognostic value depended more on treatment and co-occurrent abnormalities. VEN-HMA may abrogate the prognostic impact of RUNX1, which merits a larger prospective cohort to illustrate.

Visible-Light-Promoted Selenylation/Cyclization of o-Alkynyl Benzylazides/o-Propargyl Arylazides: Synthesis of Seleno-Substituted Isoquinolines and Quinolines.

A simple and efficient visible-light-promoted selenylation/cyclization of o-alkynyl benzylazides/o-propargyl arylazides have been realized for the practical synthesis of seleno-substituted isoquinolines and quinolines. This strategy provides the synthesis of valuable seleno-substituted isoquinoline and quinoline derivatives via the construction of one C(sp2)-Se bond and one C-N bond within one process.

[Research Progress of Immune Heterogeneity in Leukemia Microenvironment--Review].

Although the body has a strong immune system which can resists the invasion of leukemia cells, leukemia cells disseminate systemically and form an immunosuppressive microenvironment through a variety of mechanisms, including regulation of antigen presentation, utilization of immunosuppressive enzyme AXL, immune cell inhibitory checkpoint NKG2A and immunoregulatory gene VISTA, resulting in immune escape. Therefore, most types of leukemia are inevitable for the affliction of drug resistance or relapse, and the immune efficacy is not as significant as that of other hematological tumors and the prognosis is suboptimal. This article reviews the immune heterogeneity of leukemia microenvironment from many aspects, including anti-leukemia immunity and immune escape. In addition, it also reviews the latest progress and future prospects of immune checkpoint inhibition, adoptive cell therapy and vaccine therapy in leukemia, providing a theoretical basis for the development of personalized combination therapy strategies with less toxic side effects.

Clinical efficacy of low-dose glucocorticoid therapy for critically ill patients with severe fever with thrombocytopenia syndrome: A retrospective cohort study.

OBJECTIVES: To determine whether glucocorticoids can improve clinical outcomes of severe fever with thrombocytopenia syndrome (SFTS) patients, and how to identify patients who may benefit from the treatment. METHODS: A retrospective study was performed to include patients with confirmed SFTS from designated hospitals. The effect of glucocorticoids in reducing case fatality rate (CFR) and improving clinical recovery was evaluated by multivariate logistic regression models. RESULTS: A total of 2478 eligible patients were analyzed, of whom 331 received glucocorticoids. An integrated parameter (L-index) based on Log10(lactate dehydrogenase*blood urea nitrogen/lymphocyte count) was constructed to discriminate disease severity. In patients with L-index >3.823 indicating severe SFTS, significantly reduced CFR was observed in patients receiving low-moderate glucocorticoid doses with ≤60 mg daily methylprednisolone or equivalent (odds ratio [OR] 0.46, 95% confidence interval [CI], 0.23-0.88), but not in patients receiving high doses. In patients with L-index ≤3.823 indicating mild SFTS, glucocorticoid treatment was significantly associated with increased CFR (OR 3.34, 95% CI, 1.35-9.51), and mainly attributable to high-dose glucocorticoids (OR 2.83, 95% CI, 1.72-4.96). Disaggregated data analysis revealed a significant effect only in patients ≤65 years old, male, and early admission within 7 days after onset, but not in their counterparts. CONCLUSION: Glucocorticoids are not recommended for mild patients defined by L-index <3.823; however, patients with severe SFTS may benefit from low-moderate doses of glucocorticoids.

[Research Progress of Long Non-Coding RNA in Hematological Tumors --Review].

Long non-coding RNA (lncRNA) is a hot topic in the field of researching tumor pathogenesis, and the importance in hematologic malignancies has been gradually being elucidated. LncRNA not only regulates hematological tumorigenesis and progression through affecting various biological processes such as cell proliferation, differentiation, pluripotency and apoptosis; moreover, abnormal expression and mutation of lncRNA are closely related to drug resistance and prognosis. Thus lncRNA can be used as novel biomarker and potential therapeutic target for hematological tumors. In this review, we will focus on the latest progress of lncRNA in hematological tumors to provide new ideas for the clinical diagnosis, prognostic evaluation together with research and development of target drugs for hematologic malignancies.

Discovery of two biotin-PEG4­diarylidenyl piperidone prodrugs as potent antitumor agents with good efficacy, limited toxicity, and low resistance.

Two biotin-polyethylene glycol (PEG)4­diarylidenyl piperidone (DAP) prodrugs, compounds 3a and 3b, were designed as antineoplastic agents and synthesized by coupling biotin to bifluoro- and binitro-substituted DAP derivatives (DAP-F and DAP-NO2) through a PEG4 linker, respectively. The results of the MTT (3-(4, 5)-dimethylthiahiazo (-z-y1)-3, 5-di- phenytetrazoliumromide) assay and a SW480 xenograft model identified compounds 3a and 3b as candidate antitumor agents with good efficacy, limited toxicity, and low resistance, as compared to the original drugs (DAP-F and DAP-NO2), cisplatin, and doxorubicin (dox). The results of a preliminary pharmacokinetic study showed that compounds 3a and 3b slowly released their original drug DAP-F and DAP-NO2 within 12 h after intraperitoneal injection, respectively. Western blot analysis and computer docking simulations indicated that DAP-F, DAP-NO2, and compounds 3a and 3b were indeed inhibitors of signal transducer and activator of transcription 3 (STAT3) and the antitumor effects of compounds 3a and 3b were exerted by sequentially interacting with the SH2-binding domain followed by the DNA-binding domain after releasing the original drugs DAP-F and DAP-NO2, respectively. These results suggest that the targeted prodrug model led to good antitumor efficacy with reduced toxicity, while a dual STAT3-binding model may promote antitumor efficacy and resistance.

Fatal patients with severe fever with thrombocytopenia syndrome in China.

OBJECTIVES: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease with a high case fatality rate. Key gaps remained as to the assessment of the clinical picture in fatal cases. METHODS: A retrospective study was performed on 496 patients with fatal SFTS. The dynamic pattern of clinical manifestations and laboratory indicators were delineated. RESULTS: The mean age of the fatal cases was 69.0 years (standard deviation: 9.3), and 52.8% were male. The median clinical course from disease onset to death was 11 (interquartile range: 10-13) days. A total of 11 laboratory indicators (neutrophil %, platelet, aspartate aminotransferase, aspartate aminotransferase/alanine transaminase, lactate dehydrogenase, creatine kinase, cystatin C, D-dimer, activated partial thromboplastin time, thrombin time, glucose) persistently deviated from normality across hospitalization. The critical time points when the rapid worsening of the indicators was at 6-9 days after disease onset. Alanine transaminase, AST, lactate dehydrogenase, total bile acid, gamma-glutamyl transpeptidase, and glucose were all elevated to a more pronounced level in fatal cases of those aged ≤70 years. CONCLUSION: The fatal outcome was developed in rather a short course after the disease onset of SFTS. High vigilance should be put on the key time points when the severe worsening and severe complications occur.

Long-Term Follow-Up Study of COVID-19: Evaluation on Thin-Slice CT.

Purpose: To retrospectively analyse the CT imaging during the long-term follow-up of COVID-19 patients after discharge. Patients and Methods: A total of 122 patients entered the study group. All patients underwent CT examinations. The CT images, which included distribution and imaging signs, were evaluated by two chest radiologists. Laboratory examinations included routine blood work, biochemical testing, and SARS-CoV-2 antibody screening. Statistical methods include chi-square, Fisher's exact test, one-way analysis of variance, rank sum test and logistic regression by SPSS 17.0. Results: There were 22 (18.0%) patients in the mild group, 74 (60.7%) patients in the moderate group, and 26 (21.3%) patients in the severe-critical group. The median follow-up interval was 405 days (378.0 days, 462.8 days). Only monocytes, prothrombin activity, and γ-glutamyltransferase showed significant differences among the three groups. We found that the more severe the patient's condition, the more SARS-CoV-2 IgG antibodies existed. Only 11 patients (11.0%) showed residual lesions on CT. The CT manifestations included irregular linear opacities in nine cases (9.0%), reticular patterns in six cases (6.0%), and GGOs in five cases (5.0%). Conclusion: The proportion of residual lesions on CT in COVID-19 patients was significantly reduced after long-term follow-up. The patients' age and disease conditions were positively correlated with residual lesions.

[Research Progress of m6A Methylation Modification in Hematological Tumors--Review].

N6-methyladenosine (m6A) is one of the most common epigenetic modifications of eukaryotic mRNAs, which is involved in the regulation of gene expressions and biological processes in a variety of cells with dynamic and reversible methylation processes. In recent years, many studies have shown that m6A methylation modification not only acts on the growth, proliferation, and medullary differentiation of acute myeloid leukemia cells, but also participates in the regulation of the proliferation and apoptosis of other hematological tumor cells such as chronic myeloid leukemia and diffuse large B-cell lymphoma, and it can even weaken the efficacy of anti-hematological tumor immunotherapy and induce immune escape leading to tumor resistance. With the successive development of a variety of m6A methylation-related enzyme inhibitors, it will provide new therapeutic ideas for patients with relapsed and refractory hematological tumors. In this paper, we review the research progress on the mechanism of m6A methylation on the occurrence, development, and tumor immunity of various hematological tumors.

Visible-Light-Promoted bis(Difluoromethylation)/Cyclization of 2-Vinyloxy Arylalkynes to Prepare Benzofuran Derivatives.

A visible-light-promoted difluoromethylation/cyclization of 2-vinyloxy arylalkynes was developed, providing a variety of bis(difluoromethyl)-substituted benzofurans in moderate to good yields. A plausible mechanism involving difluoromethyl radical cascade cyclization and solvent-promoted ionic addition was proposed. This protocol has the advantages of having mild reaction conditions, simple operation, and good functional group tolerance.

Synthesis of Selenyl-Substituted Quinoline Derivatives via Substrate-Controlled Three-Component Domino Reactions.

A simple and efficient method for the preparation of selenyl-substituted quinoline derivatives through a CSp3-H selenylation of in situ-generated 3-acetyl quinoline has been developed. This protocol is easy to handle, scalable, and good functional group tolerant, providing a rapid method to 3-selenoacetyl quinoline and 3-diselenoacetyl quinoline derivatives.

Coinfections in hospitalized patients with severe fever with thrombocytopenia syndrome: A retrospective study.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease with a high case fatality rate. Few studies have been performed on bacterial or fungal coinfections or the effect of antibiotic therapy. A retrospective, observational study was performed to assess the prevalence of bacterial and fungal coinfections in patients hospitalized for SFTSV infection. The most commonly involved microorganisms and the effect of antimicrobial therapy were determined by the site and source of infection. A total of 1201 patients hospitalized with SFTSV infection were included; 359 (29.9%) had microbiologically confirmed infections, comprised of 292 with community-acquired infections (CAIs) and 67 with healthcare-associated infections (HAIs). Death was independently associated with HAIs, with a more significant effect than that observed for CAIs. For bacterial infections, only those acquired in hospitals were associated with fatal outcomes, while fungal infection, whether acquired in hospital or community, was related to an increased risk of fatal outcomes. The infections in the respiratory tract and bloodstream were associated with a higher risk of death than that in the urinary tract. Both antibiotic and antifungal treatments were associated with improved survival for CAIs, while for HAIs, only antibiotic therapy was related to improved survival, and no effect from antifungal therapy was observed. Early administration of glucocorticoids was associated with an increased risk of HAIs. The study provided novel clinical and epidemiological data and revealed risk factors, such as bacterial coinfections, fungal coinfections, infection sources, and treatment strategies associated with SFTS deaths/survival. This report might be helpful in curing SFTS and reducing fatal SFTS.

Theoretical Study on the Mechanism of the Acylate Reaction of ß-Lactamase.

Using density functional theory and a cluster approach, we study the reaction potential surface and compute Gibbs free energies for the acylate reaction of ß-lactamase with penicillin G, where the solvent effect is important and taken into consideration. Two reaction paths are investigated: one is a multi-step process with a rate-limit energy barrier of 19.1 kcal/mol, which is relatively small, and the reaction can easily occur; the other is a one-step process with a barrier of 45.0 kcal/mol, which is large and thus makes the reaction hard to occur. The reason why the two paths have different barriers is explained.

Highly enantioselective one-pot sequential synthesis of valerolactones and pyrazolones bearing all-carbon quaternary stereocentres.

Highly enantiopure and bioactive δ-valerolactones and pyrazolones, bearing α-all-carbon quaternary stereocentres, were successfully and sequentially prepared via a one-pot procedure starting from readily available, inexpensive materials, catalysed by a new chiral squaramide under mild reaction conditions. An organocatalytic Michael reaction afforded the valerolactones, while a one-pot Michael-hydrazinolysis-imidization cascade yielded the pyrazolones. This procedure is economically efficient and environmentally benign.

Pattern of liver injury in adult patients with COVID-19: a retrospective analysis of 105 patients.

BACKGROUND: Recent studies reported that patients with coronavirus disease-2019 (COVID-19) might have liver injury. However, few data on the combined analysis and change patterns of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBil) have been shown. METHODS: This is a single-center retrospective study. A total of 105 adult patients hospitalized for confirmed COVID-19 in Beijing Ditan Hospital between January 12, and March 17, 2020 were included, and divided into mild group (n = 79) and severe group(n = 26). We compared liver functional test results between the two groups. Category of ALT change during the disease course was also examined. RESULTS: 56.2% (59/105) of the patients had unnormal ALT, AST, or total TBil throughout the course of the disease, but in 91.4% (96/105) cases the level of ALT, AST or TBil ≤3 fold of the upper limit of normal reference range (ULN). The overall distribution of ALT, AST, and TBil were all significantly difference between mild and severe group (P <  0.05). The percentage of the patients with elevated both ALT and AST was 12.7% (10/79) in mild cases vs. 46.2% (12/26) in severe cases (P = 0.001). 34.6% (9/26) severe group patients started to have abnormal ALT after admission, and 73.3% (77/105) of all patients had normal ALT before discharge. CONCLUSIONS: Elevated liver function index is very common in patients with COVID-19 infection, and the level were less than 3 × ULN, but most are reversible. The abnormality of 2 or more indexes is low in the patients with COVID-19, but it is more likely to occur in the severe group.

Peptide-Catalyzed Highly Asymmetric Cross-Aldol Reaction of Aldehydes to Biomimetically Synthesize 1,4-Dicarbonyls.

ß-Turn tetrapeptides were demonstrated to catalyze asymmetric aldol reaction of α-branched aldehydes and α-carbonyl aldehydes, i.e. glyoxylates and α-ketoaldehydes, to biomimetically synthesize acyclic all-carbon quaternary center-bearing 1,4-dicarbonyls in high yield and excellent enantioselectivity under mild conditions. The spatially restricted environment of the tetrapeptide warrants high enantioselectivity and yield with broad substrates. Using this protocol, (R)-pantolactone, the key intermediate of vitamin B5, was readily accessed in a practical, efficient, and environmentally benign process from inexpensive starting materials.

Visible-Light-Promoted Selenylative Spirocyclization of Indolyl-ynones toward the Formation of 3-Selenospiroindolenine Anticancer Agents.

A metal-free and efficient visible-light-induced spirocyclization of indolyl-ynones with diselenides at room temperature under air atmosphere to prepare 3-selenospiroindolenines in moderate to good yields has been developed. The resulting products were tested for in vitro anticancer activity by MTT assay, and compounds 3 c and 3 e showed potent cancer cell-growth inhibition activities.

OcUGT1-Catalyzing Glycodiversification of Steroids through Glucosylation and Transglucosylation Actions.

Steroidal glycosides are important sources of innovative drugs. The increased diversification of steroidal glycosides will expand the probability of discovering active molecules. It is an efficient approach to diversify steroidal glycosides by using steroidal glycosyltransferases. OcUGT1, a uridine diphosphate-d-glucose (UDP-Glc)-dependent glycosyltransferase from Ornithogalum caudatum, is a multifunctional enzyme, and its glycodiversification potential towards steroids has never been fully explored. Herein, the glycodiversification capability of OcUGT1 towards 25 steroids through glucosylation and transglucosylation reactions were explored. Firstly, each of 25 compounds was glucosylated with UDP-Glc. Under the action of OcUGT1, five steroids (testosterone, deoxycorticosterone, hydrocortisone, estradiol, and 4-androstenediol) were glucosylated to form corresponding mono-glucosides and biosides. Next, OcUGT1-mediated transglucosylation activity of these compounds with another sugar donor ortho-nitrophenyl-ß-d-glucopyranoside (oNPGlc) was investigated. Results revealed that the same five steroids could be glucosylated to generate mono-glucosides and biosides by OcUGT1 through transglucosylation reactions. These data indicated that OcUGT1-assisted glycodiversification of steroids could be achieved through glucosylation and transglucosylation reactions. These results provide a way to diversify steroidal glycosides, which lays the foundation for the increase of the probability of obtaining active lead compounds.

Photocatalytic Construction of S-S and C-S Bonds Promoted by Acridinium Salt: An Unexpected Pathway To Synthesize 1,2,4-Dithiazoles.

An unexpected cyclization of thioamides with p-quinone methides promoted by acridinium salt under the irradiation of visible light furnished 1,2,4-dithiazoles in moderate to good yields. In addition, the reaction of the obtained 1,2,4-dithiazoles with isocyanides offered a new entry for the synthesis of thiazol-5(4 H)-imines in moderate yields.

Copper-Catalyzed Decarboxylative/Click Cascade Reaction: Regioselective Assembly of 5-Selenotriazole Anticancer Agents.

A simple and efficient Cu-catalyzed decarboxylative/click reaction for the preparation of 1,4-disubstituted 5-arylselanyl-1,2,3-triazoles from propiolic acids, diselenides, and azides has been developed. The mechanistic study revealed that the intermolecular AAC reaction of an alkynyl selenium intermediate occurred. The resulting multisubstituted 5-seleno-1,2,3-triazoles were tested for in vitro anticancer activity by MTT assay, and compounds 4f, 4h, and 4p showed potent cancer cell-growth inhibition activities.