Antibacterial Activities and Underlying Mechanisms of the Compound SYAUP-491 against Xanthomonas oryzae pv. oryzae.

SYAUP-491 is a novel alkyl sulfonamide. In this study, in vivo and in vitro tests were performed along with a proteomic analysis to determine the effects and underlying mechanisms of the antibacterial activity of SYAUP-491 against the causative agent of bacterial leaf blight in rice. The antibacterial test results suggested that SYAUP-491 exhibited significant activities against Xanthomonas oryzae pv. oryzae (Xoo) in vitro and in vivo. The minimal EC50 values reached 6.96 µg/mL and the curative activity reached 74.1%. Detailed studies demonstrated that SYAUP-491 altered membrane permeability and caused morphological changes. Based on proteomics results, SYAUP-491 might inhibit bacterial protein synthesis. SYAUP-491 may disrupt and alter cell membrane permeability and could further act on ribosomes in the bacterial body. Given the above results, SYAUP-491 could serve as a new lead compound in the research of antibacterial control of plant pathogenic bacterial disease.

Risk assessment of pneumothorax in colorectal lung metastases treated by percutaneous thermal ablation: a multicenter retrospective cohort study.

PURPOSE: To evaluate the risk of pneumothorax in the percutaneous image-guided thermal ablation (IGTA) treatment of colorectal lung metastases (CRLM). METHODS: Data regarding patients with CRLM treated with IGTA from five medical institutions in China from 2016 to 2023 were reviewed retrospectively. Pneumothorax and non-pneumothorax were compared using the Student's t -test, χ 2 test and Fisher's exact test. Univariate logistic regression analysis was conducted to identify potential risk factors, followed by multivariate logistic regression analysis to evaluate the predictors of pneumothorax. Interactions between variables were examined and used for model construction. Receiver operating characteristic curves and nomograms were generated to assess the performance of the model. RESULTS: A total of 254 patients with 376 CRLM underwent 299 ablation sessions. The incidence of pneumothorax was 45.5%. The adjusted multivariate logistic regression model, incorporating interaction terms, revealed that tumour number [odds ratio (OR)=8.34 (95% CI: 1.37-50.64)], puncture depth [OR=0.53 (95% CI: 0.31-0.91)], pre-procedure radiotherapy [OR=3.66 (95% CI: 1.17-11.40)], peribronchial tumour [OR=2.32 (95% CI: 1.04-5.15)], and emphysema [OR=56.83 (95% CI: 8.42-383.57)] were significant predictive factors of pneumothorax (all P <0.05). The generated nomogram model demonstrated a significant prediction performance, with an area under the receiver operating characteristic curve of 0.800 (95% CI: 0.751-0.850). CONCLUSIONS: Pre-procedure radiotherapy, tumour number, peribronchial tumour, and emphysema were identified as risk factors for pneumothorax in the treatment of CRLM using percutaneous IGTA. Puncture depth was found to be a protective factor against pneumothorax.

A dose-escalation study of HP501, a highly selective URAT1 inhibitor, in male Chinese patients with hyperuricemia.

HP501 is a highly selective renal urate transporter 1 (URAT1) inhibitor used for treating hyperuricemia. This study aimed to evaluate the tolerability, pharmacokinetics, and pharmacodynamics of HP501 in male Chinese patients. Patients with hyperuricemia were sequentially assigned to receive oral doses of HP501 (30, 50, 60, 90, and 120 mg) as a single dose on Day 1 and as once-daily doses from Days 4 to 13. Safety, pharmacokinetic, and pharmacodynamic data were collected. Multiple oral doses of HP501 were well-tolerated in all the cohorts. The most common adverse events (≥ 10% of patients) of any grade regardless of drug relationship were gout flare (14 patients, 25.93%), diarrhea (12 patients, 22.22%), elevated ALT (8 patients, 14.81%), hypertriglyceridemia (7 patients, 12.96%), dry mouth (7 patients, 12.96%) and oral ulcer (7 patients, 12.96%). All adverse events were mild or moderate. The Cmax and exposure (AUC) of HP501 was approximately dose-proportional between 30 and 120 mg. A dose-dependent serum uric acid (UA)-lowering effect was observed in the dose range of 30 to 60 mg and the serum UA lowering effect was similar between 90 and 120 mg on day 13, indicating that the maximal serum UA lowering effect of HP501 was achieved at 90 mg in the patients with hyperuricemia. In conclusion, the tolerability, pharmacokinetics, and pharmacodynamics supported 90 mg HP501 for subsequent clinical studies of this highly selective URAT1 inhibitor.Clinical Trial registration: No. CTR20212259 ( http://www.chinadrugtrials.org.cn/ ) was registered in September 2021, and No. CTR20222257 was registered in September 2022.

Multiparametric MRI-based model for prediction of local progression of hepatocellular carcinoma after thermal ablation.

PURPOSE: To develop a deep learning radiomics of multiparametric magnetic resonance imaging (DLRMM)-based model that incorporates preoperative and postoperative signatures for prediction of local tumor progression (LTP) after thermal ablation (TA) in hepatocellular carcinoma (HCC). METHODS: From May 2017 to October 2021, 417 eligible patients with HCC were retrospectively enrolled from three hospitals (one primary cohort [PC, n = 189] and two external test cohorts [ETCs][n = 135, 93]). DLRMM features were extracted from T1WI + C, T2WI, and DWI using ResNet18 model. An integrative model incorporating the DLRMM signature with clinicopathologic variables were further built to LTP risk stratification. The performance of these models were compared by areas under receiver operating characteristic curve (AUC) using DeLong test. RESULTS: A total of 1668 subsequences and 31,536 multiparametric MRI slice including T1WI, T2WI, and DWI were collected simultaneously. The DLRMM signatures were extracted from tumor and ablation zone, respectively. Ablative margin, multiple tumors, and tumor abutting major vessels were regarded as risk factors for LTP in clinical model. The AUC of DLRMM model were 0.864 in PC, 0.843 in ETC1, and 0.858 in ETC2, which was higher significantly than those in clinical model (p < 0.001). After integrating clinical variable, DLRMM model obtained significant improvement with AUC of 0.870-0.869 in three cohorts (all, p < 0.001), which can provide the risk stratification for overall survival of HCC patients. CONCLUSIONS: The DLRMM model is essential to identify LTP risk of HCC patients who underwent TA and may potentially benefit personalized decision-making.

Domain Adaptation Based on Semi-Supervised Cross-Domain Mean Discriminative Analysis and Kernel Transfer Extreme Learning Machine.

Good data feature representation and high precision classifiers are the key steps for pattern recognition. However, when the data distributions between testing samples and training samples do not match, the traditional feature extraction methods and classification models usually degrade. In this paper, we propose a domain adaptation approach to handle this problem. In our method, we first introduce cross-domain mean approximation (CDMA) into semi-supervised discriminative analysis (SDA) and design semi-supervised cross-domain mean discriminative analysis (SCDMDA) to extract shared features across domains. Secondly, a kernel extreme learning machine (KELM) is applied as a subsequent classifier for the classification task. Moreover, we design a cross-domain mean constraint term on the source domain into KELM and construct a kernel transfer extreme learning machine (KTELM) to further promote knowledge transfer. Finally, the experimental results from four real-world cross-domain visual datasets prove that the proposed method is more competitive than many other state-of-the-art methods.

Meta-analysis of liver injury in patients with COVID-19.

BACKGROUND: The coronavirus disease 2019 (COVID-19) is a major public health problem threatening human health. It can lead to multiple system complications, among which liver damage is also a common complication of COVID-19. The pathogenesis of liver injury is complex and involves the interaction of multiple factors. This study aims to investigate the incidence and risk factors of liver injury in COVID-19 patients and analyze the impact of liver injury on clinical prognosis of patients, so as to provide corresponding basis for clinical diagnosis and treatment. METHODS: PubMed and Cochrane Library were searched in computer to collect original studies on liver injury cases, laboratory indicators and clinical outcomes in COVID-19 patients. Articles were screened according to inclusion and exclusion criteria, and data were meta-analyzed using Stata12.0 software. RESULTS: A total of 49 studies, including 23,611 patients with COVID-19, had a prevalence of liver injury of 39.63%. Subgroup analysis found that patients in the Americas had the highest incidence of liver injury at 43.7% and lowest in Africa (25.99%). The vast majority of liver injury is manifested by aminotransferase or bilirubin levels greater than 1 times the upper limit of normal (49.16%). The older the age, the male, the associated chronic liver disease, and the higher the levels of white blood cells, neutrophils, and C-reactive protein, the higher the risk of liver injury. The use of hormones, hydroxychloroquine, and tocilizumab increases the risk of liver injury. Patients with concurrent liver injury have longer hospital stays, are more likely to progress to severe cases, and have a higher risk of death than patients without liver injury. CONCLUSION: The incidence of liver injury in COVID-19 patients was high, affected by age, gender, chronic liver disease, inflammatory state and medication, and patients with liver injury were hospitalized longer and were more likely to have a poor prognosis. Therefore, clinical attention should be paid to early intervention.

Immature human engineered heart tissues engraft in a guinea pig chronic injury model.

Engineered heart tissue (EHT) transplantation represents an innovative, regenerative approach for heart failure patients. Late preclinical trials are underway, and a first clinical trial started recently. Preceding studies revealed functional recovery after implantation of in vitro-matured EHT in the subacute stage, whereas transplantation in a chronic injury setting was less efficient. When transplanting matured EHTs, we noticed that cardiomyocytes undergo a dedifferentiation step before eventually forming structured grafts. Therefore, we wanted to evaluate whether immature EHT (EHTIm) patches can be used for transplantation. Chronic myocardial injury was induced in a guinea pig model. EHTIm (15×106 cells) were transplanted within hours after casting. Cryo-injury led to large transmural scars amounting to 26% of the left ventricle. Grafts remuscularized 9% of the scar area on average. Echocardiographic analysis showed some evidence of improvement of left-ventricular function after EHTIm transplantation. In a small translational proof-of-concept study, human scale EHTIm patches (4.5×108 cells) were epicardially implanted on healthy pig hearts (n=2). In summary, we provide evidence that transplantation of EHTIm patches, i.e. without precultivation, is feasible, with similar engraftment results to those obtained using matured EHT.

A Phase I Study to Evaluate the Pharmacokinetic Drug‒Drug Interaction of HP501, Febuxostat, and Colchicine in Male Chinese Patients with Hyperuricemia.

BACKGROUND AND OBJECTIVE: HP501 is a highly selective renal urate transporter 1 (URAT1) inhibitor that is being developed for the treatment of hyperuricemia and gout. The primary aim of the present study was to study the pharmacokinetic drug‒drug interactions (DDIs) of HP501, febuxostat, and colchicine in hyperuricemic patients. METHODS: Hyperuricemic patients were randomly divided into group A, receiving HP501 40 mg once daily on days 1 and 4-10, and group B, receiving febuxostat 40 mg once daily on day 1 and HP501 40 mg plus febuxostat 40 mg on days 4-10. All patients received 0.5 mg colchicine once daily from day 4 to 12. Blood samples were collected for measurement of drug concentrations and serum uric acid (sUA) levels. RESULTS: Coadministration of colchicine with HP501 or HP501 plus febuxostat did not affect steady-state exposure to colchicine. Coadministration of HP501 and febuxostat did not significantly change the pharmacokinetic profiles of either drug. Following multiple administrations of HP501 40 mg once daily for 7 days, the maximal percent sUA change from baseline in group A was - 24.77%. The coadministration of HP501 40 mg and febuxostat 40 mg in group B for 7 days resulted in a - 55.82% maximal sUA reduction from baseline, and all patients achieved the goal of sUA < 360 µmol/L. All adverse events (AEs) were either mild or moderate, and the most frequently reported AEs were diarrhea and elevated alanine aminotransferase (ALT) levels. CONCLUSIONS: The concomitant use of HP501, febuxostat, and colchicine did not produce clinically meaningful DDIs in terms of their pharmacokinetic properties. CLINICAL TRIAL REGISTRATION: No. CTR20212261 ( http://www.chinadrugtrials.org.cn/ ) registered September 2021.

Evaluation of efficacy and mechanism of Bacillus velezensis CB13 for controlling peanut stem rot caused by Sclerotium rolfsii.

Peanut stem rot, caused by Sclerotium rolfsii, considerably affects crop productivity. Application of chemical fungicides harms the environment and induces drug resistance. Biological agents are valid and eco-friendly alternatives to chemical fungicides. Bacillus spp. are important biocontrol agents that are now widely used against several plant diseases. This study aimed to evaluate the efficacy and mechanism of a potential biocontrol agent Bacillus sp. for controlling peanut stem rot caused by S. rolfsii. Here, we isolated a strain of Bacillus from pig biogas slurry that considerably inhibits the radial growth of S. rolfsii. The strain CB13 was identified as Bacillus velezensis on the basis of morphological, physiological, biochemical characteristics and phylogenetic trees based on the 16S rDNA and gyrA, gyrB, and rpoB gene sequences. The biocontrol efficacy of CB13 was evaluated on the basis of colonization ability, induction of defense enzyme activity, and soil microbial diversity. The control efficiencies of B. velezensis CB13-impregnated seeds in four pot experiments were 65.44, 73.33, 85.13, and 94.92%. Root colonization was confirmed through green fluorescent protein (GFP)-tagging experiments. The CB13-GFP strain was detected in peanut root and rhizosphere soil, at 104 and 108 CFU/g, respectively, after 50 days. Furthermore, B. velezensis CB13 enhanced the defense response against S. rolfsii infection by inducing defense enzyme activity. MiSeq sequencing revealed a shift in the rhizosphere bacterial and fungal communities in peanuts treated with B. velezensis CB13. Specifically, the treatment enhanced disease resistance by increasing the diversity of soil bacterial communities in peanut roots, increasing the abundance of beneficial communities, and promoting soil fertility. Additionally, real-time quantitative polymerase chain reaction results showed that B. velezensis CB13 stably colonized or increased the content of Bacillus spp. in the soil and effectively inhibited S. rolfsii proliferation in soil. These findings indicate that B. velezensis CB13 is a promising agent for the biocontrol of peanut stem rot.

An injectable PEG-like conjugate forms a subcutaneous depot and enables sustained delivery of a peptide drug.

Many biologics have a short plasma half-life, and their conjugation to polyethylene glycol (PEG) is commonly used to solve this problem. However, the improvement in the plasma half-life of PEGylated drugs' is at an asymptote because the development of branched PEG has only had a modest impact on pharmacokinetics and pharmacodynamics. Here, we developed an injectable PEG-like conjugate that forms a subcutaneous depot for the sustained delivery of biologics. The PEG-like conjugate consists of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) conjugated to exendin, a peptide drug used in the clinic to treat type 2 diabetes. The depot-forming exendin-POEGMA conjugate showed greater efficacy than a PEG conjugate of exendin as well as Bydureon, a clinically approved sustained-release formulation of exendin. The injectable depot-forming exendin-POEGMA conjugate did not elicit an immune response against the polymer, so that it remained effective and safe for long-term management of type 2 diabetes upon chronic administration. In contrast, the PEG conjugate induced an anti-PEG immune response, leading to early clearance and loss of efficacy upon repeat dosing. The exendin-POEGMA depot also showed superior long-term efficacy compared to Bydureon. Collectively, these results suggest that an injectable POEGMA conjugate of biologic drugs that forms a drug depot under the skin, providing favorable pharmacokinetic properties and sustained efficacy while remaining non-immunogenic, offers significant advantages over other commonly used drug delivery technologies.

Brachytherapy via a depot of biopolymer-bound 131I synergizes with nanoparticle paclitaxel in therapy-resistant pancreatic tumours.

Locally advanced pancreatic tumours are highly resistant to conventional radiochemotherapy. Here we show that such resistance can be surmounted by an injectable depot of thermally responsive elastin-like polypeptide (ELP) conjugated with iodine-131 radionuclides (131I-ELP) when combined with systemically delivered nanoparticle albumin-bound paclitaxel. This combination therapy induced complete tumour regressions in diverse subcutaneous and orthotopic mouse models of locoregional pancreatic tumours. 131I-ELP brachytherapy was effective independently of the paclitaxel formulation and dose, but external beam radiotherapy (EBRT) only achieved tumour-growth inhibition when co-administered with nanoparticle paclitaxel. Histological analyses revealed that 131I-ELP brachytherapy led to changes in the expression of intercellular collagen and junctional proteins within the tumour microenvironment. These changes, which differed from those of EBRT-treated tumours, correlated with the improved delivery and accumulation of paclitaxel nanoparticles within the tumour. Our findings support the further translational development of 131I-ELP depots for the synergistic treatment of localized pancreatic cancer.

Design, Synthesis and Structure-Activity Relationship of Novel Pinacolone Sulfonamide Derivatives against Botrytis cinerea as Potent Antifungal Agents.

To develop new fungicides with high efficiency, 46 novel sulfonamide derivatives were designed and synthesized by introducing pinacolone fragment into chesulfamide which was used as lead compound. All compounds were characterized by 1H NMR, 13C NMR, and MS spectra, and the structure of compound P-27 was also confirmed by X-ray single crystal diffraction. It was found that a variety of compounds present excellent inhibitory effect against Botrytis cinerea. The inhibition rates of P-29 on tomato and strawberry were 90.24% (200 mg/L) and 100% (400 mg/L) in vivo respectively, which were better than the lead compound chesulfamide (59.23% on tomato seedlings and 29.63% on strawberries).

Antiviral modes of action of the novel compound GLY-15 containing pyrimidine heterocycle and moroxydine skeleton against tobacco mosaic virus.

BACKGROUND: Plant virus diseases are difficult to prevent and control, causing serious economic losses to the agricultural production world. To develop new pesticides with antiviral activity, a serial of compounds containing the structure of pyrimidine and moroxydine were synthesized, among which GLY-15 exhibited good antiviral activity against tobacco mosaic virus (TMV), while the mechanism of antiviral activity remains to be clarified. RESULTS: GLY-15 treatment significantly inhibited the formation of necrotic spots caused by TMV in Nicotiana glutinosa, and effectively suppressed the systemic transportation of TMV expressing a reporter gene (p35S-30B:GFP) in N. benthamiana and markedly reduced the accumulation of a movement deficient TMV in plants as well as viral RNA accumulation in tobacco protoplasts. The results of RNA sequencing showed that GLY-15 induced significant differential expression of genes or pathways involved in the stress response, defense response and signal transduction, phytohormone response and metabolism. Among them, real-time quantitative PCR validated that the expression of 12 critical genes such as heat shock protein, receptor kinase, cell-wall-related protein, disease-related protein and glucan endo-1,3-ß-glucosidase were significantly up-regulated. In addition, GLY-15 triggered reactive oxygen species (ROS) production and induced the activity of several crucial defense related enzymes in plants. The results of molecular docking showed potential binding ability of GLY-15 with TMV helicase and the coat protein. CONCLUSION: This study provide valuable insights into antiviral mechanism of action for GLY-15, which is expected to be applied as a pesticide for the management of plant viruses. © 2022 Society of Chemical Industry.

HC-1119, a deuterated Enzalutamide, inhibits Migration, Invasion and Metastasis of the AR-positive triple-negative breast Cancer cells.

Triple-negative breast cancers (TNBCs) are aggressive, and they develop metastasis at earlier stages, relapse more frequently, and exhibits poorer prognosis than other subtypes of breast cancer. Due to the lack of estrogen receptor for endocrine therapy and HER2 for targeted therapy, new targeted therapies for TNBCs are urgently needed. Enzalutamide is a second-generation androgen receptor (AR) inhibitor, and HC-1119 is a new synthetic deuterated enzalutamide. Owing to the isotope effect, HC-1119 has many advantages over enzalutamide, including slow metabolism, high plasma concentration and low brain exposure. However, the efficacy of HC-1119 in inhibition of AR function in triple-negative breast cancer (TNBC) has not been studied. In this study, we found high-level AR expression in both Hs578T and SUM159PT TNBC cell lines. Activation of AR by dihydrotestosterone (DHT) in both cell lines increased AR protein, induced AR-nuclear localization, enhanced cell migration and invasion in culture, and promoted liver metastasis in mice. Importantly, cotreatment with HC-1119 of these cells efficiently abolished all of these effects of DHT on both Hs578T and SUM159PT cells. These results indicate that HC-1119 is a very effective new second-generation AR antagonist that can inhibit the migration, invasion and metastasis of the AR-positive TNBC cells.

TSTELM: Two-Stage Transfer Extreme Learning Machine for Unsupervised Domain Adaptation.

As a single-layer feedforward network (SLFN), extreme learning machine (ELM) has been successfully applied for classification and regression in machine learning due to its faster training speed and better generalization. However, it will perform poorly for domain adaptation in which the distributions between training data and testing data are inconsistent. In this article, we propose a novel ELM called two-stage transfer extreme learning machine (TSTELM) to solve this problem. At the statistical matching stage, we adopt maximum mean discrepancy (MMD) to narrow the distribution difference of the output layer between domains. In addition, at the subspace alignment stage, we align the source and target model parameters, design target cross-domain mean approximation, and add the output weight approximation to further promote the knowledge transferring across domains. Moreover, the prediction of test sample is jointly determined by the ELM parameters generated at the two stages. Finally, we investigate the proposed approach in classification task and conduct experiments on four public domain adaptation datasets. The result indicates that TSTELM could effectively enhance the knowledge transfer ability of ELM with higher accuracy than other existing transfer and non-transfer classifiers.

Colchicine Impacts Leukocyte Trafficking in Atherosclerosis and Reduces Vascular Inflammation.

Background: Inflammation strongly contributes to atherosclerosis initiation and progression. Consequently, recent clinical trials pharmacologically targeted vascular inflammation to decrease the incidence of atherosclerosis-related complications. Colchicine, a microtubule inhibitor with anti-inflammatory properties, reduced cardiovascular events in patients with recent acute coronary syndrome and chronic coronary disease. However, the biological basis of these observations remains elusive. We sought to explore the mechanism by which colchicine beneficially alters the course of atherosclerosis. Methods and Results: In mice with early atherosclerosis (Apoe-/- mice on a high cholesterol diet for 8 weeks), we found that colchicine treatment (0.25 mg/kg bodyweight once daily over four weeks) reduced numbers of neutrophils, inflammatory monocytes and macrophages inside atherosclerotic aortas using flow cytometry and immunohistochemistry. Consequently, colchicine treatment resulted in a less inflammatory plaque composition and reduced plaque size. We next investigated how colchicine prevented plaque leukocyte expansion and found that colchicine treatment mitigated recruitment of blood neutrophils and inflammatory monocytes to plaques as revealed by adoptive transfer experiments. Causally, we found that colchicine reduced levels of both leukocyte adhesion molecules and receptors for leukocyte chemoattractants on blood neutrophils and monocytes. Further experiments showed that colchicine treatment reduced vascular inflammation also in post-myocardial infarction accelerated atherosclerosis through similar mechanisms as documented in early atherosclerosis. When we examined whether colchicine also decreased numbers of macrophages inside atherosclerotic plaques by impacting monocyte/macrophage transitioning or in-situ proliferation of macrophages, we report that colchicine treatment did not influence macrophage precursor differentiation or macrophage proliferation using cell culture experiments with bone marrow derived macrophages. Conclusions: Our data reveal that colchicine prevents expansion of plaque inflammatory leukocytes through lowering recruitment of blood myeloid cells to plaques. These data provide novel mechanistic clues on the beneficial effects of colchicine in the treatment of atherosclerosis and may inform future anti-inflammatory interventions in patients at risk.

Genetically Engineered Nanoparticles of Asymmetric Triblock Polypeptide with a Platinum(IV) Cargo Outperforms a Platinum(II) Analog and Free Drug in a Murine Cancer Model.

The development of platinum(Pt)-drugs for cancer therapy has stalled, as no new Pt-drugs have been approved in over a decade. Packaging small molecule drugs into nanoparticles is a way to enhance their therapeutic efficacy. To date, there has been no direct comparison of relative merits of the choice of Pt oxidation state in the same nanoparticle system that would allow its optimal design. To address this lacuna, we designed a recombinant asymmetric triblock polypeptide (ATBP) that self-assembles into rod-shaped micelles and chelates Pt(II) or enables covalent conjugation of Pt(IV) with similar morphology and stability. Both ATBP-Pt(II) and ATBP-Pt(IV) nanoparticles enhanced the half-life of Pt by ∼45-fold, but ATBP-Pt(IV) had superior tumor regression efficacy compared to ATBP-Pt(II) and cisplatin. These results suggest loading Pt(IV) into genetically engineered nanoparticles may yield a new generation of more effective platinum-drug nanoformulations.

P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia.

Selinexor is a first-in-class inhibitor of the nuclear exportin XPO1 that was recently approved by the US Food and Drug Administration for the treatment of multiple myeloma and diffuse large B-cell lymphoma. In relapsed/refractory acute myeloid leukemia (AML), selinexor has shown promising activity, suggesting that selinexor-based combination therapies may have clinical potential. Here, motivated by the hypothesis that selinexor's nuclear sequestration of diverse substrates imposes pleiotropic fitness effects on AML cells, we systematically catalog the pro- and anti-fitness consequences of selinexor treatment. We discover that selinexor activates PI3Kγ-dependent AKT signaling in AML by upregulating the purinergic receptor P2RY2. Inhibiting this axis potentiates the anti-leukemic effects of selinexor in AML cell lines, patient-derived primary cultures and multiple mouse models of AML. In a syngeneic, MLL-AF9-driven mouse model of AML, treatment with selinexor and ipatasertib outperforms both standard-of-care chemotherapy and chemotherapy with selinexor. Together, these findings establish drug-induced P2RY2-AKT signaling as an actionable consequence of XPO1 inhibition in AML.

Safety, Efficacy, and Pharmacokinetics of HP501 in Healthy Volunteers and Hyperuricemic Patients: A Phase I/IIa Study.

CONTEXT: Uricosuric agents are the typical approach to the control of hyperuricemia; however, their use has been eclipsed by adverse reactions, and a safer uricosuric drug is badly needed. OBJECTIVE: HP501 is a novel renal urate transporter 1 inhibitor for the treatment of hyperuricemia. In this first-in-human study, we investigated the safety, efficacy, and pharmacokinetics of HP501 in healthy volunteers and hyperuricemic patients. METHODS: The placebo-controlled, double-blind, randomized, 3-part, phase I/IIa study consists of a single ascending dose (SAD) part with 32 participants, a multiple ascending dose part with 48 participants, and a drug-drug interaction part with 20 participants. Effects of food in healthy volunteers administered 45 mg HP501 in the fed state were also assessed in the SAD part. RESULTS: A total of 68 healthy volunteers and 32 hyperuricemic patients were enrolled. HP501 appeared to be safe and well tolerated in both groups. In hyperuricemic patients dosed with 45 mg HP501 over 10 days, 2/10 and 3/10 patients had elevated AST (< 2 times upper limit of normal [ULN]) and ALT (< 2.5 times ULN), respectively. No dose-limiting adverse events were observed. Across doses of HP501 from 5 to 60 mg, the concentrations of serum uric acid (sUA) are reduced by a maximum of about 50%. HP501 exhibited predictable pharmacokinetics across different dose levels in healthy volunteers or hyperuricemic patients. HP501 and febuxostat have obvious synergistic sUA-lowering effects with no apparent pharmacokinetics interaction. CONCLUSION: HP501 was effective at reducing sUA in healthy volunteers and hyperuricemic patients with a tolerable safety profile, warranting further development.

Polyethylene Glycol-Like Brush Polymer Conjugate of a Protein Drug Does Not Induce an Antipolymer Immune Response and Has Enhanced Pharmacokinetics than Its Polyethylene Glycol Counterpart.

Protein therapeutics, except for antibodies, have a short plasma half-life and poor stability in circulation. Covalent coupling of polyethylene glycol (PEG) to protein drugs addresses this limitation. However, unlike previously thought, PEG is immunogenic. In addition to induced PEG antibodies, ≈70% of the US population has pre-existing anti-PEG antibodies. Both induced and preexisting anti-PEG antibodies result in accelerated drug clearance, reduced clinical efficacy, and severe hypersensitivity reactions that have limited the clinical utility of uricase, an enzyme drug for treatment for refractory gout that is decorated with a PEG corona. Here, the authors synthesize a poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) conjugate of uricase that decorates the protein with multiple polymer chains to create a corona to solve these problems. The resulting uricase-POEGMA is well-defined, has high bioactivity, and outperforms its PEG counterparts in its pharmacokinetics (PK). Furthermore, the conjugate does not induce anti-POEGMA antibodies and is not recognized by anti-PEG antibodies. These findings suggest that POEGMA conjugation may provide a solution to the immunogenicity and antigenicity limitations of PEG while improving upon its PK benefits. These results transcend uricase and can be applied to other PEGylated therapeutics and the broader class of biologics with suboptimal PK.