IMPORTANCE: Programmed cell death ligand 1 inhibitors combined with chemotherapy has changed the approach to first-line treatment in patients with extensive-stage small cell lung cancer (SCLC). It ...remained unknown whether adding a programmed cell death 1 (PD-1) inhibitor to chemotherapy provided similar or better benefits in patients with extensive-stage SCLC, which would add evidence on the efficacy of checkpoint inhibitors in the treatment of extensive-stage SCLC. OBJECTIVE: To evaluate the efficacy and adverse event profile of the PD-1 inhibitor serplulimab plus chemotherapy compared with placebo plus chemotherapy as first-line treatment in patients with extensive-stage SCLC. DESIGN, SETTING, AND PARTICIPANTS: This international, double-blind, phase 3 randomized clinical trial (ASTRUM-005) enrolled patients at 114 hospital sites in 6 countries between September 12, 2019, and April 27, 2021. Of 894 patients who were screened, 585 with extensive-stage SCLC who had not previously received systemic therapy were randomized. Patients were followed up through October 22, 2021. INTERVENTIONS: Patients were randomized 2:1 to receive either 4.5 mg/kg of serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 12 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival (prespecified significance threshold at the interim analysis, 2-sided P < .012). There were 13 secondary outcomes, including progression-free survival and adverse events. RESULTS: Among the 585 patients who were randomized (mean age, 61.1 SD, 8.67 years; 104 17.8% women), 246 (42.1%) completed the trial and 465 (79.5%) discontinued study treatment. All patients received study treatment and were included in the primary analyses. As of the data cutoff (October 22, 2021) for this interim analysis, the median duration of follow-up was 12.3 months (range, 0.2-24.8 months). The median overall survival was significantly longer in the serplulimab group (15.4 months 95% CI, 13.3 months-not evaluable) than in the placebo group (10.9 months 95% CI, 10.0-14.3 months) (hazard ratio, 0.63 95% CI, 0.49-0.82; P < .001). The median progression-free survival (assessed by an independent radiology review committee) also was longer in the serplulimab group (5.7 months 95% CI, 5.5-6.9 months) than in the placebo group (4.3 months 95% CI, 4.2-4.5 months) (hazard ratio, 0.48 95% CI, 0.38-0.59). Treatment-related adverse events that were grade 3 or higher occurred in 129 patients (33.2%) in the serplulimab group and in 54 patients (27.6%) in the placebo group. CONCLUSIONS AND RELEVANCE: Among patients with previously untreated extensive-stage SCLC, serplulimab plus chemotherapy significantly improved overall survival compared with chemotherapy alone, supporting the use of serplulimab plus chemotherapy as the first-line treatment for this patient population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04063163
Mg–Y alloys show distinctly different slip/twinning activity under quasi-static monotonic loading at room temperature compared with pure Mg, as extensively reported. In this work, the influences of ...3% Y addition on the deformation modes and transferability during strain-controlled tension-compression low-cycle fatigue (LCF) at room temperature of Mg sheets were studied quantitatively and statistically. The activity of various slip systems and twinning-detwinning were measured at desired fatigue stages via quasi-in-situ EBSD observations together with slip trace analysis. The results indicate that the activation of deformation modes in pure Mg was featured by the cyclic transition, i.e., tension twinning (at the compressive reversal) → detwinning + basal slip (at the tensile reversal). In Mg–3Y alloy, basal slip dominated the cyclic deformation throughout the fatigue life span. Compared with pure Mg, Mg–3Y alloy displayed the enhanced activity of various slip systems, including basal, prismatic, and pyramidal slip systems, but lower twinning-detwinning activity. For deformation transferability, mk, which is the product of the Schmid factor (SF) and the geometric compatibility factor (m’) values of the adjacent grains, was used to evaluate the slip transferability and twinning transferability at grain boundaries. Mg–3Y alloy showed a higher likelihood of slip transfer but lower twinning transferability than pure Mg. The underlying mechanisms affecting the activity of various slip systems and twinning, as well as deformation transferability and mechanical behavior, were discussed.
Pilot and industrial scale tests for the preparation of permeable bricks were carried out in a refractory plant. The permeable bricks were firstly prepared using 82 wt% ceramic waste large aggregate ...by pilot test. The permeability, flexural strength and apparent porosity of the obtained permeable bricks can reach 3.2×10−2 cm/s, 6.8 MPa and 28%, respectively, and the relationships between these properties were studied. Moreover, industrial scale test was performed based on the best conditions of the pilot test, and 100 permeable bricks having a size of 140 mm × 280 mm × 80 mm were successfully produced using 600 kg of raw materials. The produced permeable brick has a high permeability of 3.0×10−2 cm/s, flexural strength of 6.3 MPa, as well as a relatively high apparent porosity of 26%, which exceed Chinese national standard GB/T 25993-2010. It has been found that a large number of through holes are homogeneously distributed within the permeable brick, which ensures the high permeability. Meanwhile, the binders make the aggregates interconnect with each other, guaranteeing sufficient mechanical strength. In addition, the energy consumption for whole producing process of permeable bricks is relatively low, about 1.4 MJ/kg. Hence, it is completely feasible to achieve industrial production of permeable bricks with good performance by using solid waste, which not only contributes to the construction of the sponge city, but also meets the requirements of cleaner production and brings obvious ecological and economic benefits.
The excessive colonization of Propionibacterium acnes (P. acnes) is responsible for the genesis of acne vulgaris, a common inflammatory disease of skin. However, the conventional anti-acne therapies ...are always limited by various side effects, drug resistance, and poor skin permeability. Microneedles (MNs) are emerging topical drug delivery systems capable of noninvasively breaking through the skin stratum corneum barrier to efficiently enhance the transdermal drug penetration. Herein, MNs loaded with intelligent pH-sensitive nanoplatforms were constructed for amplified chemo-photodynamic therapy against acne vulgaris, jointly exerting antimicrobial and anti-inflammatory effects. The photosensitizer indocyanine green (ICG) was loaded into the zeolitic imidazolate framework-8 (ZIF-8) to improve its photostability, which would be triggered by 808 nm laser irradiation to generate cytotoxic reactive oxygen species (ROS) to result in oxidative damage and disturbed metabolic activities of P. acnes. In addition to the efficient drug delivery, the ZIF-8 carrier could selectively degrade in response to the acidic microenvironment of acne lesions, and the released Zn2+ also exhibited a potent antimicrobial activity. The fabricated ZIF-8-ICG@MNs presented an outstanding synergistic anti-acne efficiency both in vitro and in vivo. This bioresponsive microneedle patch is expected to be readily adapted as a generalized, modular strategy for noninvasive therapeutics delivery against superficial skin diseases.
This study explores the effect of adding 3 wt.% Y to pure magnesium (Mg) on its mechanical behavior under cyclic torsional loadings at room temperature. The research examines deformation and cracking ...modes in both pure Mg and Mg‐3Y samples. Deformation modes are monitored using quasi‐in‐situ EBSD observations coupled with slip trace analysis. The findings reveal that basal slip dominates the cyclic deformation throughout the fatigue life of the pure Mg sample, while both basal and pyramidal slip dominate the cyclic deformation in the Mg‐3Y sample. Intergranular cracking is the primary cracking mode for both samples under cyclic torsional loadings. Basal and pyramidal slip persistent slip band (PSB) cracking serves as a primary transgranular cracking mode in the pure Mg and Mg‐3Y samples, respectively. The study also investigates the underlying mechanism governing the activity of various deformation modes, cracking modes, and mechanical behavior.
Highlights
Under cyclic torsional loadings, the Mg‐3Y sample exhibited enhanced activity of nonbasal slip.
Intergranular cracking was a dominant cracking mode for the pure Mg and Mg‐3Y samples under cyclic torsional loadings.
Basal slip and pyramidal slip PSB cracking was a primary transgranular cracking mode in the pure Mg sample and Mg‐3Y sample, respectively.
The increased activity of nonbasal slip in the Mg‐3Y sample is possibly responsible for its longer fatigue life.
Abstract In this study, composites of High-density polyethylene (HDPE) / Thermoplastic polyurethane (TPU)/Calcium Sulfate Whiskers (CSW) with varying mass fractions were created by using a melt ...blending process. The aim was to analyze how the addition of CSW to the composites impacted their mechanical and thermal properties as well as the interplay between the substrates. The findings demonstrate that the inclusion of CSW whiskers in HDPE/TPU composites led to a significant enhancement in their mechanical and thermal properties. Furthermore, a robust interfacial adhesion was observed between CSW whiskers and the HDPE/TPU matrix polymer.
8100 Background: ASTRUM-005 is a randomized, double-blind, phase 3 trial comparing efficacy and safety of serplulimab (a novel anti-PD-1 antibody) plus chemotherapy (chemo) vs. placebo plus chemo as ...first-line therapy for extensive-stage small-cell lung cancer (ES-SCLC). Interim analysis presented at 2022 ASCO Annual Meeting showed significantly prolonged overall survival (OS) in the serplulimab arm. Continuing improvements were seen in all efficacy endpoints in an updated analysis reported at ESMO Asia Congress 2022. Here we present the updated results with an extended follow-up duration of 31.6 months and the previously undisclosed patient-reported outcomes (PROs). Methods: 585 patients with ES-SCLC who had not received prior systemic therapy were randomized 2:1 (serplulimab arm, n = 389; placebo arm, n = 196) to receive serplulimab 4.5 mg/kg or placebo intravenously every 3 weeks. All patients received up to 4 cycles of intravenous carboplatin and etoposide every 3 weeks. Stratification factors were PD-L1 expression level, brain metastases, and age. The primary endpoint was OS. PROs were assessed using EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L questionnaires. Results: By the data cutoff of June 13, 2023, 267 (68.6%) patients in the serplulimab arm and 160 (81.6%) in the placebo arm had died. Median OS was markedly longer in the serplulimab arm than that in the placebo arm (15.8 vs.11.1 months; stratified HR 0.61, 95% CI 0.50–0.74). Subgroup analysis by race showed similar trends of a prolonged median OS in Asians (unstratified HR 0.61, 95% CI 0.48–0.77) and non-Asians (all were White; unstratified HR 0.57, 95% CI 0.39–0.83). Estimated OS rate at 3 years was 24.6% (95% CI 19.5–30.1) and 9.8% (95% CI 5.6–15.4) in the respective arms. By-visit longitudinal changes in all domains of the 3 questionnaires were comparable between arms. Least square mean (LSM) changes from baseline to week 18 in QLQ-C30 functional and symptom domains, QLQ-LC13 symptom domains, and EQ-5D-5L VAS were similar and generally improved in both arms, with more pronounced and persistent amelioration in “pain in other parts” symptom domain for the serplulimab arm (difference in LSM change, −6.37 95% CI −11.59 to −1.15, p = 0.0170). Time to deterioration was similar between arms: median, not reached (NR) vs. NR for global health status/quality of life (HR 0.90, 95% CI 0.59–1.39), physical functioning (HR 1.01, 95% CI 0.61–1.65), and role functioning (HR 1.17, 95% CI 0.74–1.87). Conclusions: With extended follow-up, the survival benefits brought by the addition of serplulimab were maintained in the first-line therapy of ES-SCLC. PROs were not adversely impacted, and pain in other parts was significantly improved. All these results support serplulimab plus chemo as a promising first-line treatment option for ES-SCLC. Clinical trial information: NCT04063163 .
Despite vaccination having the potency to revolutionize disease treatments, some critical issues including lack of safe and effective delivery system, insufficient internalization and ineffective ...antigen cross-presentation by dendritic cells (DCs) severely hamper its extensive clinical applications. Herein, we developed a whole cell-encapsulated antitumor vaccine microneedle patch (TCV-DMNs) potentiated with transdermal co-delivery of granulocyte-macrophage colony-stimulating factor (GM-CSF) and autophagy promoter (Tat-beclin 1). After transdermal vaccination with TCV-DMNs, GM-CSF released from DMNs serves as a potent adjuvant to recruit and promote the phagocytosis of antigens by DCs. Subsequently, Tat-beclin 1 promoted DCs maturation and MHC-I-mediated cross-presentation via up-regulated autophagy of DCs. We found that vaccination with TCV-DMNs could not only effectively suppress melanoma challenge, but also lead to regression of established malignancies, followed by a relapse-free survival of >40 days. Collectively, whole cell-encapsulated microneedle-assisted transdermal vaccination TCV-DMNs in combination with autophagy regulation could induce a robust antitumor immune response via enhancing transdermal delivery efficiency, promoting antigen internalization and cross-presentation, together with boosting T cell activities.
Whole cell-encapsulated microneedle-assisted transdermal vaccination TCV-DMNs in combination with autophagy regulation could induce a robust antitumor immune response via enhancing transdermal delivery efficiency, promoting antigen internalization and cross-presentation. Display omitted
•Construction of whole cell-encapsulated antitumor vaccine microneedle patch.•Upregulating autophagy promotes tumor antigen internalization.•Upregulating autophagy promotes antigen cross-presentation of dendritic cells.•Autophagy combined with tumor cell vaccines induces a strong immune response.
The rapid release of poorly water-soluble drugs from amorphous solid dispersion (ASD) is often associated with the generation of supersaturated solution, which provides a strong driving force for ...precipitation and results in reduced absorption. Precipitation inhibitors, such as polymers and surfactants, are usually used to stabilize the supersaturated solution by blocking the way of kinetic or thermodynamic crystal growth. To evaluate the combined effect of polymers and surfactants on maintaining the supersaturated state of itraconazole (ITZ), various surfactants were integrated with enteric polymer hydroxypropyl methylcellulose acetate succinate (HPMC AS) to develop polymer⁻surfactant based solid dispersion. The supersaturation stability was investigated by in vitro supersaturation dissolution test and nucleation induction time measurement. Compared to the ASD prepared with HPMC AS alone, the addition of d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) exhibited a synergistic effect on precipitation inhibition. The results indicated that the TPGS not only significantly reduced the degree of supersaturation which is the driving force for precipitation, but also provided steric hindrance to delay crystal growth by absorbing onto the surface of small particles. Subsequently, the formulations were evaluated in vivo in beagle dogs. Compared with commercial product Sporanox
, the formulation prepared with HPMC AS/TPGS exhibited a 1.8-fold increase in the AUC (0⁻24 h) of ITZ and a 1.43-fold increase of hydroxyitraconazole (OH-ITZ) in the plasma. Similarly, the extent of absorption was increased by more than 40% when compared to the formulation prepared with HPMC AS alone. The results of this study demonstrated that the ASD based on polymer⁻surfactant system could obviously inhibit drug precipitation in vitro and in vivo, which provides a new access for the development of ASD for poorly water-soluble drug.
Immunogenic cell death (ICD) is associated with the release of damage-associated molecular patterns, including ATP, to promote an effective immune cycle against tumors. However, tumors have evolved ...an effective strategy for degrading extracellular immunostimulatory ATP via the ATP-adenosine axis, allowing the sequential action of the ectonucleotidases CD39 to degrade accumulated immunostimulatory ATP into pleiotropic immunosuppressive adenosine. Here, an ingenious dissolving microneedle patch (DMNs) is designed for the intralesional delivery of CD39 inhibitor (sodium polyoxotungstate, POM-1) and ICD inducer (IR780) co-encapsulated solid lipid nanoparticles (P/I SLNs) for antitumor therapy. Upon insertion into the tumor site, IR780 induces ICD modalities with the release of damage-associated molecular patterns from endogenous tissues, which activates the antitumor immune cycle. Simultaneously, POM-1 promotes the liberation of immunostimulatory ATP and lowers the level of immunosuppressive extracellular adenosine, which supported immune control of tumors via recruiting CD39-expressing immune cells. In vivo antitumor studies prove that this platform can effectively eliminate mice melanoma (tumor growth inhibitory rate of 96.5%) and colorectal adenocarcinoma (tumor growth inhibitory rate of 93.5%). Our results shed light on the immunological aspects of combinatorial phototherapy and ATP-adenosine regulation, which will broaden the scope of synergistic antitumor immunotherapy.
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•CD39 blockade was utilized to strengthen the effect of photoimmunotherapy by regulating the ATP-adenosine axis.•An ingenious dissolving microneedle patch was designed for the intralesional delivery of CD39 blockade and immunogenic cell death inducer co-encapsulated solid lipid nanoparticles.•This system aroused a robust immune response against B16 and MC38 tumors via suppressing the CD39 expression on the surface of relevant immune cells and subsequently inducing DCs maturation, boosting antigen-specific lymphocytes infiltration, and reversing macrophages polarization.
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