Discovery of a Highly Potent and Selective Inhibitor Targeting Protein Lysine Methyltransferase NSD2.

The histone lysine methyltransferase NSD2 has been recognized as an attractive target for cancer treatment, due to the functional implication of its dysregulation in the initiation and progression of many cancers. Although considerable efforts have been made to develop NSD2 small-molecule inhibitors, highly potent and selective ones are still rarely available till now. Here, we report the discovery of a series of novel NSD2 inhibitors via an extensive SAR exploration of the privileged quinazoline scaffold within compound 8. The most promising compound 42 showed excellent NSD2 enzymatic inhibitory activity and good antiproliferative activity in cells. In addition, it demonstrated favorable pharmacokinetic properties and significantly inhibited the tumor growth in a RS411 tumor xenograft model with good safety. Taken together, compound 42 could be a promising NSD2 inhibitor and deserves further investigation.

A seven-month-old baby presenting excessive crying for pulmonary sequestration with torsion: A case report and literature review.

Pulmonary sequestration with torsion is a rare condition. We describe a seven-month-old baby presenting excessive crying for pulmonary sequestration with torsion. Contrast-enhanced chest computed tomography demonstrated an oval-shaped mass in the posteromedial right lower chest, no systemic arterial supply was evident. The edge of the mass showed slight linear reinforcement, and its interior had no reinforcement. Thoracoscopic segmentectomy was carried out and histology confirmed pulmonary sequestration with torsion.

Identification and analysis of inflammation-related biomarkers in tetralogy of Fallot.

Background: Studies have revealed that inflammatory response is relevant to the tetralogy of Fallot (TOF). However, there are no studies to systematically explore the role of the inflammation-related genes (IRGs) in TOF. Therefore, based on bioinformatics, we explored the biomarkers related to inflammation in TOF, laying a theoretical foundation for its in-depth study. Methods: TOF-related datasets (GSE36761 and GSE35776) were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between TOF and control groups were identified in GSE36761. And DEGs between TOF and control groups were intersected with IRGs to obtain differentially expressed IRGs (DE-IRGs). Afterwards, the least absolute shrinkage and selection operator (LASSO) and random forest (RF) were utilized to identify the biomarkers. Next, immune analysis was carried out. The transcription factor (TF)-mRNA, lncRNA-miRNA-mRNA, and miRNA-single nucleotide polymorphism (SNP)-mRNA networks were created. Finally, the potential drugs targeting the biomarkers were predicted. Results: There were 971 DEGs between TOF and control groups, and 29 DE-IRGs were gained through the intersection between DEGs and IRGs. Next, a total of five biomarkers (MARCO, CXCL6, F3, SLC7A2, and SLC7A1) were acquired via two machine learning algorithms. Infiltrating abundance of 18 immune cells was significantly different between TOF and control groups, such as activated B cells, neutrophil, CD56dim natural killer cells, etc. The TF-mRNA network contained 4 mRNAs, 31 TFs, and 33 edges, for instance, ELF1-CXCL6, CBX8-SLC7A2, ZNF423-SLC7A1, ZNF71-F3. The lncRNA-miRNA-mRNA network was created, containing 4 mRNAs, 4 miRNAs, and 228 lncRNAs. Afterwards, nine SNPs locations were identified in the miRNA-SNP-mRNA network. A total of 21 drugs were predicted, such as ornithine, lysine, arginine, etc. Conclusions: Our findings detected five inflammation-related biomarkers (MARCO, CXCL6, F3, SLC7A2, and SLC7A1) for TOF, providing a scientific reference for further studies of TOF.

Discovery of a Highly Potent Lysine Methyltransferases G9a/NSD2 Dual Inhibitor to Treat Solid Tumors.

Both G9a and NSD2 have been recognized as promising therapeutic targets for cancer treatment. However, G9a inhibitors only showed moderate inhibitory activity against solid tumors and NSD2 inhibitors were limited to the treatment of hematological malignancies. Inspired by the advantages of dual-target inhibitors that show great potential in enhancing efficiency, we developed a series of highly potent G9a/NSD2 dual inhibitors to treat solid tumors. The candidate 16 demonstrated much enhanced antiproliferative activity compared to the selective G9a inhibitor 3 and NSD2 inhibitor 15. In addition, it exhibited superior potency in inhibiting colony formation, inducing cell apoptosis, and blocking cancer cell metastasis. Furthermore, it effectively inhibited the catalytic functions of both G9a and NSD2 in cells and exhibited significant antitumor efficacy in the PANC-1 xenograft model with good safety. Therefore, compound 16 as a highly potent G9a/NSD2 dual inhibitor presents an attractive anticancer drug candidate for the treatment of solid tumors.

Real-time stealth optical transmission via fast laser frequency dithering.

We report a real-time 150 kbps stealth transmission within public optical communication of 10 Gbps dual polarization QPSK. The stealth data is modulated onto the frequency tuning signals of a fast-tuning laser source in the transmitter, which causes slight frequency dithering for the transmitted optical signal. In the receiver, the stealth receiver recovers the stealth data from the estimated frequency offset by the QPSK DSP algorithm. The experiments show the stealth transmission has few impacts on the public channel over a 300 km distance. The proposed method is fully compatible with existing optical transmission systems, and the only hardware change is to upgrade the transmitter laser to support frequency tuning through an external analog port for receiving stealth signal. The proposed stealth scheme can combine with cryptographic protocols to improve the integrated security of the system, and can be used as signaling transport for low level network control to reduce the communication overhead.

Discovery of the First-in-Class RORγ Covalent Inhibitors for Treatment of Castration-Resistant Prostate Cancer.

Nuclear receptor receptor-related orphan receptor γ (RORγ) is a ligand-dependent transcription factor and has been established as a key player in castration-resistant prostate cancers (CRPC) by driving androgen receptor (AR) overexpression, representing a potential therapeutical target for advanced prostate cancers. Here, we report the identification of the first-in-class RORγ covalent inhibitor 29 via the structure-based drug design approach following structure-activity relationship (SAR) exploration. Mass spectrometry assay validated its covalent inhibition mechanism. Compound 29 significantly inhibited RORγ transcriptional activity and remarkably suppressed the expression levels of AR and AR-targeted genes. Compound 29 also exhibited much superior activity in inhibiting the proliferation and colony formation and inducing apoptosis of the CRPC cell lines relative to the positive control 2 and noncovalent control 33. Importantly, it markedly suppressed the tumor growth in a 22Rv1 mouse tumor xenograft model with good safety. These results clearly demonstrate that 29 is a highly potent and selective RORγ covalent inhibitor.

Discovery of novel indazole derivatives as SOS1 agonists that activate KRAS signaling.

KRAS serves as a vital regulator for cellular signaling and drives tumor pathogenesis after mutation. Despite extensive research efforts spanning several decades, targeting KRAS is still challenging due to the multiple KRAS mutations and the emergence of drug resistance. Interfering the interactions between KRAS and SOS1 is one of the promising approaches for modulating KRAS functions. Herein, we discovered small-molecule SOS1 agonists with novel indazole scaffold. Through structure-based optimization, compound 11 was identified with high SOS1 activation potency (p-ERK EC50 = 1.53 µM). In HeLa cells, compound 11 enhances cellular RAS-GTP levels and exhibits biphasic modulation of ERK1/2 phosphorylation through an on-target mechanism and presents the therapeutic potential to modulate RAS signaling by activating SOS1.

Enhancement of the phase sensitivity with two-mode squeezed coherent state based on a Mach-Zehnder interferometer.

We theoretically study the phase estimation based on a Mach-Zehnder interferometer (MZI) with a two-mode squeezed coherent state. By maximizing the quantum Fisher information, we find that the quantum Cramér-Rao bounds (QCRB) can reach sub-Heisenberg limit under the phase-matched condition. The optimal phase sensitivity can reach the sub-shot noise limit (SNL) and approach the QCRB by employing the intensity difference detection. Meanwhile, compared with the MZI fed with a coherent plus a single-mode squeezed vacuum state, this scheme can have better performance by adjusting the squeezing parameter and the mean photon number. With the same parameter, our scheme shows more sensitive phase measurement than the SU(1,1) interferometer with a coherent plus a vacuum state. We also show that the phase sensitivity of our proposal can still reach the SNL when the loss of the photon is 36%. This scheme can provide potential applications in optical sensors.

A Retrospective Analysis of the Therapeutic Outcomes of 117 Neuroblastoma Patients Treated at a Single Pediatric Oncology Center in China.

OBJECTIVE: Recent therapeutic advances have greatly enhanced the survival rates of patients with neuroblastoma (NB). However, the outcomes of neuroblastoma patients in China, particularly those with high-risk (HR) NB, remain limited. METHOD: We retrospectively analyzed the clinical data and outcomes of NB patients who were treated at a tertiary pediatric cancer facility in China between January 2013 and October 2021. RESULTS: A total of 117 NB patients were recruited. Patients with very low-risk (VLR), low-risk (LR), intermediate-risk (IR), and HR-NB patients made up 4%, 27%, 15%, and 54% of total patient population, respectively. Patients diagnosed between 2013 and 2018 were treated according to the protocol of Sun Yat-Sen University Cancer Center and those diagnosed between 2019 and 2021 were treated according to the COG ANBL0531 or ANBL0532 protocol with or without autologous stem cell transplantation (ASCT). The 5-year EFS and OS of all risk groups of patients were 67.29% and 77.90%, respectively. EFS and OS were significantly decreased in patients with higher risk classifications (EFS: VLR/LR vs IR vs HR: 97.22% vs 67.28% vs 51.83%; ***P = .001; OS: VLR/LR vs IR vs HR: 97.06% vs 94.12% vs 64.38%; *P = .046). In HR-NB patients treated according to the COG protocol between 2019 and 2021, the 3-year OS of patients who received tandem ASCT was significantly greater than those who did not receive ASCT (93.33% % vs 47.41%; *P = .046; log-rank test). EFS was not significantly different between patients with and without ASCT (72.16% vs 60.32%). CONCLUSION: Our findings show that patients with lower risk classification have a positive prognosis for survival. The prognosis of patients with HR-NB remains in need of improvement. ASCT may enhance OS in HR-NB patients; however, protocol adjustment may be necessary to increase EFS in these patients.

Structure-Based Design and Characterization of the Highly Potent and Selective Covalent Inhibitors Targeting the Lysine Methyltransferases G9a/GLP.

Protein lysine methyltransferases G9a and GLP, which catalyze mono- and di-methylation of histone H3K9 and nonhistone proteins, play important roles in diverse cellular processes. Overexpression or dysregulation of G9a and GLP has been identified in various types of cancer. Here, we report the discovery of a highly potent and selective covalent inhibitor 27 of G9a/GLP via the structure-based drug design approach following structure-activity relationship exploration and cellular potency optimization. Mass spectrometry assays and washout experiments confirmed its covalent inhibition mechanism. Compound 27 displayed improved potency in inhibiting the proliferation and colony formation of PANC-1 and MDA-MB-231 cell lines and exhibited enhanced potency in reducing the levels of H3K9me2 in cells compared to noncovalent inhibitor 26. In vivo, 27 showed significant antitumor efficacy in the PANC-1 xenograft model with good safety. These results clearly indicate that 27 is a highly potent and selective covalent inhibitor of G9a/GLP.

Targeting Arginine Methyltransferase PRMT5 for Cancer Therapy: Updated Progress and Novel Strategies.

As a predominant type II protein arginine methyltransferase, PRMT5 plays critical roles in various normal cellular processes by catalyzing the mono- and symmetrical dimethylation of a wide range of histone and nonhistone substrates. Clinical studies have revealed that high expression of PRMT5 is observed in different solid tumors and hematological malignancies and is closely associated with cancer initiation and progression. Accordingly, PRMT5 is becoming a promising anticancer target and has received great attention in both the pharmaceutical industry and the academic community. In this Perspective, we comprehensively summarize recent advances in the development of first-generation PRMT5 enzymatic inhibitors and highlight novel strategies targeting PRMT5 in the past 5 years. We also discuss the challenges and opportunities of PRMT5 inhibition, with the aim of shedding light on future PRMT5 drug discovery.

Real-time stealth optical transmission via dither-remodulation in a bias controller of a Mach-Zehnder modulator.

The physical layer transmission security is a promising technology against security threats. As an effective supplement to the encryption strategy, steganography has received widespread attention. We report a real-time 2 kbps stealth transmission in the 10 Gbps dual polarization QPSK public optical communication. The stealth data is embedded in dither signals via precise and stable bias control technique for a Mach-Zehnder modulator. In the receiver, the stealth data can be recovered from the normal transmission signals by low SNR signal processing and digital down conversion. The stealth transmission has been verified to pose almost no impact on the public channel over a 117 km distance. The proposed scheme is compatible with existing optical transmission systems, so that no new hardware needs to be employed. It can be accomplished and is exceeded economically by adding simple algorithms, which utilizes only a small amount of FPGA resources. The proposed method can cooperate with encryption strategies or cryptographic protocols at different network layers to reduce the communication overhead and improve the overall security of the system.

Coagulation after paediatric miniaturised versus conventional cardiopulmonary bypass: Retrospective cohort study.

BACKGROUND: Cardiopulmonary bypass (CPB) causes coagulation disorders after surgery. This study aimed to compare the coagulation parameters after congenital cardiac surgery with miniaturised CPB (MCPB) versus conventional CPB (CCPB). METHODS: We gathered information about children who underwent cardiac surgery between 1/1/2016 and 12/31/2019. Using propensity score-matched data, we compared the coagulation parameters and postoperative outcomes of the MCPB and CCPB groups. RESULTS: A total of 496 patients (327 with MCPB, 169 withCCPB) underwent congenital cardiac surgery, and 160 matched pairs in each group were enrolled in the analysis. Compared with CCPB children, MCPB children had a lowermean prothrombin time (14.9 ± 2.0 vs 16.4 ± 4.1; p < 0.001)and international normalised ratio (1.3 ± 0.2 vs. 1.4 ± 0.3; p < 0.001), but higher thrombin time (23.4 ± 20.4 vs 18.2 ± 4.4; p = 0.002). The CCPB group had greaterperioperative changes inprothrombin time, international normalised ratio, fibrinogen, and antithrombin III activity (all p < 0.01) but lower perioperative changesin thrombin time (p = 0.001) thanthe MCPB group. Ultra-fasttrack extubation and blood transfusionrates, postoperative blood loss, and intensive care unitlength of stay were considerably decreased in the MCPB group. There were no considerable intergroup differences in the activated partial thromboplastin time or platelet count. CONCLUSIONS: Compared with CCPB, MCPB was associated with lower coagulation changes and better early outcomes, including shorter intensive care unit stay and less postoperative blood loss.

A histidine-rich fusion tag enables real-time monitoring of recombinant protein expression by Pauly reaction-based colorimetric assay.

Commercially available recombinant expression systems always use fusion tags to facilitate target protein purification and SDS-PAGE analysis followed by Coomassie Brilliant Blue (CBB) staining is the classical method to validate the expression level of target protein, which is time-consuming, although not very laborious. Previously, we found that a histidine-rich elastin-like polypeptide (HRELP) tag could make its fusion proteins being quickly and specifically stained with Pauly's reagent. In this study, we designed a Pauly reaction-based colorimetric assay to real-time monitoring of the expression level of recombinant protein tagged HRELP and found that the absorption value of post-induction E. coli cells stained with Pauly's reagent correlated well with both the band intensity of the target protein from Pauly's reagent-stained and CBB-stained gels. Moreover, we found the colorimetric assay could also be helpful to roughly estimate the expression efficiency by using a poly-histidine-tagged protein, which has only 1.17% histidine residue. In our opinion, Pauly reaction-based colorimetric assay could significantly shorten the time to validate the over-expression of recombinant protein tagged with either HRELP or poly-histidine. And HRELP seemed to be an ideal fusion tag for it can not only facilitate protein purification but also simplify protein detection.

Reprogramming of TAMs via the STAT3/CD47-SIRPα axis promotes acquired resistance to EGFR-TKIs in lung cancer.

Cross-talk between the tumor microenvironment (TME) and cancer cells plays an important role in acquired drug resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). The role of tumor-associated macrophages (TAMs), the major component of the TME, in acquired resistance remains unclear. In this study, M2-like reprogramming of TAMs and reduced phagocytosis by macrophages were observed in gefitinib-resistant lung cancer cells and tumor xenografts. CD47 was upregulated in TKI-resistant lung cancer cells, and M2 macrophage polarization and cancer cell escape from macrophage phagocytosis were enhanced. Culture medium from TKI-resistant cells led to metabolic reprogramming of TAMs. STAT3 was associated with CD47 expression in TKI-resistant lung cancer cells. Genetic and pharmacological inhibition of STAT3 enhanced the phagocytic activity of TAMs and alleviated the acquired resistance to EGFR-TKIs via inhibiting the CD47-SIRPα signaling axis and M2 polarization in the co-culture system. Moreover, STAT3 transcriptionally regulated CD47 expression by binding to consensus DNA response elements in the intron of the CD47 gene. Furthermore, the combination of gefitinib with a STAT3 inhibitor and an anti-CD47 monoclonal antibody alleviated the acquired resistance to gefitinib in vitro and in vivo. Collectively, our study reveals the role of TAM reprogramming and the CD47-SIRPα axis in acquired EGFR-TKI resistance and provides a novel therapeutic strategy to overcome the acquired resistance to EGFR-TKIs in lung cancer.

Discovery of a New-Generation S-Adenosylmethionine-Noncompetitive Covalent Inhibitor Targeting the Lysine Methyltransferase Enhancer of Zeste Homologue 2.

The first-generation enhancer of zeste homologue 2 (EZH2) inhibitors suffer from several limitations, such as high dosage, cofactor S-adenosylmethionine (SAM) competition, and acquired drug resistance. Development of covalent EZH2 inhibitors that are noncompetitive with cofactor SAM offers an opportunity to overcome these disadvantages. The structure-based design of compound 16 (BBDDL2059) as a highly potent and selective covalent inhibitor of EZH2 is presented in this context. 16 inhibits EZH2 enzymatic activity at sub-nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition. The kinetic assay revealed that 16 is noncompetitive with the cofactor SAM, providing the basis for its superior activity over noncovalent and positive controls by reducing competition with cofactor SAM and offering a preliminary proof for its covalent inhibition nature. Mass spectrometric analysis and washout experiments firmly establish its covalent inhibition mechanism. This study demonstrates that covalent inhibition of EZH2 can offer a new opportunity for the development of promising new-generation drug candidates.

Successful Treatment of Rare Pulmonary Coprinopsis cinerea Infection in a 17-Year-Old Female After Hematopoietic Stem Cell Transplantation: A Case Report.

Invasive fungal infections (IFIs) are among the most severe complications in recipients of hematopoietic stem cell transplantation (HSCT) recipients and in patients with hematological malignancies. An increasing number of uncommon fungal infections have been reported in this era of antifungal prophylaxis. Coprinopsis cinerea is a rare pathogen that causes opportunistic infections in the immunocompromised patients, including HSCT recipients and is associated with very high mortality rates. Herein, we present a successfully treated pediatric HSCT patient with breakthrough pulmonary IFI caused by Coprinopsis cinerea despite posaconazole, prophylaxis using multidisciplinary approaches.

Targeting STAT3-VISTA axis to suppress tumor aggression and burden in acute myeloid leukemia.

The acute myeloid leukemia (AML) patients obtain limited benefits from current immune checkpoint blockades (ICBs), although immunotherapy have achieved encouraging success in numerous cancers. Here, we found that V-domain Ig suppressor of T cell activation (VISTA), a novel immune checkpoint, is highly expressed in primary AML cells and associated with poor prognosis of AML patients. Targeting VISTA by anti-VISTA mAb boosts T cell-mediated cytotoxicity to AML cells. Interestingly, high expression of VISTA is positively associated with hyperactive STAT3 in AML. Further evidence showed that STAT3 functions as a transcriptional regulator to modulate VISTA expression by directly binding to DNA response element of VISTA gene. We further develop a potent and selective STAT3 inhibitor W1046, which significantly suppresses AML proliferation and survival. W1046 remarkably enhances the efficacy of VISTA mAb by activating T cells via inhibition of STAT3 signaling and down-regulation of VISTA. Moreover, combination of W1046 and VISTA mAb achieves a significant anti-AML effect in vitro and in vivo. Overall, our findings confirm that VISTA is a potential target for AML therapy which transcriptionally regulated by STAT3 and provide a promising therapeutic strategy for immunotherapy of AML.

Type II congenital pulmonary airway malformation with primary ciliary dyskinesia in a 4-year-old child: A case report.

A congenital pulmonary airway malformation (CPAM) combined with primary ciliary dyskinesia (PCD) has not been described in literature. Herein, we described the case of a 4-year-old boy who presented to us with recurrent productive cough and rhinorrhea for 2 years. High resolution computed tomography of the thorax revealed multiple, cystic, transparent shadows of different sizes near the posterior thoracic cavity in the lower lobe of the left lung. Thoracoscopic segmentectomy was carried out and histology confirmed a type II CPAM. Whole-exome sequencing revealed a compound heterozygous mutation (c.10568+1G>A, c.9484delG) in the DNAH11 gene associated with PCD that originated from the boy's mother and father, respectively. This report showed that when a child with CPAM presents with a productive cough and recurrent sinusitis, irrespective of situs inversus, PCD should be suspected. Genetic testing can aid in diagnosis.

Structural optimization of Imidazo[1, 2-a]pyridine derivatives for the treatment of gastric cancer via STAT3 signaling pathway.

STAT3 is a promising therapeutic target for the treatment of gastric cancer, which is one of the most common solid tumors worldwide. In the previous works, we discovered a series of novel STAT3 inhibitors bearing an imidazo[1,2-a] pyridine scaffold. In order to improve the metabolic stability of these compounds, herein we performed a systematic structural optimization leading to a bioactive inhibitor 42, which demonstrated significant effects on inhibiting the growth, migration and invasion of human gastric cancer cells lines (AGS and MGC-803). Meanwhile, it was able to block the phosphorylation and dimerization of STAT3 at low micromolar concentration. Furthermore, compound 42 obviously suppressed tumor growth in MGC-803 derived xenograft mouse model, suggesting that it deserves further exploration as a promising anti-cancer agent for advanced gastric cancer.