Targeting tumor-infiltrating CCR8+ regulatory T cells induces antitumor immunity through functional restoration of CD4+ Tconvs and CD8+ T cells in colorectal cancer.

BACKGROUND: Chemokine (C-C motif) receptor 8 (CCR8) is a chemokine receptor selectively expressed on tumor-infiltrating regulatory T cells (Tregs). Strong immunosuppression mediated by CCR8+ Tregs observed in breast and lung malignancies suggest for their functional significance in cancer therapy. To date, detailed characterization of tumor-infiltrating CCR8+ Tregs cells in colorectal cancer (CRC) is limited. METHODS: To study the presence and functional involvement of CCR8+ Tregs in CRC, we analyzed the proportions of CCR8-expressing T cells in different T cell subsets in tumor and adjacent normal tissues and peripheral blood mononuclear cells (PBMCs) from CRC patients by Flow cytometry. Also, we compared the distribution of CCR8+ T cells in malignant tissues and peripheral lymphoid organs from a subcutaneous CRC murine model. Bioinformatic analysis was performed to address the significance of CCR8 expression levels in CRC prognosis, immune regulatory gene expression profiles and potential molecular mechanisms associated with CCR8+ Tregs in CRC tumors. Further, we administrated an anti-CCR8 monoclonal antibody to CT26 tumor-bearing mice and examined the antitumor activity of CCR8-targeted therapy both in vivo and in an ex vivo confirmative model. RESULTS: Here, we showed that Tregs was predominantly presented in the tumors of CRC patients (13.4 ± 5.8, p < 0.0001) and the CRC subcutaneous murine model (35.0 ± 2.6, p < 0.0001). CCR8 was found to be preferentially expressed on these tumor-infiltrating Tregs (CRC patients: 63.6 ± 16.0, p < 0.0001; CRC murine model: 65.3 ± 9.5, p < 0.0001), which correlated with poor survival. We found that majority of the CCR8+ Tregs expressed activation markers and exhibited strong suppressive functions. Treatment with anti-CCR8 antibody hampered the growth of subcutaneous CRC tumor through effectively restoring the anti-tumor immunity of CD4+ conventional T cells (CD4+ Tconvs) and CD8+ T cells, which was confirmed in the ex vivo examinations. CONCLUSIONS: Collectively, these findings illustrate the importance of CCR8+ Tregs for an immunosuppressive microenvironment in CRC tumors by functional inhibition of CD4+ Tconvs and CD8+ T cells, and suggest for the applicable value of CCR8-targeted therapy for CRC.

Pamiparib in combination with tislelizumab in patients with advanced solid tumours: results from the dose-escalation stage of a multicentre, open-label, phase 1a/b trial.

BACKGROUND: Rationale exists for combined treatment with immune checkpoint inhibitors and poly (ADP-ribose) polymerase (PARP) inhibitors in a variety of solid tumours. This study aimed to investigate the safety and antitumour effects of pamiparib, an oral PARP 1/2 inhibitor, combined with tislelizumab, a humanised anti-PD-1 monoclonal antibody, in patients with advanced solid tumours and to determine the optimum doses for further evaluation. METHODS: We did a multicentre, open-label, phase 1a/b study at five academic sites or community oncology centres in Australia. We recruited adults (aged ≥18 years) with advanced solid tumours who had received one or more previous lines of therapy, with an Eastern Cooperative Oncology Group performance score of 1 or less, and a life expectancy of 12 weeks or more. Patients were enrolled into one of five dose-escalation cohorts, with dose-escalation done in a 3 + 3 design. Cohorts 1-3 received intravenous tislelizumab 2 mg/kg every 3 weeks plus 20, 40, or 60 mg oral pamiparib twice daily, respectively; cohorts 4 and 5 received 200 mg intravenous tislelizumab every 3 weeks plus 40 or 60 mg oral pamiparib twice daily, respectively. The primary endpoints of the phase 1a dose-escalation part of the study were safety and tolerability, including the occurrence of dose-limiting toxicities and determination of the maximum tolerated dose and recommended phase 2 dose. All primary endpoints were analysed in the safety analysis set, which included all patients who received at least one dose of tislelizumab or pamiparib, with the exception of the occurrence of dose-limiting toxicities, which was analysed in the dose-limiting toxicity analysis set, which included all patients who received at least 90% of the first scheduled tislelizumab dose and at least 75% of scheduled pamiparib doses, or who had a dose-limiting toxicity event during cycle 1. Reported here are results of the phase 1a dose-escalation stage of the trial. This trial is registered with ClinicalTrials.gov, number NCT02660034, and is ongoing. FINDINGS: Between Jan 22, 2016, and May 16, 2017, we enrolled 49 patients (median age 63 years [IQR 55-67]), all of whom received at least one dose of pamiparib or tiselzumab. Four patients had dose-limiting toxicities (intractable grade 2 nausea [n=1] and grade 3 rash [n=1] in cohort 4, and grade 2 nausea and vomiting [n=1] and grade 4 immune-mediated hepatitis [n=1] in cohort 5). The recommended phase 2 dose was tislelizumab 200 mg every 3 weeks plus pamiparib 40 mg twice daily (the dose given in cohort 4). The most common treatment-emergent adverse events were nausea (in 31 [63%] of 49 patients), fatigue (26 [53%]), diarrhoea (17 [35%]), and vomiting (15 [31%]). 23 (47%) of 49 patients had immune-related adverse events, of whom nine (39%) had asymptomatic grade 3-4 hepatic immune-related adverse events, which were reversible with corticosteroid treatment. The most common adverse event of grade 3 or worse severity was anaemia (in six [12%] patients) and no grade 5 adverse events were reported. Hepatitis or autoimmune hepatitis was the only serious adverse event to occur in two or more patients (in four [8%] patients). At a median follow-up of 8·3 months (IQR 4·8-12·8), ten (20%) of 49 patients achieved an objective response according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, including two complete responses and eight partial responses. INTERPRETATION: Pamiparib with tislelizumab was generally well tolerated and associated with antitumour responses and clinical benefit in patients with advanced solid tumours supporting further investigation of the combination of pamiparib with tislelizumab. FUNDING: BeiGene.

Microglia TREM2 is required for electroacupuncture to attenuate neuroinflammation in focal cerebral ischemia/reperfusion rats.

Neuroinflammation plays a critical role in ischemic stroke pathology and could be a promising target in ischemic stroke. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor in the CNS that is involved in regulating neuroinflammation in cerebral ischemia. However, the role of TREM2 in ischemic stroke is controversial. Electroacupuncture (EA) is an effective therapy for alleviating stroke-induced neuroinflammation. Here, we found that ischemic stroke induced an increased microglial TREM2 expression, and EA treatment can further promote microglial TREM2 expression following cerebral ischemia. TREM2 overexpression was observed to play a neuroprotective role by improving the neurobehavioral deficit and reducing the cerebral infarct volume 72 h after reperfusion, whereas TREM2 silencing had the opposite effects. Moreover, the effects of EA on improving stroke outcome and suppressing neuroinflammation in the brain were reversed by TREM2 silencing. Finally, TREM2 silencing also suppressed the ability of EA to regulate the PI3K/Akt and NF-κB signaling pathways. Altogether, the results show that TREM2 could be a potential target in EA treatment for attenuating inflammatory injury following cerebral ischemia/reperfusion.

Lentivirus-mediated overexpression of OTULIN ameliorates microglia activation and neuroinflammation by depressing the activation of the NF-κB signaling pathway in cerebral ischemia/reperfusion rats.

BACKGROUND: Ischemic stroke-induced neuroinflammation is mainly mediated by microglial cells. The nuclear factor kappa B (NF-κB) pathway is the key transcriptional pathway that initiates inflammatory responses following cerebral ischemia. OTULIN, a critical negative regulator of the NF-κΒ signaling pathway, exerts robust effects on peripheral immune cell-mediated inflammation and is regarded as an essential mediator for repressing inflammation in vivo. The effect of OTULIN on inflammatory responses in the central nervous system (CNS) was previously unstudied. This current study investigated the anti-inflammatory effect of OTULIN both in vitro and in vivo in ischemic stroke models. METHODS: Sprague-Dawley (SD) rats were subjected to transient middle cerebral artery occlusion (tMCAO) or an intraperitoneal injection of lipopolysaccharide (LPS). Overexpression of the OTULIN gene was utilized to observe the effect of OTULIN on ischemic stroke outcomes. The effect of OTULIN overexpression on microglia-mediated neuroinflammation was examined in rat primary microglia (PM) and in the microglial cell line N9 after induction by oxygen-glucose deprivation (OGD)-treated neuronal medium. The activation and inflammatory responses of microglia were detected using immunofluorescence, ELISA, and qRT-PCR. The details of molecular mechanism were assessed using Western blotting. RESULTS: In the tMCAO rats, the focal cerebral ischemia/reperfusion injury induced a continuous increase in OTULIN expression within 72 h, and OTULIN expression was increased in activated microglial cells. OTULIN overexpression obviously decreased the cerebral infarct volume, improved the neurological function deficits, and reduced neuronal loss at 72 h after reperfusion, and it also inhibited the activation of microglia and attenuated the release of TNF-α, IL-1ß, and IL-6 by suppressing the NF-κB pathway at 24 h after tMCAO. In vitro, OTULIN overexpression inhibited the microglia-mediated neuroinflammation by reducing the production of TNF-α, IL-1ß, and IL-6 via depressing the NF-κB pathway in both PM and N9 cells. CONCLUSIONS: OTULIN provides a potential therapeutic target for ischemic brain injury by ameliorating the excessive activation of microglial cells and neuroinflammation through repressing the NF-κB signaling pathway.

Synthesis, iron binding and antimicrobial properties of hexadentate 3-hydroxypyridinones-terminated dendrimers.

Macromolecular chelators have potential applications in the medical area, for instance, in treatment of iron overload-related disorders and in the treatment of external infections. In this investigation, several novel iron(III)-selective hydroxypyridinone hexadentate-terminated first and second generation dendrimeric chelators were synthesized using a convergent strategy. Their iron chelating ability was demonstrated by UV/Visible spectrometry and high resolution mass spectrometry (HRMS). The iron binding affinities were also investigated by the competition with a fluorescent iron chelator CP691. The result indicated that these dendrimers possesses a high affinity for iron with a very high pFe3+ value, which is close to that of an isolated hexadentate unit. These dendrimeric chelators were found to exhibit inhibitory effect on the growth of both Gram-positive and Gram-negative bacteria.

Panobinostat PK/PD profile in combination with bortezomib and dexamethasone in patients with relapsed and relapsed/refractory multiple myeloma.

PURPOSE: Panobinostat, a potent pan-deacetylase inhibitor, improved progression-free survival (PFS) in patients with relapsed and refractory multiple myeloma when combined with bortezomib and dexamethasone in a phase 3 trial, PANORAMA-1. This study aims to explore exposure-response relationship for panobinostat in this combination in a phase 1 trial, B2207 and contrast with data from historical single-agent studies. METHODS: Panobinostat plasma concentration-time profiles were obtained in patients from PANORAMA-1 (n = 12) and B2207 (n = 12) trials. Overall response rates (ORR) and major adverse events (AE) by panobinostat exposure were investigated in the B2207 trial. Panobinostat PK data from combination trials were contrasted with data from single-agent studies. RESULTS: At maximum tolerated dose (MTD), the geometric mean of panobinostat area under curve from 0 to 24 h (AUC0-24) was 47.5 ng h/mL (77 % CV), and maximum plasma concentration (Cmax) was 8.1 ng/mL (90 % CV). These values were comparable with exposure data obtained in PANORAMA-1, but were 20 % lower than those without dexamethasone, and ∼ 50 % lower from single-agent trials, likely due to enzyme induction by dexamethasone. Higher levels of panobinostat exposure were associated with higher response rates and higher incidences of diarrhea and thrombocytopenia. CONCLUSIONS: Apparent panobinostat exposure-AE and exposure-ORR relationships were observed when combined with bortezomib and dexamethasone in the treatment of patients with relapsed and refractory multiple myeloma. The addition of dexamethasone facilitated best response even though plasma exposure of panobinostat was reduced. Combination with a strong enzyme inducer should be avoided in future trials to prevent further reduction of panobinostat exposure.

Population pharmacokinetics of intravenous and oral panobinostat in patients with hematologic and solid tumors.

PURPOSE: The study aimed to characterize the population pharmacokinetics of panobinostat, a pan-deacetylase inhibitor that has demonstrated efficacy in combination with bortezomib and dexamethasone in patients with multiple myeloma. METHODS: A nonlinear mixed-effect model was used to fit plasma panobinostat concentration-time data collected from patients across 14 phase 1 and phase 2 trials following either oral or intravenous (IV) administration. The model was used to estimate bioavailabilities of the two oral formulations and the effects of demographic and clinical covariates on the central volume of distribution and clearance of panobinostat. RESULTS: A total of 7834 samples from 581 patients were analyzed. Panobinostat pharmacokinetic parameters were best characterized by a three-compartment model with first-order absorption and elimination. Bioavailability was 21.4 %. Median clearance was 33.1 L/h. Interindividual variability in clearance was 74 %. For Caucasian patients of median age 61 years, area under the curve (AUC) decreased from 104 to 88 ng · h/mL as body surface area (BSA) increased from the first to third quartiles, 1.8 to 2.1 m(2). For Caucasian patients of median BSA 1.9 m(2), AUC decreased from 102 to 95 ng · h/mL as age increased from the first to third quartiles, 51 to 70 years. For patients of median BSA and median age, AUC ranged across the four race categories from 80 to 116 ng · h/mL. Covariate analysis showed no impact on panobinostat clearance and volume by patients' sex, tumor type, kidney function, liver markers, or coadministered medications. However, separate analyses of dedicated studies have demonstrated effects of liver impairment and CYP3A4 inhibition. CONCLUSIONS: Although covariate analyses revealed significant effects of body size, age, and race on panobinostat pharmacokinetics, these effects were minor compared to the interindividual variability and therefore not clinically relevant when dosing panobinostat in populations similar to those studied.

Phase 1b study to assess the safety, tolerability, and clinical activity of pamiparib in combination with temozolomide in patients with locally advanced or metastatic solid tumors.

BACKGROUND: Pamiparib is a potent, selective, poly (ADP-ribose) polymerase 1/2 inhibitor that demonstrates synthetic lethality in cells with breast cancer susceptibility gene mutations or other homologous recombination deficiency. This two-stage phase 1b study (NCT03150810) assessed pamiparib in combination with temozolomide (TMZ) in adult patients with histologically confirmed locally advanced and metastatic solid tumors. METHODS: Oral pamiparib 60 mg was administered twice daily. During the dose-escalation stage, increasing doses of TMZ (40-120 mg once daily pulsed or 20-40 mg once daily continuous) were administered to determine the recommended dose to be administered in the dose-expansion stage. The primary objectives were to determine safety and tolerability, maximum tolerated/administered dose, recommended phase 2 dose and schedule, and antitumor activity of pamiparib in combination with TMZ. Pharmacokinetics of pamiparib and TMZ and biomarkers were also assessed. RESULTS: Across stages, 139 patients were treated (dose escalation, n = 66; dose expansion, n = 73). The maximum tolerated dose of TMZ, which was administered during dose expansion, was 7-day pulsed 60 mg once daily. The most common treatment-emergent adverse events (TEAEs) were anemia (dose escalation, 56.1%; dose expansion, 63.0%), nausea (dose escalation, 54.5%; dose expansion, 49.3%), and fatigue (dose escalation, 48.5%; dose expansion, 47.9%). In the dose-escalation stage, four patients experienced dose-limiting toxicities (three neutropenia and one neutrophil count decreased). No TEAEs considered to be related to study drug treatment resulted in death. Antitumor activity was modest, indicated by confirmed overall response rate (dose escalation, 13.8%; dose expansion, 11.6%), median progression-free survival (3.7 and 2.8 months), and median overall survival (10.5 and 9.2 months). Administration of combination therapy did not notably impact pamiparib or TMZ pharmacokinetics. CONCLUSIONS: Pamiparib in combination with TMZ had a manageable safety profile. Further investigation of the efficacy of this combination in tumor types with specific DNA damage repair deficiencies is warranted.

RAGE: a potential target for Epimedium's anti-neuroinflammation role in vascular dementia-insights from network pharmacology and molecular simulation.

Vascular dementia (VaD), a cognitive impairment resulting from cerebrovascular issues, could be mitigated by Epimedium. This study investigates Epimedium's efficacy in VaD management through a systematic review, network pharmacology, molecular docking, and molecular dynamic simulations (MDS). Comprehensive literature searches were conducted across various databases. Epimedium's pharmacological properties were analyzed using the TCMSP database. Integration with the Aging Atlas database enabled the identification of shared targets between Epimedium and VaD. A protein-protein interaction (PPI) network was constructed, and central targets' topological attributes were analyzed using Cytoscape 3.9.1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using "ClusterProfiler" R package. The interactions between Epimedium and central targets were assessed by Molecular docking and MDS. Epimedium and its 23 bioactive components counteracted oxidative stress, neuroinflammation, and neuronal damage, thereby attenuating cognitive deterioration in VaD. A total of 78 common targets were identified, with 22 being significantly related to aging. Enrichment analysis identified 1769 GO terms and 139 KEGG pathways, highlighting the AGE-RAGE signaling pathway. Molecular docking revealed that 23 bioactive components, except Linoleyl acetate, effectively interacted with top central targets (JUN, MAPK14, IL6, FOS, TNF). MDS demonstrated that flavonoids Icariin, Kaempferol, Luteolin, and Quercetin formed stable complexes with RAGE. The study identifies RAGE as a novel therapeutic target for Epimedium in the mitigation of VaD via its anti-inflammatory properties.

3,3'-Dihy-droxy-6,6'-bis-(hy-droxy-meth-yl)-2,2'-(pentane-1,1-di-yl)di-4H-pyran-4-one.

In the title mol-ecule, C(17)H(20)O(8), the two pyran rings form a dihedral angle of 61.2 (2)°. The two hy-droxy-methyl groups are each disordered over two sets of sites in a 0.764 (3):0.236 (3) ratio. In the crystal, O-H⋯O hydrogen bonds link the mol-ecules into layers parallel to the ac plane.

Effect of Temperature on the Physical Salt Attack of Cement Mortars under Repeated Partial Immersion in Sodium Sulfate Solution.

Physical salt attack (PSA) is one of the dominant durability issues of cement-based materials, where salt crystallization pressure is the driving force inducing damage. However, research on the temperature-related deterioration behavior of cement-based materials is limited. In this study, salt-contaminated cement mortars were rewetted at different temperatures. The assessment criteria were based on the visual appearance, weight evolution and size distribution of scaled materials, and the alterations in the microstructure were investigated by microscopy, thermal and mineralogical analyses. The results indicated that more severe damage developed at 5 °C than that at 20 °C due to the greater crystallization pressure caused by the conversion from thenardite (Na2SO4) to mirabilite (Na2SO4·10H2O) at the lower temperature. No damage was observed at 35 °C, since the repeated dissolution and re-crystallization of thenardite were harmless for the specimens. In addition, two distinct damage patterns were observed for PSA performed at 5 °C and 20 °C, namely, granular disintegration and contour scaling.

Influence of a Nano-Hydrophobic Admixture on Concrete Durability and Steel Corrosion.

Steel corrosion is major reason of the deterioration of reinforced concrete structures. Decreasing the transportation of erosion ions in concrete is one of effective methods to protect the steel from corrosion. In the present work, a novel nano-hydrophobic admixture is introduced to improve the ion-diffusion properties and the corrosion resistance of reinforced steel. Compared with unmodified concrete, the nano-hydrophobic admixture effectively decreases the water adsorption, water evaporation, and chloride ions transport in a concrete structure, and then improved the concrete's durability. The concrete's water adsorption decreased more than 78%, and the initial corrosion time of reinforced steel is prolonged more than one time by treatment with the nano-hydrophobic admixture. The inhibition penetration of the medium in concrete modified by hydrophobic nanoparticles is the key to provide the protective properties of steel reinforcement from chloride erosion.

Neutralizing antibodies from the rare convalescent donors elicited antibody-dependent enhancement of SARS-CoV-2 variants infection.

Currently, neutralizing antibody and vaccine strategies have been developed by targeting the SARS-CoV-2 strain identified during the early phase of the pandemic. Early studies showed that the ability of SARS-CoV-2 RBD or NTD antibodies to elicit infection enhancement in vivo is still controversial. There are growing concerns that the plasma and neutralizing antibodies from convalescent patients or people receiving vaccines mediate ADE of SARS-CoV-2 variants infections in immune cells. Here, we constructed engineered double-mutant variants containing an RBD mutation and D614G in the spike (S) protein and natural epidemic variants to gain insights into the correlation between the mutations in S proteins and the ADE activities and tested whether convalescent plasma and TOP10 neutralizing antibodies in our laboratory mediated the ADE effects of these SARS-CoV-2 variants. We found that one out of 29 convalescent plasma samples caused the ADE effect of pandemic variant B.1.1.7 and that the ADE effect of wild-type SARS-CoV-2 was not detected for any of these plasma samples. Only one antibody, 55A8, from the same batch of convalescent patients mediated the ADE effects of multiple SARS-CoV-2 variants in vitro, including six double-mutant variants and four epidemic variants, suggesting that ADE activities may be closely related to the antibody itself and the SARS-CoV-2 variants' S proteins. Moreover, the ADE activity of 55A8 depended on FcγRII on immune cells, and the introduction of LALA mutations at the Fc end of 55A8 eliminated the ADE effects in vitro, indicating that 55A8LALA may be a clinical drug used to prevent SARS-CoV-2 variants. Altogether, ADE may occur in rare convalescent patients or vaccinees with ADE-active antibodies who are then exposed to a SARS-CoV-2 variant. These data suggested that potential neutralizing antibodies may need to undergo ADE screening tests for SARS-CoV-2 variants, which should aid in the future design of effective antibody-based therapies.

Extended SARS-CoV-2 RBD booster vaccination induces humoral and cellular immune tolerance in mice.

The repetitive applications of vaccine boosters have been brought up in face of continuous emergence of SARS-CoV-2 variants with neutralization escape mutations, but their protective efficacy and potential adverse effects remain largely unknown. Here, we compared the humoral and cellular immune responses of an extended course of recombinant receptor binding domain (RBD) vaccine boosters with those from conventional immunization strategy in a Balb/c mice model. Multiple vaccine boosters after the conventional vaccination course significantly decreased RBD-specific antibody titers and serum neutralizing efficacy against the Delta and Omicron variants, and profoundly impaired CD4+ and CD8+T cell activation and increased PD-1 and LAG-3 expressions in these T cells. Mechanistically, we confirmed that extended vaccination with RBD boosters overturned the protective immune memories by promoting adaptive immune tolerance. Our findings demonstrate potential risks with the continuous use of SARS-CoV-2 vaccine boosters, providing immediate implications for the global COVID-19 vaccination enhancement strategies.

Pamiparib Monotherapy for Patients with Germline BRCA1/2-Mutated Ovarian Cancer Previously Treated with at Least Two Lines of Chemotherapy: A Multicenter, Open-Label, Phase II Study.

PURPOSE: Phase I results of this phase I/II study showed that pamiparib 60 mg twice a day had antitumor activity and an acceptable safety profile in Chinese patients with advanced cancer, including epithelial ovarian cancer. PATIENTS AND METHODS: This open-label phase II study was conducted in China and enrolled adult (≥18 years) patients with platinum-sensitive ovarian cancer (PSOC; disease progression occurring ≥6 months after last platinum treatment) or platinum-resistant ovarian cancer (PROC; disease progression occurring <6 months after last platinum treatment). Eligible patients had known or suspected deleterious germline BRCA mutation (gBRCAmut) and had previously received ≥2 lines of therapy. Pamiparib 60 mg orally twice a day was administered until disease progression, toxicity, or patient withdrawal. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per RECIST version 1.1. RESULTS: In the total patient population (N = 113; PSOC, n = 90; PROC, n = 23), median age was 54 years (range, 34-79) and 25.6% of patients received ≥4 prior systemic chemotherapy lines. Median study follow-up was 12.2 months (range, 0.2-21.5). Eighty-two patients with PSOC and 19 patients with PROC were evaluable for efficacy. In patients with PSOC, 8 achieved a complete response (CR) and 45 achieved a partial response (PR); ORR was 64.6% [95% confidence interval (CI), 53.3-74.9]. In patients with PROC, 6 achieved a PR; ORR was 31.6% (95% CI, 12.6-56.6). Frequently reported grade ≥3 adverse events were hematologic toxicities, including anemia and decreased neutrophil count. CONCLUSIONS: Pamiparib 60 mg twice a day showed antitumor activity with durable responses in patients with PSOC or PROC with gBRCAmut, and had a manageable safety profile.

Synthesis, iron(III)-binding affinity and in vitro evaluation of 3-hydroxypyridin-4-one hexadentate ligands as potential antimicrobial agents.

Iron is a critical element for the survival of bacteria. We have designed and synthesized two novel 3-hydroxypyridin-4-one hexadentate ligands with high affinity for iron(III), which disrupt bacterial iron absorption. Biological studies demonstrate that these two chelators have significant inhibitory effect against both Gram-positive and Gram-negative bacteria, and therefore have potential as antimicrobial agents.

Novel Nano-Precursor Inhibiting Material for Improving Chloride Penetration Resistance of Concrete: Evaluation and Mechanism.

Durability improvement is always important for steel-concrete structures exposed to chloride salt environment. The present research investigated the influence of a novel nano-precursor inhibiting material (NPI), organic carboxylic acid ammonium salt, on the mechanical and transport properties of concrete. The NPI caused a slight reduction in the strength of concrete at later ages. NPI significantly decreased water absorption and slowed down the speed of water absorption of concrete. In addition, the NPI decreased the charge passed and the chloride migration coefficient, and the results of the natural chloride diffusion showed that the NPI decreased the chloride concentration and the chloride diffusion coefficient. The NPI effectively improved the resistance of chloride penetration into testing concrete. The improvement in the impermeability of concrete was ascribed to the incorporation with the NPI, which resulted in increasing the contact angle of cement pastes. The contact angle went up from 17.8° to 85.8° for 0% and 1.2% NPI, respectively, and cement pastes became less hydrophilic. Some small pore throats were unconnected. Besides, the NPI also optimized the pore size distribution of hardened cement paste.

Human Mass Balance and Metabolite Profiling of [14 C]-Pamiparib, a Poly (ADP-Ribose) Polymerase Inhibitor, in Patients With Advanced Cancer.

Pamiparib, a selective poly (ADP-ribose) polymerase 1/2 inhibitor, demonstrated tolerability and antitumor activity in patients with solid tumors at 60 mg orally twice daily. This phase 1 open-label study (NCT03991494; BGB-290-106) investigated the absorption, metabolism, and excretion (AME) of 60 mg [14 C]-pamiparib in 4 patients with solid tumors. The mass balance in excreta, blood, and plasma radioactivity and plasma pamiparib concentration were determined along with metabolite profiles in plasma, urine, and feces. Unchanged pamiparib accounted for the most plasma radioactivity (67.2% ± 10.2%). Pamiparib was rapidly absorbed with a median time to maximum plasma concentration (Cmax ) of 2.00 hours (range, 1.00-3.05 hours). After reaching Cmax , pamiparib declined in a biphasic manner, with a geometric mean terminal half-life (t1/2 ) of 28.7 hours. Mean cumulative [14 C]-pamiparib excretion was 84.7% ± 3.5%. Pamiparib was mainly cleared through metabolism, primarily via N-oxidation and oxidation of the pyrrolidine ring. A dehydrogenated oxidative product (M3) was the most abundant metabolite in biosamples. A mean of 2.11% and 1.11% of [14 C]-pamiparib was excreted as unchanged pamiparib in feces and urine, respectively, indicating near-complete absorption and low renal clearance of parent drug. Cytochrome P450 (CYP) phenotyping demonstrated CYP2C8 and CYP3A involvement in pamiparib metabolism. These findings provide an understanding of pamiparib AME mechanisms and potential drug-drug interaction liability.

The pharmacokinetics of pamiparib in the presence of a strong CYP3A inhibitor (itraconazole) and strong CYP3A inducer (rifampin) in patients with solid tumors: an open-label, parallel-group phase 1 study.

PURPOSE: Pamiparib is an investigational, selective, oral poly(ADP-ribose) polymerase 1/2 (PARP1/2) inhibitor that has demonstrated PARP-DNA complex trapping and CNS penetration in preclinical models, as well as preliminary anti-tumor activity in early-phase clinical studies. We investigated whether the single-dose pharmacokinetic (PK) profile of pamiparib is altered by coadministration of a strong CYP3A inducer (rifampin) or a strong CYP3A inhibitor (itraconazole) in patients with solid tumors. METHODS: In this open-label, phase 1 study, adults with advanced solid tumors received either oral pamiparib 60 mg (days 1 and 10) and once-daily oral rifampin 600 mg (days 3-11) or oral pamiparib 20 mg (days 1 and 7) and once-daily oral itraconazole 200 mg (days 3-8). Primary endpoints included pamiparib maximum observed concentration (Cmax), and area under the plasma concentration-time curve from zero to last quantifiable concentration (AUC0-tlast) and infinity (AUC0-inf). Secondary endpoints included safety and tolerability. RESULTS: Rifampin coadministration did not affect pamiparib Cmax (geometric least-squares [GLS] mean ratio 0.94; 90% confidence interval 0.83-1.06), but reduced its AUC0-tlast (0.62 [0.54-0.70]) and AUC0-inf (0.57 [0.48-0.69]). Itraconazole coadministration did not affect pamiparib Cmax (1.05 [0.95-1.15]), AUC0-tlast (0.99 [0.91-1.09]), or AUC0-inf (0.99 [0.90-1.09]). There were no serious treatment-related adverse events. CONCLUSIONS: Pamiparib plasma exposure was reduced 38-43% with rifampin coadministration but was unaffected by itraconazole coadministration. Pamiparib dose modifications are not considered necessary when coadministered with CYP3A inhibitors. Clinical safety and efficacy data will be used with these results to recommend dose modifications when pamiparib is coadministered with CYP3A inducers.

A Highly Conserved Peptide Vaccine Candidate Activates Both Humoral and Cellular Immunity Against SARS-CoV-2 Variant Strains.

Facing the imminent need for vaccine candidates with cross-protection against globally circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants, we present a conserved antigenic peptide RBD9.1 with both T-cell and B-cell epitopes. RBD9.1 can be recognized by coronavirus disease 2019 (COVID-19) convalescent serum, particularly for those with high neutralizing potency. Immunization with RBD9.1 can successfully induce the production of the receptor-binding domain (RBD)-specific antibodies in Balb/c mice. Importantly, the immunized sera exhibit sustained neutralizing efficacy against multiple dominant SARS-CoV-2 variant strains, including B.1.617.2 that carries a point mutation (SL452R) within the sequence of RBD9.1. Specifically, SY451 and SY454 are identified as the key amino acids for the binding of the induced RBD-specific antibodies to RBD9.1. Furthermore, we have confirmed that the RBD9.1 antigenic peptide can induce a S448-456 (NYNYLYRLF)-specific CD8+ T-cell response. Both RBD9.1-specific B cells and the S448-456-specific T cells can still be activated more than 3 months post the last immunization. This study provides a potential vaccine candidate that can generate long-term protective efficacy over SARS-CoV-2 variants, with the unique functional mechanism of activating both humoral and cellular immunity.