Nicotinamide phosphoribosyltransferase prompts bleomycin-induced pulmonary fibrosis by driving macrophage M2 polarization in mice.

Rationale: Idiopathic pulmonary fibrosis (IPF) is an irreversible, fatal interstitial lung disease lacking specific therapeutics. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the nicotinamide adenine dinucleotide (NAD) salvage biosynthesis pathway and a cytokine, has been previously reported as a biomarker for lung diseases; however, the role of NAMPT in pulmonary fibrosis has not been elucidated. Methods: We identified the NAMPT level changes in pulmonary fibrosis by analyzing public RNA-Seq databases, verified in collected clinical samples and mice pulmonary fibrosis model by Western blotting, qRT-PCR, ELISA and Immunohistochemical staining. We investigated the role and mechanism of NAMPT in lung fibrosis by using pharmacological inhibition on NAMPT and Nampt transgenic mice. In vivo macrophage depletion by clodronate liposomes and reinfusion of IL-4-induced M2 bone marrow-derived macrophages (BMDMs) from wild-type mice, combined with in vitro cell experiments, were performed to further validate the mechanism underlying NAMPT involving lung fibrosis. Results: We found that NAMPT increased in the lungs of patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis. NAMPT inhibitor FK866 alleviated BLM-induced pulmonary fibrosis in mice and significantly reduced NAMPT levels in bronchoalveolar lavage fluid (BALF). The lung single-cell RNA sequencing showed that NAMPT expression in monocytes/macrophages of IPF patients was much higher than in other lung cells. Knocking out NAMPT in mouse monocytes/macrophages (Namptfl/fl;Cx3cr1CreER) significantly alleviated BLM-induced pulmonary fibrosis in mice, decreased NAMPT levels in BALF, reduced the infiltration of M2 macrophages in the lungs and improved mice survival. Depleting monocytes/macrophages in Namptfl/fl;Cx3cr1CreER mice by clodronate liposomes and subsequent pulmonary reinfusion of IL-4-induced M2 BMDMs from wild-type mice, reversed the protective effect of monocyte/macrophage NAMPT-deletion on lung fibrosis. In vitro experiments confirmed that the mechanism of NAMPT engaged in pulmonary fibrosis is related to the released NAMPT by macrophages promoting M2 polarization in a non-enzyme-dependent manner by activating the STAT6 signal pathway. Conclusions: NAMPT prompts bleomycin-induced pulmonary fibrosis by driving macrophage M2 polarization in mice. Targeting the NAMPT of monocytes/macrophages is a promising strategy for treating pulmonary fibrosis.

The cost-effectiveness of iruplinalkib versus alectinib in anaplastic lymphoma kinase-positive crizotinib-resistant advanced non-small-cell lung cancer patients in China.

Background: Iruplinalkib is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with efficacy in patients with ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC), which is independently developed by a Chinese pharmaceutical company. This study examined the cost-effectiveness of iruplinalkib versus alectinib in the Chinese healthcare setting. Methods: A partitioned survival model was developed to project the economic and health outcomes. Efficacy was derived using unanchored matching-adjusted indirect comparison (MAIC). Cost and utility values were obtained from the literature and experts' opinions. Deterministic and probabilistic sensitivity analyses (PSA) were carried out to evaluate the model's robustness. Results: Treatment with iruplinalkib versus alectinib resulted in a gain of 0.843 quality-adjusted life years (QALYs) with incremental costs of $20,493.27, resulting in an incremental cost-effectiveness ratio (ICER) of $24,313.95/QALY. Parameters related to relative efficacy and drug costs were the main drivers of the model outcomes. From the PSA, iruplinalkib had a 90% probability of being cost-effective at a willingness-to-pay threshold of $37,863.56/QALY. Conclusion: Compared to alectinib, iruplinalkib is a cost-effective therapy for patients with ALK-positive crizotinib-resistant advanced NSCLC.

Novel PLGA-encapsulated-nanopiperine promotes synergistic interaction of p53/PARP-1/Hsp90 axis to combat ALX-induced-hyperglycemia.

The present study predicts the molecular targets and druglike properties of the phyto-compound piperine (PIP) by in silico studies including molecular docking simulation, druglikeness prediction and ADME analysis for prospective therapeutic benefits against diabetic complications. PIP was encapsulated in biodegradable polymer poly-lactide-co-glycolide (PLGA) to form nanopiperine (NPIP) and their physico-chemical properties were characterized by AFM and DLS. ∼ 30 nm sized NPIP showed 86.68% encapsulation efficiency and - 6 mV zeta potential, demonstrated great interactive stability and binding with CT-DNA displaying upsurge in molar ellipticity during CD spectroscopy. NPIP lowered glucose levels in peripheral circulation by > 65 mg/dL compared to disease model and improved glucose influx in alloxan-induced in vivo and in vitro diabetes models concerted with 3-folds decrease in ROS production, ROS-induced DNA damage and 27.24% decrease in nuclear condensation. The 25% increase in % cell viability and inhibition in chromosome aberration justified the initiation of p53 and PARP DNA repairing protein expression and maintenance of Hsp90. Thus, the experimental study corroborated well with in silico predictions of modulating the p53/PARP-1/Hsp90 axis, with predicted dock score value of - 8.72, - 8.57, - 8.76 kcal/mol respectively, validated docking-based preventive approaches for unravelling the intricacies of molecular signalling and nano-drug efficacy as therapeutics for diabetics.

The new preservative-free ophthalmic formulation of bilastine 0.6% preserves the ocular surface epithelial integrity in a comparative in vitro study.

Allergic conjunctivitis (AC) is the most common form of allergic eye disease and an increasingly prevalent condition. Topical eye drop treatments are the usual approach for managing AC, although their impact on the ocular surface is not frequently investigated. The aim of this study was to perform a comparative physicochemical characterization, and in vitro biological evaluations in primary conjunctival and corneal epithelial cells of the new multidose preservative-free bilastine 0.6% and main commercially available eye drops. MTT assay was used to measure cell viability; oxidative stress was analyzed with a ROS-sensitive probe; and apoptosis was evaluated monitoring caspase 3/7 activation. Differences in pH value, osmolarity, viscosity and phosphate levels were identified. Among all formulations, bilastine exhibited pH, osmolarity and viscosity values closer to tear film (7.4, 300 mOsm/l and ~ 1.5-10 mPa·s, respectively), and was the only phosphates-free solution. Single-dose ketotifen did not induce ROS production, and single-dose azelastine and bilastine only induced a mild increase. Bilastine and single-dose ketotifen and azelastine showed high survival rates attributable to the absence of preservative in its formulation, not inducing caspase-3/7-mediated apoptosis after 24 h. Our findings support the use of the new bilastine 0.6% for treating patients with AC to preserve and maintain the integrity of the ocular surface.

Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma.

Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma, but resistance to ALK tyrosine kinase inhibitors (ALK TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing neuroblastoma; inhibition of miR-1304-5p decreases, while mimics of this miRNA increase the sensitivity of neuroblastoma cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse.

Inhibition of SRC-3 as a potential therapeutic strategy for aggressive mantle cell lymphoma.

Mantle cell lymphoma (MCL) has a poor prognosis and high relapse rates despite current therapies, necessitating novel treatment regimens. Inhibition of SRC-3 show effectiveness in vivo and in vitro in other B cell lymphomas. Additionally, previous studies have shown that SRC-3 is highly expressed in the lymph nodes of B cell non-Hodgkin's lymphoma patients, suggesting SRC-3 may play a role in the progression of B cell lymphoma. This study aimed to investigate novel SRC-3 inhibitors, SI-10 and SI-12, in mantle cell lymphoma. The cytotoxic effects of SI-10 and SI-12 were evaluated in vitro and demonstrated dose-dependent cytotoxicity in a panel of MCL cell lines. The in vivo efficacy of SI-10 was confirmed in two ibrutinib-resistant models: an immunocompetent disseminated A20 mouse model of B-cell lymphoma and a human PDX model of MCL. Notably, SI-10 treatment also resulted in a significant extension of survival in vivo with low toxicity in both ibrutinib-resistant murine models. We have investigated SI-10 as a novel anti-lymphoma compound via the inhibition of SRC-3 activity. These findings indicate that targeting SRC-3 should be investigated in combination with current clinical therapeutics as a novel strategy to expand the therapeutic index and to improve lymphoma outcomes.

Predicting the optimal concentration of remifentanil for skull pin fixation with hemodynamic and analgesia nociception index monitoring.

Inadequate antinociception during skull pin fixation may cause hemodynamic instability in intracranial surgery. The optimal concentration of remifentanil to provide adequate antinociception and stable hemodynamics during skull pin fixation under analgesia nociception index monitoring is unknown. This study is to assess the 90% effective concentration of remifentanil for skull pin fixation under hemodynamic and analgesia nociception index monitoring. Twenty-six patients were enrolled for intracranial surgery, anesthesia was induced and maintained under total intravenous anesthesia using target-controlled infusion for remifentanil and propofol under analgesia nociception index and bispectral index monitoring. Skull pin fixation was performed at different effect-site concentrations of remifentanil required for Dixon's up-and-down method with a step size of 0.5 ng/ml under bispectral index 40-60. Inadequate antinociception is defined when either ANI < 30 or > 20% in hemodynamic changes from baseline (e.g. heart rate > 100 beats/min, or blood pressure > 180/100 mmHg) and the effect-site concentration of remifentanil is considered as failure. It is considered success as ANI > 30 and < 20% hemodynamic changes from baseline simultaneously. Seven pairs of failure/success were used for probit analysis. The 90% effective concentration of remifentanil for skull pin fixation with adequate antinociception and hemodynamic stability was 4.7 ng/ml.

Formulation and evaluation of dissolving microneedle for transdermal delivery of piperine: the effect of polymers concentration.

This research aims to develop the formulation of Dissolving Microneedle Piperine (DMNs PIP) and evaluate the effect of polymer concentration on characterisation and permeation testing results in ex vivo. DMNs PIP were prepared from varying concentrations of piperine (PIP) (10, 15, and 20% w/w) and polymers of polyvinyl alcohol (PVA): Polyvinyl pyrrolidone (30:60 and 60:25), respectively. Then the morphological evaluation of the formula was carried out, followed by mechanical strength testing. Furthermore, the density, LOD, and weight percentage of piperine in the dried microneedle were calculated and the determination of volume, needle weight and piperine weight and analysed. Ex vivo testing, X-Ray Diffraction, FTIR and hemolysis tests were carried out. PIP with PVA and PVP (F1) polymers produced DMN with mechanical strength (8.35 ± 0.11%) and good penetration ability. In vitro tests showed that the F1 polymer mixture gave good penetration (95.02 ± 1.42 µg/cm2), significantly higher than the F2, F3, F4, and F5 polymer mixtures. The DMNs PIP characterisation results through XRD analysis showed a distinctive peak in the 20-30 region, indicating the presence of crystals. The FTIR study showed that the characteristics of piperine found in DMNs PIP indicated that piperine did not undergo interactions with polymers. The results of the ex vivo study through DMNs PIP hemolytic testing showed no hemolysis occurred, with the hemolysis index below the 5% threshold reported in the literature. These findings indicate that DMNs PIP is non-toxic and safe to use as alternative for treating inflammation.

Antiproliferative piperidine alkaloids from the leaves of Alocasia macrorrhiza.

Seventeen piperidine alkaloids, including 15 previously undescribed 2-substituted-6-(9-phenylnonyl)-piperidine-3,4-diol alkaloids and a previously undescribed 2-substituted-6-(9-phenylnonyl)-piperidine-3-ol alkaloid, were isolated from the leaves of Alocasia macrorrhiza (L.) Schott. Their planar structures and configurations were elucidated based on HR-ESI-MS, 1D and 2D NMR, Snatzke's method, modified Mosher method, single-crystal X-ray crystallography, as well as quantum chemical calculation. It was found that ΔδH5b-H5a can be used to elucidate the relative configuration of 2,3,4,6-tetrasubstituted piperidine, by analyzing the NMR data of 2-substituted-6-(9-phenylnonyl)-piperidine-3,4-diol. Antiproliferative activity was evaluated for all of the alkaloids, and compounds 6-8 showed considerable inhibitory activity against K562 cell line, with the IC50 values of 17.24 ± 1.62, 19.31 ± 0.9 and 18.77 ± 1.09µM, respectively. Furthermore, compounds 6 and 7 exerted an antiproliferative effect by inducing apoptosis.

Computational Investigation of the Covalent Inhibition Mechanism of Bruton's Tyrosine Kinase by Ibrutinib.

Covalent inhibitors represent a promising class of therapeutic compounds. Nonetheless, rationally designing covalent inhibitors to achieve a right balance between selectivity and reactivity remains extremely challenging. To better understand the covalent binding mechanism, a computational study is carried out using the irreversible covalent inhibitor of Bruton tyrosine kinase (BTK) ibrutinib as an example. A multi-µs classical molecular dynamics trajectory of the unlinked inhibitor is generated to explore the fluctuations of the compound associated with the kinase binding pocket. Then, the reaction pathway leading to the formation of the covalent bond with the cysteine residue at position 481 via a Michael addition is determined using the string method in collective variables on the basis of hybrid quantum mechanical-molecular mechanical (QM/MM) simulations. The reaction pathway shows a strong correlation between the covalent bond formation and the protonation/deprotonation events taking place sequentially in the covalent inhibition reaction, consistent with a 3-step reaction with transient thiolate and enolates intermediate states. Two possible atomistic mechanisms affecting deprotonation/protonation events from the thiolate to the enolate intermediate were observed: a highly correlated direct pathway involving proton transfer to the Cα of the acrylamide warhead from the cysteine involving one or a few water molecules and a more indirect pathway involving a long-lived enolate intermediate state following the escape of the proton to the bulk solution. The results are compared with experiments by simulating the long-time kinetics of the reaction using kinetic modeling.

Haemodynamic effects of remifentanil during induction of general anaesthesia with propofol. A randomised trial.

BACKGROUND: Remifentanil may have a dose-dependent haemodynamic effect during the induction of general anaesthesia combined with propofol. Our objective was to investigate whether systolic arterial blood pressure (SAP) was reduced to a greater extent when the remifentanil dose was increased. METHODS: This randomised, double-blind, dose-controlled study was conducted at the Day Surgery Unit of Haugesund Hospital, Norway. Ninety-nine healthy women scheduled for gynaecological surgery were randomly allocated in a 1:1:1 ratio to receive remifentanil induction with a low, medium or high dose corresponding to maximum effect-site concentrations (Ce) of 2, 4 and 8 ng/mL. The induction dose of propofol was 1.8 mg/kg, with a Ce of 2.9 µg/mL. Anaesthesia was induced using target-controlled infusion. After 150 s of sedation, a bolus of remifentanil and propofol was administered. Baseline was defined as 55-5 s before the bolus dose, and the total observation time was 450 s. We used beat-to-beat haemodynamic monitoring with LiDCOplus. The primary outcome variable was the maximum decrease in SAP within 5 min after bolus administration of remifentanil and propofol. Absolute and relative changes from baseline to minimal values and the area under the curve (AUC) were used as effect measures. Comparisons of groups were performed using analysis of variance (ANOVA). RESULTS: Median remifentanil doses were 0.75, 1.5 and 3.0 µg/kg in the low-, medium- and high-dose groups, respectively. The absolute changes (mean ± standard deviation) in SAP in the low-, medium- and high-dose groups of remifentanil were -39 ± 9.6 versus -43 ± 9.1, and -41 ± 10 mmHg, respectively. No difference (95% confidence interval) in the absolute change in SAP was observed between the groups (ANOVA, p = .29); medium versus low dose 3.7 (-2.0, 9.4) mmHg, and high versus medium dose -2.2 (-8.0; 3.5) mmHg. The relative changes from baseline to minimum SAP values were -30% versus -32% versus -32% (p = .52). The between-group differences in the AUC were not statistically significant. Relative changes in heart rate (-20% vs. -21% vs. -21%), stroke volume (-19% vs. -16% vs. -16%), cardiac output (-32% vs. -32% vs. -32%), systemic vascular resistance (-24% vs. -27% vs. -28%), and AUC were not statistically significant. CONCLUSION: This trial demonstrated major haemodynamic changes during the induction of anaesthesia with remifentanil and propofol. However, we did not observe any statistically significant differences between low, medium or high doses of remifentanil when using continuous invasive high-accuracy beat-to-beat monitoring.

Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor.

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infection in infants, older adults and the immunocompromised. Effective directly acting antivirals are not yet available for clinical use. To address this, we screen the ReFRAME drug-repurposing library consisting of 12,000 small molecules against RSV. We identify 21 primary candidates including RSV F and N protein inhibitors, five HSP90 and four IMPDH inhibitors. We select lonafarnib, a licensed farnesyltransferase inhibitor, and phase III candidate for hepatitis delta virus (HDV) therapy, for further follow-up. Dose-response analyses and plaque assays confirm the antiviral activity (IC50: 10-118 nM). Passaging of RSV with lonafarnib selects for phenotypic resistance and fixation of mutations in the RSV fusion protein (T335I and T400A). Lentiviral pseudotypes programmed with variant RSV fusion proteins confirm that lonafarnib inhibits RSV cell entry and that these mutations confer lonafarnib resistance. Surface plasmon resonance reveals RSV fusion protein binding of lonafarnib and co-crystallography identifies the lonafarnib binding site within RSV F. Oral administration of lonafarnib dose-dependently reduces RSV virus load in a murine infection model using female mice. Collectively, this work provides an overview of RSV drug repurposing candidates and establishes lonafarnib as a bona fide fusion protein inhibitor.

Effect of remifentanil on three effect-site concentrations of propofol and their relationship during electroencephalography at loss of response, at maximum alpha power, and at onset of burst suppression: a prospective randomized trial.

PURPOSE: The effect-site concentration (Ce) at loss of response (Ce-LOR) to propofol closely correlates both with Ce as electroencephalographic alpha power becomes highest (Ce-alpha) and with Ce at onset of burst suppression (BS) (Ce-OBS), when no opioids are administered. Co-administration of opioids dose-dependently decreases Ce-LOR. We investigated the influence of remifentanil on the relationship between these three Ces. METHODS: After receiving approval from our local ethical committee, with written informed consent, we enrolled 90 participants (ASA-PS I or II) who were scheduled for elective surgery. Participants were randomly assigned to three groups: constant remifentanil Ce 0 ng/ml (Remi_0); 1 ng/mL (Remi_1); and 2 ng/mL (Remi_2). We recorded both raw EEG and EEG-derived parameters on a computer. After reaching remifentanil equilibrium, we administered propofol using a target-controlled infusion pump such that propofol Ce increased to about 0.3 µg/mL/min. After determining Ce-LOR, we administered 0.6 mg/kg of rocuronium and started mask ventilation. The study protocol ended after observation of BS. RESULTS: Three participants were excluded. Ce-LOR in each group (Remi_0, Remi_1, Remi_2) was 2.00 ± 0.58 µg/mL, 1.43 ± 0.49 µg/mL, and 1.37 ± 0.42 µg/mL. Ce-alpha was 2.91 ± 0.63 µg/mL, 2.30 ± 0.41 µg/mL, and 2.12 ± 0.39 µg/mL. Ce-OBS was 3.80 ± 0.69 µg/mL, 3.25 ± 0.68 µg/mL, and 2.90 ± 0.57 µg/mL. In three other instances, Ce was decreased by remifentanil. Generalized linear model analysis revealed that remifentanil had no influence on the relationship between the three Ces. CONCLUSION: During propofol anesthesia, even low concentrations of remifentanil shifted concentration-related electroencephalographic changes.

Effects of propofol versus sevoflurane on surgical field visibility during arthroscopic rotator cuff repair: a randomized trial.

BACKGROUND: During arthroscopic rotator cuff repair (ARCR), clear surgical field visibility (SFV) is the basis of successful surgery, but the choice of anesthesia maintenance drugs may have different effects on SFV. In this study, we aimed to compare the effects of propofol- and sevoflurane-based general anesthesia on SFV in patients undergoing ARCR. METHODS: Patients (n = 130) undergoing elective ARCR in the lateral decubitus position were randomized into either the propofol group or sevoflurane group (65 per group). The duration of surgery and increased pressure irrigation (IPI), Boezaart score, rocuronium consumption and usage of remifentanil were recorded. The time of both spontaneous respiration recovery and extubation and the incidences of postoperative nausea and vomiting and agitation were also recorded. RESULTS: The Boezaart score, duration of IPI and ratio of the duration of IPI to the duration of surgery (IPI/S ratio) were similar between the groups (P > 0.05). Rocuronium consumption, number of patients requiring remifentanil infusion and total remifentanil consumption were significantly lower in the sevoflurane group (P < 0.05). The spontaneous respiration recovery time was significantly longer in the propofol group (P < 0.05), but there were no differences in the extubation time between the groups(P > 0.05). CONCLUSIONS: Compared with propofol, sevoflurane provides equally clear SFV while improving the convenience of anesthesia maintenance in ARCR patients with interscalene plexus (ISB) combined with general anesthesia. TRIAL REGISTRATION: This single-center, prospective, RCT was retrospective registered at Chinese Clinical Trial Registry with the registration number ChiCTR2300072110 (02/06/2023).

CP41, a novel curcumin analogue, induces apoptosis in endometrial cancer cells by activating the H3F3A/ proteasome-MAPK signaling pathway and enhancing oxidative stress.

AIMS: Curcumin is a natural compound and has good antitumor properties, but its clinical use is limited by its low bioavailability. We constructed the derivative CP41 (3,5-bis(2-chlorobenzylidene)-1-piperidin-4-one) by enhancing the bioavailability of curcumin while retaining its antitumor properties. MAIN METHODS: CCK-8 (Cell Counting Kit-8) was used to detect the effect of CP41 on cell proliferation; Western blotting, immunofluorescence, immunoprecipitation, quantitative PCR and enzyme-linked immunosorbent assay were used to evaluate the expression of subcutaneous tumor-related molecules in cells and mice. KEY FINDINGS: Our results showed that CP41 inhibited the proliferation of endometrial cancer cells by suppressing the proliferation of AN3CA and HEC-1-B cells. We found that CP41 significantly increased H3F3A and inhibited proteasome activity, which activated MAPK signaling and led to apoptosis. Further experiments showed that H3F3A is a potential target of CP41. Correlation analysis showed that H3F3A was positively correlated with the sensitivity to chemotherapeutic agents in endometrial cancer. CP41 significantly induced reactive oxygen species (ROS) levels and activated endoplasmic reticulum stress, which led to apoptosis. The safety profile of CP41 was also evaluated, and CP41 did not cause significant drug toxicity in mice. SIGNIFICANCE: CP41 showed stronger antitumor potency than curcumin, and its antitumor activity may be achieved by inducing ROS and activating H3F3A-mediated apoptosis.

NanoSHP099-Targeted SHP2 Inhibition Boosts Ly6Clow Monocytes/Macrophages Differentiation to Accelerate Thrombolysis.

Tumor-associated thrombus (TAT) accounts for a high proportion of venous thromboembolism. Traditional thrombolysis and anticoagulation methods are not effective due to various complications and contraindications, which can easily lead to patients dying from TAT rather than the tumor itself. These clinical issues demonstrate the need to research diverse pathways for adjuvant thrombolysis in antitumor therapy. Previously, the phenotypic and functional transformation of monocytes/macrophages is widely reported to be involved in intratribal collagen regulation. This study finds that myeloid deficiency of the oncogene SHP2 sensitizes Ly6Clow monocyte/macrophage differentiation and can alleviate thrombus organization by increasing thrombolytic Matrix metalloproteinase (MMP) 2/9 activities. Moreover, pharmacologic inhibition by SHP099, examined in mouse lung metastatic tumor models, reduces tumor and thrombi burden in tumor metastatic lung tissues. Furthermore, SHP099 increases intrathrombus Ly6Clow monocyte/macrophage infiltration and exhibits thrombolytic function at high concentrations. To improve the thrombolytic effect of SHP099, NanoSHP099 is constructed to achieve the specific delivery of SHP099. NanoSHP099 is identified to be simultaneously enriched in tumor and thrombus foci, exerting dual tumor-suppression and thrombolysis effects. NanoSHP099 presents a superior thrombus dissolution effect than that of the same dosage of SHP099 because of the higher Ly6Clow monocyte/macrophage proportion and MMP2/MMP9 collagenolytic activities in organized thrombi.

Hepatitis B virus reactivation after ibrutinib treatment.

New immunosuppressive and antineoplastic drugs are becoming both more numerous and more widely used, even during several years. Most of them present a low-moderate risk of hepatitis B virus (HBV) reactivation in HBsAg-negative and anti-HBc-positive patients. However, their reactivation capacity has not been clearly studied. We present the clinical case of a patient with these serological characteristics who, after 5 years of treatment with ibrutinib for chronic lymphocytic leukaemia, developed VHB reactivation, which was controlled with tenofovir. The occurrence of this event with drugs such as ibrutinib may lead to changes in HBV reactivation prophylaxis.

Insights on discovery, efficacy, safety and clinical applications of ghrelin receptor agonist capromorelin in veterinary medicine.

Growth hormone and insulin like growth factor-1 plays an important role in the regulation of body composition and metabolism. Growth Hormone is released from the pituitary through a specific G-protein coupled receptor (GPCR) called growth hormone secretagogue receptor 1a expressed in the hypothalamus. Ghrelin is a peptide hormone released from the cells in the stomach, which stimulates appetite and food intake in mammals, regulates gut motility, gastric acid secretion, taste sensation, circadian rhythm, learning and memory, oxidative stress, autophagy, glucose metabolism etc. When the release of the endogenous ligand GHSR-1a, i.e., ghrelin is malfunctioned or stopped, external substitutes are administrated to induce the stimulation of growth hormone and appetite. A class of compound known as ghrelin receptor agonists are developed as an external substitute of ghrelin for regulation and stimulation of growth hormone in frailty, for body weight gain, muscle mass gain, prevention of cachexia and for the treatment of chronic fatigue syndromes. Capromorelin [Entyce™ (Aratana Therapeutics, Leawood, KS, USA)] is the only FDA (Food and Drug Administration) approved (May 2016) drug used for stimulating appetite in dogs and was marketed in the fall of 2017. In 2020, USFDA approved Capromorelin [Elura™ (Elanco US Inc.)] for the management of weight loss in chronic kidney disease of cats. This article reviews the discovery of the ghrelin receptor agonist capromorelin, its efficacy, safety, clinical applications and aims to delineate its further scope of use in veterinary practice.

Lysine-Reactive N-Acyl-N-aryl Sulfonamide Warheads: Improved Reaction Properties and Application in the Covalent Inhibition of an Ibrutinib-Resistant BTK Mutant.

The covalent inhibition of a target protein has gained widespread attention in the field of drug discovery. Most of the current covalent drugs utilize the high reactivity of cysteines toward modest electrophiles. However, there is a growing need for warheads that can target lysine residues to expand the range of covalently druggable proteins and to deal with emerging proteins with mutations resistant to cysteine-targeted covalent drugs. We have recently developed an N-acyl-N-alkyl sulfonamide (NASA) as a lysine-targeted electrophile. Despite its successful application, this NASA warhead suffered from instability in physiological environments, such as serum-containing medium, because of its high intrinsic reactivity. In this study, we sought to modify the structure of the NASA warhead and found that N-acyl-N-aryl sulfonamides (ArNASAs) are promising electrophiles for use in a lysine-targeted covalent inhibition strategy. We prepared a focused library of ArNASA derivatives with diverse structures and reactivity and identified several warhead candidates with suppressed hydrolysis-mediated inactivation and reduced nonspecific reactions with off-target proteins, without sacrificing the reactivity toward the target. These reaction properties enabled the improved covalent inhibition of intracellular heat shock protein 90 (HSP90) in the presence of serum and the development of the first irreversible inhibitor for ibrutinib-resistant Bruton's tyrosine kinase (BTK) bearing the C481S mutation. This study clearly demonstrated the use of a set of ArNASA warheads to create highly potent covalent drugs and highlighted the importance of enriching the current arsenal of lysine-reactive warheads.

Efficacy and Safety of Niraparib as First-Line Maintenance Treatment for Patients with Advanced Ovarian Cancer: Real-World Data from a Multicenter Study in China.

BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibitors are a new maintenance therapy option for patients with ovarian cancer (OC). OBJECTIVE: To evaluate the efficacy and influencing factors of the novel PARP inhibitor niraparib for maintenance treatment of Chinese patients with advanced OC. PATIENTS AND METHODS: In this retrospective multicenter real-world study patients with advanced OC from 15 hospitals throughout China were enrolled. The primary endpoint was progression-free survival (PFS) and the secondary endpoints included the time to treatment discontinuation and safety. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to identify possible risk factors for PFS, after which a prediction model was established to evaluate the likelihood of achieving an 18-month PFS. The relationship between the dose of niraparib and PFS was also evaluated. RESULTS: The PFS rates of 199 patients at 6, 12, 18, 24, and 30 months were 87.4%, 75.9%, 63.6%, 56.1%, and 51.8%, respectively. LASSO regression model revealed that only age < 65 years (P = 0.011), BRCA mutations (P < 0.001), and R0 status after cytoreductive surgery (P = 0.01) were significant factors associated with prolonged PFS times. Based on the LASSO logistic regression analysis, a clinical prediction formula was developed: - 2.412 + 1.396Age≥65yr + 2.374BRCAwt + 1.387R1 + 0.793Interval≥12w + 0.178BMI>24kg/m2 which yielded a cut-off value of 0.091, an area under the curve (AUC) of 0.839 (0.763-0.916), a sensitivity of 94.3%, and an accuracy of 78.5%. A nomogram was then built to visualize the results. The major treatment-emergent adverse events of ≥ grade 3 included a platelet count decrease (19.1%), white blood cell count decrease (15.1%), neutrophil count decrease (13.1%), and anemia (18.6%). The 18-month PFS rates in patients treated with 200 mg niraparib were somewhat higher than in patients treated with 100 mg after 3-months of therapy. CONCLUSIONS: For Chinese OC patients, niraparib, particularly at a 200 mg individual starting dose, was an effective therapy with easily manageable safety.

Maintenance therapy with poly (ADP-ribose) polymerase inhibitors is a new option for patients with ovarian cancer (OC) after they have received platinum-based chemotherapy to reduce the recurrence or relapse rates, but it remains unclear whether there are any changes in efficacy and safety when different starting doses of niraparib are administrated to Chinese patients, who typically have a bodyweight < 77 kg. We found that niraparib exhibited satisfactory efficacy with tolerable safety during maintenance therapy for advanced OC whether administered at 100 mg or 200 mg doses. We believe these regimens can serve as a valuable addition to the previous results of randomized controlled trials.