NOTCH pathway mutation contributes to inferior prognosis in HBV-infected chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) patients with hepatitis B virus (HBV) infection have a poor prognosis, underlying mechanism remains unclear. NOTCH mutations are frequent in CLL and associated with disease progression and drug resistance. It is also reported to be associated with hepatitis infection in lymphoid malignancies. In order to investigate the relation between the NOTCH pathway and HBV-associated CLL, we studied 98 previously untreated HBV-positive CLL patients and 244 HBV-negative CLL. NOTCH mutations were more frequent in HBV-positive CLL subgroup (p = 0.033). By survival analysis, HBV infection was associated with disease progression and poor survival (p = 0.0099 for overall survival (OS) and p = 0.0446 for time-to-treatment (TTT)). Any lesions of the NOTCH pathway (NOTCH1, NOTCH2, and SPEN) aggravated prognosis. In multivariate analysis, NOTCH mutation retained an independent significance for HBV-infected patients (p = 0.016 for OS and p = 0.023 for TTT). However, HBV positive with NOTCH unmutated had no statistical difference in prognosis compared with HBV-negative patients (p = 0.1706 for OS and p = 0.2387 for TTT), which indicated that NOTCH pathway mutation contributed to inferior prognosis in HBV-infected CLL. In conclusion, a cohort of CLL patients with HBV positive displayed a worse clinical outcome and the status of the NOTCH signaling pathway might play a crucial role.

25-Hydroxy vitamin D deficiency is an inferior predictor of peripheral T-cell lymphomas.

The aim of the study was to explore the significance and prognostic value of 25-hydroxy vitamin D (25-(OH) D) deficiency in peripheral T-cell lymphomas (PTCLs). One hundred fifty-six patients of newly diagnosed PTCLs were enrolled in the study. Univariate and multivariate regression analyses were performed to determine independent risk factors for progression-free survival (PFS) and overall survival (OS). Receiver operating characteristic (ROC) curves were plotted, and corresponding areas under the curve (AUC) were calculated to estimate the accuracy of International Prognostic Index (IPI) plus 25-(OH) D deficiency and Prognostic Index for T-cell lymphoma (PIT) plus 25-(OH) D deficiency respectively in PTCL risk stratification. Our results showed that the 25-(OH) D deficiency was an independent inferior prognostic factor for both PFS (P = 0.0019) and OS (P = 0.005) for PTCLs, especially for AITL and PTCL-not otherwise specified (PTCL-NOS). Additionally, adding 25-(OH) D deficiency to PIT indeed has a superior prognostic significance than PIT alone for PFS (P = 0.043) and OS (P = 0.036). Multivariate COX regression analysis revealed that PIT 2‒4, albumin (ALB) ≤ 35 g/L, and 25-(OH) D deficiency were regarded as independent risk factors of PFS and OS. Our results showed that 25-(OH) D deficiency was associated with inferior survival outcome of PTCLs, especially for AITL and PTCL-NOS. PIT plus 25-(OH) D deficiency could better indicate the prognosis for PFS and OS of PTCLs than PIT.

Analysis of CCND3 mutations in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL), accounts for 30-40% of newly diagnosed lymphomas, has an overall cure rate of approximately 60%. Despite previous reports suggesting a negative prognostic association between CCND3 mutations and Burkitt lymphoma, their prognostic implications in DLBCL remain controversial. To investigate this, we evaluated CCND3 mutation status in 2059 DLBCL patient samples from four database (integrated cohort) and additional 167 DLBCL patient samples in our center (JSPH cohort). The mutation was identified in 5.5% (113/2059) of the cases in the integrated cohort, with 86% (97/113) found in exon 5. Furthermore, P284, R271, I290 and Q276 are described as CCND3 mutation hotspots. CCND3 mutation was associated with decreased overall survival (OS) in the integrated cohort (P = 0.0407). Further subgroup analysis revealed that patients diagnosed as EZB subtype DLBCL by LymphGen algorithm with CCND3 mutations had poorer OS than patients diagnosed as EZB subtype without CCND3 mutations (P = 0.0140). Using the next-generation sequencing (NGS) in the JSPH cohort, it was found that both cell cycle and DNA replication pathways were highly upregulated in patients with CCND3 mutations. Our results suggest that CCND3 mutations can serve as a novel prognostic factor in DLBCL pathogenesis. Consequently, the development of personalized therapeutic strategies for DLBCL patients with CCND3 mutations might enhance their prognosis.

Cause-specific mortality in a population-level cohort of diffuse large B-cell lymphoma following chemotherapy in the early 21st century.

Diffuse large B-cell lymphoma (DLBCL) is a severe non-Hodgkin's lymphoma. Life expectancy has improved with rituximab, but cause-specific mortality data is lacking. Using the Surveillance, Epidemiology, and End Results (SEER) database to study 27,449 individuals aged 20-74 years diagnosed with primary DLBCL who received chemotherapy between 2000 and 2019, we calculated standardized mortality rate (SMR) and excess absolute risk (EAR) and examined the connection between age, sex, time after diagnosis, and cause of death. Based on 12,205 deaths, 68.7% were due to lymphoma, 20.1% non-cancer causes, and 11.2% other cancers. Non-cancer mortality rates (SMR 1.2; EAR, 21.5) increased with DLBCL compared to the general population. The leading non-cancer death causes were cardiovascular (EAR, 22.6; SMR, 1.6) and infectious (EAR, 9.0; SMR, 2.9) diseases with DLBCL. Risks for non-cancer death and solid neoplasms are highest within the first diagnosis year, then decrease. Among socioeconomic factors, being white, being married, and having a higher income were favorable factors for reducing non-cancer mortality. To improve survival, close surveillance, assessment of risk factors, and early intervention are needed.

Chiral anomaly and Weyl orbit in three-dimensional Dirac semimetal Cd3As2grown on Si.

Preparing Cd3As2, which is a three-dimensional (3D) Dirac semimetal in certain crystal orientation, on Si is highly desirable as such a sample may well be fully compatible with existing Si CMOS technology. However, there is a dearth of such a study regarding Cd3As2films grown on Si showing the chiral anomaly. Here,for the first time, we report the novel preparation and fabrication technique of a Cd3As2(112) film on a Si (111) substrate with a ZnTe (111) buffer layer which explicitly shows the chiral anomaly with a nontrivial Berry's phase ofπ. Despite the Hall carrier density (n3D≈9.42×1017cm-3) of our Cd3As2film, which is almost beyond the limit for the portents of a 3D Dirac semimetal to emerge, we observe large linear magnetoresistance in a perpendicular magnetic field and negative magnetoresistance in a parallel magnetic field. These results clearly demonstrate the chiral magnetic effect and 3D Dirac semimetallic behavior in our silicon-based Cd3As2film. Our tailoring growth of Cd3As2on a conventional substrate such as Si keeps the sample quality, while also achieving a low carrier concentration.

Chemical Composition, Toxicity, and Repellency of Essential Oils from Three Hedychium Species Against Stored-Product Insects.

Stored products are constantly infested by insects, so finding eco-friendly bioinsecticides for insect management is important. The work aimed to assess the insecticidal and repellent activity of essential oil (EO) from Hedychium glabrum S. Q. Tong, Hedychium coronarium Koen., and Hedychium yunnanense Gagnep. against Tribolium castaneum, Lasioderma serricorne, and Liposcelis bostrychophila. Results showed that 88 chemical components were identified in the extracted Hedychium EOs, indicating that they exhibited diversity in components. According to principal component analysis (PCA), the composition of the EO from the H. yunnanense stem and leaf (EOHYSL) was significantly different from other EOs due to the different organs and species. The biological activity also varied continuously with plant species and organs. Only the EO of H. yunnanense (EOHY) showed strong fumigant toxicity. While in the contact tests, EOHGR showed the strongest toxicity effect on L. bostrychophila, with a LC50 value of 71.76 µg/cm2, which was closest to the positive control (Pyrethrin). All EOs had remarkable repellent activities against the three target insects, and repellency increased with concentration. According to the results of the comprehensive score, EOHY had the highest potential, which ranged from 0.7999 to 0.8689. Thus, Hedychium EOs possess potential biorational traits to be biological insecticides.

Prognostic significance of absolute monocyte count and lymphocyte to monocyte ratio in mucosa-associated lymphoid tissue (MALT) lymphoma.

To investigate the prognostic significance of peripheral blood absolute monocyte count (AMC) and lymphocyte to monocyte ratio (LMR) in mucosa-associated lymphoid tissue (MALT) lymphoma, we retrospectively analyzed 316 newly diagnosed patients with MALT lymphoma. The best cut-off value of AMC was 0.6 × 109/L and LMR was 1.8 by x-tile according to progression-free survival (PFS). Multivariate analysis showed that MALT-IPI (p < 0.001), Eastern Cooperative Oncology Group performance status (ECOG PS) (p = 0.010), and LMR (p = 0.003) have independent prognostic significance for PFS, MALT-International Prognostic Index (MALT-IPI) (p = 0.018), ß2-microglobulin (ß2-MG) (p = 0.015), and LMR (p = 0.029) predicted poor overall survival (OS). Receiver-operator characteristic (ROC) curves were used to compare the prognostic prediction capability of MALT-IPI and MALT-IPI-M (MALT-IPI combined with LMR); area under the curves (AUCs) for MALT-IPI-M were larger than that for MALT-IPI both PFS (0.682 vs 0.654) and OS (0.804 vs 0.788). Our results indicated that that low level LMR at diagnosis was associated with inferior prognosis. The new prognostic index, MALT-IPI-M, enabled the risk stratification capability for MALT lymphoma survival.

Dynamic changes in circulating EBV-DNA load during treatment have prognostic values in EBV+ DLBCL-NOS: a Chinese cohort study.

EBV-positive diffuse large B-cell lymphoma, not otherwise specified (EBV+ DLBCL-NOS), is an EBV-positive clonal B-cell lymphoid proliferation and circulating EBV-DNA is a great indicator for prognosis among EBV associated disease. In this retrospective study, we report 66 EBV+ DLBCL cases among 2137 DLBCL-NOS cases diagnosed from 2013 to 2021 (prevalence of 6.0%). After a median follow-up of 27 months, progression-free survival (PFS) and overall survival (OS) at 2 years were 39.5% ± 6.2% and 53.6% ± 6.4%, respectively. Multivariate analysis showed that only the biomarker of the positivity of post treatment EBV-DNA had a borderline correlation with shorter PFS and OS (PFS: P = 0.053; OS: P = 0.065). Patients were divided into three subgroups according to dynamic changes of EBV-DNA status: EBV-DNA persistently negative group, EBV-DNA persistently positive group, and EBV-DNA transformed from positive to negative group; among the three groups, patients of the persistently positive group had worst PFS and OS (P = 0.0527 and P = 0.0139, respectively). Decline in EBV copies correlated significantly with treatment response as well. In conclusion, circulating EBV-DNA level played a vital role in prognostic and monitoring marker for EBV+ DLBCL-NOS.

Assessment of Contact Toxicity and Repellent Effects of Essential Oils from Piper Plants Piper yunnanense and Piper boehmeriifolium against Three Stored-Product Insects.

Storage is a crucial part during grain production for the massive spoilage caused by stored product insects. Essential oils (EOs) of plant origin have been highly recommended to combating insects which are biodegradable and safe mode of action. Hence, to make the fullest use of natural resources, essential oils of different parts from Piper yunnanense (the whole part, PYW; fruits, PYF; leaves, PYL) and Piper boehmeriifolium (leaves, PBL) were extracted by steam distillation method in the present study. Gas chromatography-mass spectrometry (GC-MS) characterization revealed bicyclogermacrene (PYW), γ-muurolene (PYF), δ-cadinene (PYL) and methyl 4,7,10,13,16,19-docosahexaenoate (PBL) as the principal compound of each essential oil. Sesquiterpene hydrocarbons were also recognized as the richest class accounting for 56.3 %-94.9 % of the total oil. Three storage pests, Tribolium castaneum, Lasioderma serricorne and Liposceis bostrychophila, were exposed to different concentrations of EOs to determine their insecticidal effects. All tested samples performed modest contact toxicity in contrast to a bioactive ingredient pyrethrin, among which the most substantial effects were observed in PYF EOs against T. castaneum (35.84 µg/adult), PBL EOs against L. serricorne (15.76 µg/adult) and PYW EOs against L. bostrychophila (57.70 µg/cm2 ). In terms of repellency tests, essential oils of PYF at 78.63 nL/cm2 demonstrated to have a remarkable repellence against T. castaneum at 2h and 4h post-exposure. The investigations indicate diverse variations in the chemical profiles and insecticidal efficacies of P. yunnanense and P. boehmeriifolium EOs, providing more experimental evidence for the use of the Piper plants.

Prognostic significance of serum immunoglobulin paraprotein in mucosa-associated lymphoid tissue (MALT) lymphoma.

To assess the prognostic significance of immunoglobulin (Ig) paraproteinaemia in mucosa-associated lymphoid tissue (MALT) lymphoma, 218 patients diagnosed with MALT lymphoma were enrolled in this study. Serum Ig paraprotein was detected in 42 of 218 patients (19.3%), mostly IgM-K (15, 35.7%), followed by IgM-L and IgG-L. Advanced age (p = 0.025), poor Eastern Cooperative Oncology Group performance status (p = 0.014), bone marrow involvement (p = 0.019), B symptoms (p = 0.039), advanced disease stage (III-IV) (p < 0.0001), elevated serum ß2-microglobulin level (p < 0.0001), multiple extranodal sites of involvement (p < 0.0001), nodal involvement (p < 0.0001), systemic therapy (p < 0.0001) and higher MALT-lymphoma International Prognostic Index (MALT-IPI) scores (p = 0.001) were significantly associated with the presence of serum Ig paraprotein. Multivariate Cox regression analysis showed that Ig paraproteinaemia was an independent prognostic predictor for inferior progression-free survival (PFS) and overall survival. A new prognostic index based on MALT-IPI and Ig paraproteinaemia, as assessed using receiver operating characteristic curves and the area under the curve statistics, showed better discriminative ability than MALT-IPI in predicting PFS. In conclusion, Ig paraproteinaemia was a promising prognostic predictor for MALT lymphoma. Ig paraproteinaemia together with MALT-IPI might contribute to optimising therapeutic management in clinical practice.

Dithiocarbamates combined with copper for revitalizing meropenem efficacy against NDM-1-producing Carbapenem-resistant Enterobacteriaceae.

The worldwide prevalence of NDM-1-producing Gram-negative pathogens has drastically undermined the clinical efficacy of carbapenems, prompting a need to devise an effective strategy to preserve their clinical value. Here we constructed a focused compound library of dithiocarbamates and systematically evaluated their potential synergistic antibacterial activities combined with copper. SA09-Cu exhibited excellent inhibition against a series of clinical NDM-1-producing carbapenem-resistant Enterobacteriaceae (CRE) in restoring meropenem effect, and slowed down the development of carbapenem resistance. Enzymatic kinetic and isothermal titration calorimetry studies demonstrated that SA09-Cu was a noncompetitive NDM-1 inhibitor. The electron paramagnetic resonance (EPR) and X-ray photoelectron spectroscopy (XPS) revealed a novel inhibition mechanism, which is that SA09-Cu could convert NDM-1 into an inactive state by oxidizing the Zn(II)-thiolate site of the enzyme. Importantly, SA09-Cu showed a unique redox tuning ability, and avoided to be reduced by intracellular thiols of bacteria. In vivo experiments indicated that SA09 combined with CuGlu could effectively potentiate MER's effect against NDM-1-producing E. coli (EC23) in the murine infection model. This study provides a highly promising scaffold in developing novel inhibitors to combat NDM-1-producing CREs.

Quinolinyl sulfonamides and sulphonyl esters exhibit inhibitory efficacy against New Delhi metallo-ß-lactamase-1 (NDM-1).

The "superbug" infection caused by metallo-ß-lactamases (MßLs) has grown into anemergent health threat, and development of effective MßL inhibitors to restore existing antibiotic efficacy is an ideal alternative. Although the serine-ß-lactamase inhibitors have been used in clinical settings, MßL inhibitors are not available to date. In this work, thirty-one quinolinyl sulfonamides 1a-p and sulphonyl esters 2a-o were synthesized and assayed against MßL NDM-1. The obtained molecules specifically inhibited NDM-1, 1a-p and 2a-o exhibited an IC50 value in the range of 0.02-1.4 and 8.3-24.8 µM, respectively, and 1e and 1f were found to be the most potent inhibitors, with an IC50 of 0.02 µM using meropenem (MER) as substrate. Structure-activity relationship reveals that the substitute phenyl and the phenyl with a halogen atom more significantly improve inhibitory effect of quinolinederivatives on NDM-1. 1a-p restored antimicrobial effect of MER on E. coli with NDM-1, EC01 and EC08, resulting in a 2-64-fold reduction in MIC values. Most importantly, 1e synergized MER and significantly reduced the load of EC08 in the spleen and liver of mice after a single intraperitoneal dose. Docking studies suggested that the endocyclic nitrogen of the quinoline ring, and exocyclic nitrogen of the sulfonamide functional group are coordinate with Zn(II) ion at active sites of NDM-1. Cytotoxicity assays indicated that 1e had low cytotoxicity. This work offers potential lead compounds for further development of the clinically useful inhibitor targeting NDM-1.

Hydroxamate and thiosemicarbazone: Two highly promising scaffolds for the development of SARS-CoV-2 antivirals.

The emerging COVID-19 pandemic generated by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has severely threatened human health. The main protease (Mpro) of SARS-CoV-2 is promising target for antiviral drugs, which plays a vital role for viral duplication. Development of the inhibitor against Mpro is an ideal strategy to combat COVID-19. In this work, twenty-three hydroxamates 1a-i and thiosemicarbazones 2a-n were identified by FRET screening to be the potent inhibitors of Mpro, which exhibited more than 94% (except 1c) and more than 69% inhibition, and an IC50 value in the range of 0.12-31.51 and 2.43-34.22 µM, respectively. 1a and 2b were found to be the most effective inhibitors in the hydroxamates and thiosemicarbazones, with an IC50 of 0.12 and 2.43 µM, respectively. Enzyme kinetics, jump dilution and thermal shift assays revealed that 2b is a competitive inhibitor of Mpro, while 1a is a time-dependently inhibitor; 2b reversibly but 1a irreversibly bound to the target; the binding of 2b increased but 1a decreased stability of the target, and DTT assays indicate that 1a is the promiscuous cysteine protease inhibitor. Cytotoxicity assays showed that 1a has low, but 2b has certain cytotoxicity on the mouse fibroblast cells (L929). Docking studies revealed that the benzyloxycarbonyl carbon of 1a formed thioester with Cys145, while the phenolic hydroxyl oxygen of 2b formed H-bonds with Cys145 and Asn142. This work provided two promising scaffolds for the development of Mpro inhibitors to combat COVID-19.

Dihydroxyphenyl-substituted thiosemicarbazone: A potent scaffold for the development of metallo-ß-lactamases inhibitors and antimicrobial.

The superbug infection mediated by metallo-ß-lactamases (MßLs) has grown into anemergent health threat, and development of MßL inhibitors is an ideal strategy to combat the infection. In this work, twenty-five thiosemicarbazones 1a-e, 2a-e, 3a-e, 4a-d, 5a-d and 6a-b were synthesized and assayed against MßLs ImiS, NDM-1 and L1. The gained molecules specifically inhibited NDM-1 and ImiS, exhibiting an IC50 value in the range of 0.37-21.35 and 0.45-8.76 µM, and 2a was found to be the best inhibitor, with an IC50 of 0.37 and 0.45 µM, respectively, using meropenem (MER) as substrate. Enzyme kinetics and dialysis tests revealed and confirmed by ITC that 2a is a time-and dose-dependent inhibitor of ImiS and NDM-1, it competitively and reversibly inhibited ImiS with a Ki value of 0.29 µM, but irreversibly inhibited NDM-1. Structure-activity relationship disclosed that the substitute dihydroxylbenzene significantly enhanced inhibitory activity of thiosemicarbazones on ImiS and NDM-1. Most importantly, 1a-e, 2a-e and 3a-b alone more strongly sterilized E. coli-ImiS and E. coli-NDM-1 than the MER, displaying a MIC value in the range of 8-128 µg/mL, and 2a was found to be the best reagent with a MIC of 8 and 32 µg/mL. Also, 2a alone strongly sterilized the clinical isolates EC01, EC06-EC08, EC24 and K. pneumonia-KPC-NDM, showing a MIC value in the range of 16-128 µg/mL, and exhibited synergistic inhibition with MER on these bacteria tested, resulting in 8-32-fold reduction in MIC of MER. SEM images shown that the bacteria E. coli-ImiS, E. coli-NDM-1, EC24, K. pneumonia-KPC and K. pneumonia-KPC-NDM treated with 2a (64 µg/mL) suffered from distortion, emerging adhesion between individual cells and crumpled membranes. Mice tests shown that monotherapy of 2a evidently limited growth of EC24 cells, and in combination with MER, it significantly reduced the bacterial load in liver and spleen. Docking studies suggest that the 2,4-dihydroxylbenzene of 2a acts as zinc-binding group with the Zn(II) and the residual amino acids in CphA active center, tightly anchoring the inhibitor at active site. This work offered a promising scaffold for the development of MßLs inhibitors, specifically the antimicrobial for clinically drug-resistant isolates.

lncRNA IGF2-AS promotes the osteogenic differentiation of bone marrow mesenchymal stem cells by sponging miR-3,126-5p to upregulate KLK4.

BACKGROUND: Osteoporosis (OP) is a bone disease characterized by reduced amount and quality of bone. This study was designed to explore the role and mechanism of lncRNA IGF2-AS in the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). METHODS: Human lncRNA and miRNA microarray analyses were performed to measure the differential expression levels of lncRNAs and miRNAs in undifferentiated and osteogenically differentiated BMSCs. lncRNA IGF2-AS, miR-3,126-5p, and KLK4 levels were measured by real-time quantitative polymerase chain reaction (RT-qPCR). Osteogenic differentiation of BMSCs was assessed by alkaline phosphatase (ALP) staining and Alizarin Red staining (ARS). Protein levels of osterix (Osx), osteocalcin (OCN), and runt-related transcription factor 2 (RUNX2) were examined by RT-PCR and western blot assays. The binding relationship between miR-3,126-5p and lncRNA IGF2-AS or KLK4 was predicted by TargetScan (http://www.targetscan.org/vert_72/) and then verified with a dual-luciferase reporter assay. RESULTS: lncRNA IGF2-AS and KLK4 were highly expressed and miR-3,126-5p was weakly expressed in osteogenically differentiated BMSCs. Moreover, lncRNA IGF2-AS overexpression enhanced the osteogenic differentiation of BMSCs. In contrast, lncRNA IGF2-AS knockdown showed the opposite trend. Moreover, miR-3,126-5p overexpression abolished the lncRNA IGF2-AS-mediated osteogenic differentiation of BMSCs. lncRNA IGF2-AS functions as a sponge of miR-3,126-5p to regulate KLK4 expression. CONCLUSION: lncRNA IGF2-AS enhances the osteogenic differentiation of BMSCs by modulating the miR-3,126-5p/KLK4 axis, suggesting a promising therapeutic target for bone-related diseases.

Prognostic value of 25-hydroxy vitamin D in extranodal NK/T cell lymphoma.

25-hydroxy vitamin D [25-(OH)D] is widely used to determine vitamin D status in clinic. The aim of our study was to evaluate the prognostic value of 25-(OH)D in extranodal NK/T cell lymphoma (ENKTL). Ninety-three (93) ENKTL patients with available serum 25-(OH)D values were enrolled in our study. Vitamin D deficiency is defined as a 25-(OH)D below 50 nmol/L (20 ng/ml). Univariate and multivariate regression analyses were performed to determine independent risk factors for progression-free survival (PFS) and overall survival (OS). Receiver operator characteristic (ROC) curves were plotted, and corresponding areas under the curves (AUC) were calculated to estimate the accuracy of PINK-E (prognostic index of natural killer lymphoma added with Epstein-Barr virus-DNA status) and 25-(OH)D deficiency in ENKTL risk-stratification. Our results suggested that the vitamin D deficiency was an independent inferior prognostic factor for both PFS [hazard ratio (HR), 2.869; 95% confidence interval (CI), 1.540 to 5.346; P = 0.003] and OS (HR, 3.204; 95% CI, 1.559 to 6.583; P = 0.006) in patients with ENKTL. Additionally, we demonstrated that adding 25-(OH)D deficiency to PINK-E score system indeed has a superior prognostic significance than PINK-E alone for PFS [AUC: 0.796 (95% CI: 0.699 to 0.872) vs. 0.759 (95% CI: 0.659 to 0.841), P = 0.020] and OS [AUC: 0.755 (95% CI: 0.655 to 0.838) vs. 0.721 (95% CI: 0.618 to 0.809), P = 0.040]. In conclusion, our study proved that 25-(OH)D deficiency was associated with inferior survival outcome of ENKTL patients.

Dipyridyl-substituted thiosemicarbazone as a potent broad-spectrum inhibitor of metallo-ß-lactamases.

To combat the superbug infection caused by metallo-ß-lactamases (MßLs), a dipyridyl-substituted thiosemicarbazone (DpC), was identified to be the broad-spectrum inhibitor of MßLs (NDM-1, VIM-2, IMP-1, ImiS, L1), with an IC50 value in the range of 0.021-1.08 µM. It reversibly and competitively inhibited NDM-1 with a Ki value of 10.2 nM. DpC showed broad-spectrum antibacterial effect on clinical isolate K. pneumonia, CRE, VRE, CRPA and MRSA, with MIC value ranged from 16 to 32 µg/mL, and exhibited synergistic antibacterial effect with meropenem on MßLs-producing bacteria, resulting in a 2-16-, 2-8-, and 8-fold reduction in MIC of meropenem against EC-MßLs, EC01-EC24, K. pneumonia, respectively. Moreover, mice experiments showed that DpC also had synergistic antibacterial action with meropenem. In this work, DpC was identified to be a potent scaffold for the development of broad-spectrum inhibitors of MßLs.

Diaryl-substituted thiosemicarbazone: A potent scaffold for the development of New Delhi metallo-ß-lactamase-1 inhibitors.

The superbug infection caused by New Delhi metallo-ß-lactamase (NDM-1) has become an emerging public health threat. Inhibition of NDM-1 has proven challenging due to its shuttling between pathogenic bacteria. A potent scaffold, diaryl-substituted thiosemicarbazone, was constructed and assayed with metallo-ß-lactamases (MßLs). The obtained twenty-six molecules specifically inhibited NDM-1 with IC50 0.038-34.7 µM range (except 1e, 2e, and 3d), and 1c is the most potent inhibitor (IC50 = 0.038 µM). The structure-activity relationship of synthetic thiosemicarbazones revealed that the diaryl-substitutes, specifically 2-pyridine and 2-hydroxylbenzene improved inhibitory activities of the inhibitors. The thiosemicarbazones exhibited synergistic antimycobacterial actions against E. coli-NDM-1, resulted a 2-512-fold reduction in MIC of meropenem, while 1c restored 16-256-, 16-, and 2-fold activity of the antibiotic on clinical isolates ECs, K. pneumonia and P. aeruginosa harboring NDM-1, respectively. Also, mice experiments showed that 1c had a synergistic antibacterial ability with meropenem, reduced the bacterial load clinical isolate EC08 in the spleen and liver. This work provided a highly promising scaffold for the development of NDM-1 inhibitors.

N-acylhydrazones confer inhibitory efficacy against New Delhi metallo-ß-lactamase-1.

The expression of ß-lactamases, especially metallo-ß-lactamases (MßLs) in bacteria is one of the main causes of drug resistance. In this work, an effective N-acylhydrazone scaffold as MßL inhibitor was constructed and characterized. The biological activity assays indicated that the synthesized N-acylhydrazones 1-11 preferentially inhibited MßL NDM-1, and 1 was found to be the most effective inhibitor with an IC50 of 1.2 µM. Analysis of IC50 data revealed a structure-activity relationship, which is that the pyridine and hydroxylbenzene substituents at 2-position improved inhibition of the compounds on NDM-1. ITC and enzyme kinetics assays suggested that it reversibly and competitively inhibited NDM-1 (Ki = 0.29 ± 0.05 µM). The synthesized N-acylhydrazones showed synergistic antibacterial activities with meropenem, reduced 4-16-fold MIC of meropenem on NDM-1- producing E. coli BL21 (DE3), while 1 restored 4-fold activity of meropenem on K. pneumonia expressing NDM-1 (NDM-K. pneumoniae). The mice experiments suggested that 1 combined meropenem to fight against NDM-K. pneumoniae infection in the spleen and liver. Cytotoxicity assays showed that 1 and 2 have low cytotoxicity. This study offered a new framework for the development of NDM-1 inhibitors.

Ebsulfur and Ebselen as highly potent scaffolds for the development of potential SARS-CoV-2 antivirals.

The emerging COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised a global catastrophe. To date, there is no specific antiviral drug available to combat this virus, except the vaccine. In this study, the main protease (Mpro) required for SARS-CoV-2 viral replication was expressed and purified. Thirty-six compounds were tested as inhibitors of SARS-CoV-2 Mpro by fluorescence resonance energy transfer (FRET) technique. The half-maximal inhibitory concentration (IC50) values of Ebselen and Ebsulfur analogs were obtained to be in the range of 0.074-0.91 µM. Notably, the molecules containing furane substituent displayed higher inhibition against Mpro, followed by Ebselen 1i (IC50 = 0.074 µM) and Ebsulfur 2k (IC50 = 0.11 µM). The action mechanism of 1i and 2k were characterized by enzyme kinetics, pre-incubation and jump dilution assays, as well as fluorescent labeling experiments, which suggested that both compounds covalently and irreversibly bind to Mpro, while molecular docking suggested that 2k formed an SS bond with the Cys145 at the enzymatic active site. This study provides two very potent scaffolds Ebsulfur and Ebselen for the development of covalent inhibitors of Mpro to combat COVID-19.