Electrochemical Sulfonylation/Cyclization of N-Alkenylacrylamides with Sodium Sulfinates or Sulfonyl Hydrazides.

Two general protocols for the regioselective electrochemically enabled sulfonylation cyclization of N-alkenylacrylamides with sodium sulfinates or sulfonyl hydrazides were described. These methods were carried out under mild, chemical oxidant-free, and transition-metal-free conditions with a broad substrate scope and good functional group tolerance to provide sulfonyl-containing 4-pyrrolin-2-ones, which is readily scalable to the gram scale.

RGC-32 facilitates pancreatic cancer via activating Wnt/ß-catenin signaling.

Longitudinal studies have indicated the facilitating effect of RGC-32 during diverse disease progression including pancreatic cancer, yet the systematic and detailed effect of RGC-32 during pancreatic cancer is largely unknowable. For this purpose, we took advantage of the pancreatic cancer cell line (BXPC3) with RGC-32 expression and then modulated its expression by lentivirus-mediated knockdown (shRGC-32) and overexpression (pcDNA-RGC-32). To verify the effect of Wnt/ß-catenin signaling in RGC-32-based tumorigenicity, we added the agonist CT99021 to the shRGC-32 BXPC3 cell line and pancreatic cancer mouse model. The deficiency in cellular vitality (cell survival, apoptosis, cell cycle) and migration of BXPC3 were sharply rescued by shRGC-32 in vitro. Notably, the aforementioned phenotypes as well as the expression pattern of EMT-associated biomarkers of BXPC3 with shRGC-32 expression could largely rescued by the agonist of Wnt/ß-catenin in vitro and in vivo. Our data indicated the facilitating effect of RGC-32 upon pancreatic cancer cell line and mouse model via activating the Wnt/ß-catenin signaling, which collectively suggested the feasibility of RGC-32 as a potent diagnostic and therapeutic target of pancreatic cancer in the future.

The Immunosuppressive Roles of PD-L1 during Influenza A Virus Infection.

The clinical benefits of targeting programmed death-ligand 1 (PD-L1) in various cancers represent a strategy for the treatment of immunosuppressive diseases. Here, it was demonstrated that the expression levels of PD-L1 in cells were greatly upregulated in response to H1N1 influenza A virus (IAV) infection. Overexpression of PD-L1 promoted viral replication and downregulated type-I and type-III interferons and interferon-stimulated genes. Moreover, the association between PD-L1 and Src homology region-2, containing protein tyrosine phosphatase (SHP2), during IAV/H1N1 infection was analyzed by employing the SHP2 inhibitor (SHP099), siSHP2, and pNL-SHP2. The results showed that the expressions of PD-L1 mRNA and protein were decreased under SHP099 or siSHP2 treatment, whereas the cells overexpressing SHP2 exhibited the opposite effects. Additionally, the effects of PD-L1 on the expression of p-ERK and p-SHP2 were investigated in PD-L1-overexpressed cells following WSN or PR8 infection, determining that the PD-L1 overexpression led to the decreased expression of p-SHP2 and p-ERK induced by WSN or PR8 infection. Taken together, these data reveal that PD-L1 could play an important role in immunosuppression during IAV/H1N1 infection; thus, it may serve as a promising therapeutic target for development of novel anti-IAV drugs.

Mrz1, a Novel Mitochondrial Outer Membrane RING Finger Protein, is Degraded Through the Ubiquitin-Proteasome Pathway in Schizosaccharomyces pombe.

The RING (Really Interesting New Gene) finger proteins are a large diverse group of Zinc finger proteins. Many determined RING finger proteins are ubiquitin-protein E3 ligases and RING E3s are the most abundant type of ubiquitin ligase. RING finger and RING finger E3s have been discovered in many organisms where they play various functions, including DNA repair, ubiquitination and mitochondrial protein quality control. In this study, we identified a novel mitochondrial protein (SPBC16G5.03) with predicted RING finger domain within an N-terminal 21-60 amino acids and named it Mrz1 (mitochondrial RING finger protein). Our results showed that Mrz1 is localized in the mitochondrial outer membrane. Deletion of mrz1 did not affect cell growth in an unstressed state, but increases sensitivity to selenite. We showed that Mrz1 was degraded during the stationary phase and blocked by addition proteasome inhibitor MG132. We further showed that the E2 enzyme Ubc13 was identified among 8 candidate proteins as the ubiquitin-conjugating enzyme in this system. These data suggested that the Mrz1 was degraded likely through the ubiquitin-proteasome system.

Microwave-Assisted Enzymatic Extraction, Partial Characterization, and Antioxidant Potential of Polysaccharides from Sagittaria trifolia Tuber.

Sagittaria trifolia tuber is an aquatic vegetable. In this work, microwave-assisted enzymatic extraction (MEE) was used to extract S. trifolia tuber polysaccharides (STTPs). Optimum conditions were complex enzyme of 2 %, liquid-to-solid ratio of 43 : 1 mL g-1 , microwave power of 506 W, and time of 8 min, under which STTPs yield was 36.22±0.69 %, higher than those of other methods. STTPs were sulfated polysaccharides with sulfur valence of S6+ . STTPs comprised mannose, glucose, galactose, and arabinose at a mole ratio of 3.69 : 19.33 : 6.21 : 1.00, molecular weights of 3606 kDa and 149.6 kDa, particle size of 220 nm, and zeta potential of -5.02 mV. The surface of STTPs was full of bumps and holes, and abundant in O1s and non-functionalized C1s. STTPs would scavenge reactive oxygen species with advantage. It would provide an efficient MEE method to obtain antioxidant STTPs, also a clue for extracting polysaccharides from starch-rich crops.

Comparison of case-based learning combined with Rain Classroom teaching and traditional method in complete denture course for undergraduate interns.

BACKGROUND: Complete denture, as an important restoration method for edentulism, is difficult to study for beginners, especially in linking the theory with clinical practice. OBJECTIVE: This study was aimed to compare the teaching effects between case-based learning combined with Rain Classroom teaching and traditional lecture method in the clinical course of complete denture prosthesis for undergraduate interns. METHODS: In a course called "Problems and treatment strategies of complete denture after wearing", interns were divided into two groups: one for traditional lecture-based teaching with PowerPoint slideshow (the control group, n = 28); and the other for case-based learning combined with Rain Classroom teaching, which published information before class, discussed specific clinic cases in class and got real-time interns' feedback via WeChat (the test group, n = 22). Both groups received the same exam and questionnaire survey after class. The Q&A participation of interns in class, theoretical test scores and questionnaire survey responses were used to evaluate the teaching effects. An independent sample t-test and the chi-square test or Fisher's exact test were used for statistical analysis in this study. RESULTS: The Q&A participation of interns in the test group was much better than that of the control group. The average score on the theoretical test after class in the test group (72.14 ± 12.24) was significantly higher than that in the control group (61.29 ± 20.12) (P < 0.05). In the test group, 94.54% (21/22) of the interns preferred the new teaching mode. CONCLUSION: Case-based learning combined with Rain Classroom teaching is helpful to enliven the classroom atmosphere, inspire studying enthusiasm, and achieve a good learning effect in both theory and clinical practice related to complete denture prosthesis.

Peptidomic Analysis on Mouse Lung Tissue Reveals AGDP as a Potential Bioactive Peptide against Pseudorabies Virus Infection.

Pseudorabies virus (PRV) infection could cause severe histopathological damage via releasing multiple factors, including cytokines, peptides, etc. Here, peptidomic results showed that 129 peptides were identified in PRV-infected mouse lungs and were highly involved in the process of PRV infection. The role of one down-regulated biological peptide (designated as AGDP) during PRV infection was investigated. To verify the expression profiles of AGDP in response to PRV infection, the expression level of the precursor protein of AGDP mRNA was significantly decreased in PRV-infected mouse lungs and cells. The synthesized AGDP-treating cells were less susceptible to PRV challenges than the controls, as demonstrated by the decreased virus production and gE expression. AGDP not only inhibited the expression of TNF-α and IL-8 but also appeared to suppress the extracellular release of high-mobility group box 1 (HMGB1) by inhibiting the output of nuclear HMGB1 in cells. AGDP could also inhibit the degradation of IκBα and the phosphorylation levels of P65 after PRV infection. In total, our results revealed many meaningful peptides involved in PRV infection, thereby enhancing the current understanding of the host response to PRV infection, and how AGDP may serve as a promising candidate for developing novel anti-PRV drugs.

Eleocharis dulcis corm: phytochemicals, health benefits, processing and food products.

Eleocharis dulcis, an aquatic plant belonging to Cyperaceae family, is indigenous to Asia, and also occurs in tropical Africa and Australia. The edible corm part of E. dulcis is a commonly consumed aquatic vegetable with a planting area of 44.46 × 103 hm2 in China. This work aims to explore the potential of E. dulcis corm for use as a new food source for sufficient nutrients and health benefits by reviewing its nutrients, phytochemicals, functions, processing and food products. Eleocharis dulcis corm contains starches, dietary fibers, non-starch polysaccharides, proteins, amino acids, phenolics, sterols, puchiin, saponins, minerals and vitamins. Among them, phenolics including flavonoids and quinones could be the major bioconstituents that largely contribute to antioxidant, anti-inflammatory, antibacterial, antitumor, hepatoprotective, neuroprotective and hypolipidemic functions. Peel wastes of E. dulcis corm tend to be enriched in phenolics to a much higher extent than the edible pulp. Fresh-cut E. dulcis corm can be consumed as a ready-to-eat food or processed into juice for beverage production, and anti-browning processing is a key to prolonging shelf life. Present food products of E. dulcis corm are centered on various fruit and vegetable beverages, and suffer from single categories and inadequate development. In brief, underutilized E. dulcis corm possesses great potential for use as a new food source for sufficient nutrients and health benefits. © 2021 Society of Chemical Industry.

Sagittaria trifolia tuber: bioconstituents, processing, products, and health benefits.

Sagittaria trifolia is an aquatic plant that is distributed worldwide. The edible tuber part of S. trifolia is a very common and popular vegetable in China. The aim of the present review is to discuss the discovery of nutraceuticals from S. trifolia tuber by reviewing its major constituents, food processing, food products, and health-promoting benefits. Sagittaria trifolia tuber comprises a series of nutritional and bioactive constituents, including dietary fibers, amino acids, minerals, starches, non-starch polysaccharides, diterpenoids, colchicine, phenols, and organic acids. Food processing affects its flavor, biocomponents, and bioactivity. Numerous S. trifolia tuber-based food products and nutraceuticals have been developed, but new categories of products and the anticipated functions still need to be explored. The non-starch polysaccharides could be the central ingredients that contribute to the plant's antioxidant, hepatoprotective, hypoglycemic, lipid-regulating, and immunostimulatory properties. Of these, antioxidant and hepatoprotective effects have been thoroughly investigated. Procedures for the extraction and purification of polysaccharides influence their health-promoting actions. Overall, S. trifolia tuber is an underutilized aquatic vegetable species that is an emerging subject for nutraceutical research. © 2020 Society of Chemical Industry.

A new dynamic culture device suitable for rat skin culture.

Cultured skin has been used extensively for testing therapeutic drugs because it replicates the physical and biochemical properties of whole skin. However, traditional static culture cannot fully maintain cell viability and skin morphology because of the limitations involved with nutrient transmission. Here, we develop a new dynamic perfusion platform for skin culture and compare it with a static culture device. Rat skins were cultured in either static or dynamic condition for 0, 3, 6, 9 and 12 days. H&E, periodic acid-Schiff (PAS) and picrosirius red (PSR) staining were used for skin morphology detection, immunostaining against cytokeratin 10 (CK10) for differentiation detection, immunostaining against proliferating cell nuclear antigen (PCNA) for cell proliferation detection and TUNEL staining for apoptosis detection. After culturing for 12 days, the epidermis, basement membrane, hair follicles and connective tissue were disrupted in the static group, whereas these features were preserved in the dynamic group. Moreover, compared to the static group, proliferation in the epidermis and hair follicles was significantly improved and apoptosis in dermis was significantly decreased in the dynamic group. These findings suggest that our device is effective for extending the culture period of rat skin to maintain its characteristics and viability in vitro.

Role of neuromedin B and its receptor in the innate immune responses against influenza A virus infection in vitro and in vivo.

The peptide neuromedin B (NMB) and its receptor (NMBR) represent a system (NMB/NMBR) of neuromodulation. Here, it was demonstrated that the expression of NMBR in cells or murine lung tissues was clearly upregulated in response to H1N1/PR8 influenza A virus infection. Furthermore, the in vitro and in vivo activities of NMB/NMBR during PR8 infection were investigated. It was observed that A549 cells lacking endogenous NMBR were more susceptible to virus infection than control cells, as evidenced by the increased virus production in the cells. Interestingly, a significant decrease in IFN-α and increased IL-6 expression were observed in these cells. The role of this system in innate immunity against PR8 infection was probed by treating mice with NMB. The NMB-treated mice were less susceptible to virus challenge, as evidenced by increased survival, increased body weight, and decreased viral NP expression compared with the control animals. Additionally, the results showed that exogenous NMB not only enhanced IFN-α expression but also appeared to inhibit the expression of NP and IL-6 in PR8-infected cells and animals. As expected, opposing effects were observed in the NMBR antagonist-treated cells and mice, which further confirmed the effects of NMB. Together, these data suggest that NMB/NMBR may be an important component of the host defence against influenza A virus infection. Thus, these proteins may serve as promising candidates for the development of novel antiviral drugs.

SCF/c-kit signaling is required in 12-O-tetradecanoylphorbol-13-acetate-induced migration and differentiation of hair follicle melanocytes for epidermal pigmentation.

Hair follicle melanocyte stem cells (McSCs) are responsible for hair pigmentation and also function as a major melanocyte reservoir for epidermal pigmentation. However, the molecular mechanism promoting McSCs for epidermal pigmentation remains elusive. 12-O-tetradecanoylphorbol-13-acetate (TPA) mimics key signaling involved in melanocyte growth, migration and differentiation. We therefore investigated the molecular basis for the contribution of hair follicle McSCs to epidermal pigmentation using the TPA induction model. We found that repetitive TPA treatment of female C57BL/6 mouse dorsal skin induced epidermal pigmentation by increasing the number of epidermal melanocytes. Particularly, TPA treatment induced McSCs to initiate proliferation, exit the stem cell niche and differentiate. We also demonstrated that TPA promotes melanoblast migration and differentiation in vitro. At the molecular level, TPA treatment induced robust expression of stem cell factor (SCF) in keratinocytes and c-kit in melanoblasts and melanocytes. Administration of ACK2, a neutralizing antibody against the Kit receptor, suppressed mouse epidermal pigmentation, decreased the number of epidermal melanocytes, and inhibited melanoblast migration. Taken together, our data demonstrate that TPA promotes the expansion, migration and differentiation of hair follicle McSCs for mouse epidermal pigmentation. SCF/c-kit signaling was required for TPA-induced migration and differentiation of hair follicle melanocytes. Our findings may provide an excellent model to investigate the signaling mechanisms regulating epidermal pigmentation from mouse hair follicle McSCs, and a potential therapeutic option for skin pigmentation disorders.

EphB4 inhibitor overcome the acquired resistance to cisplatin in melanomas xenograft model.

The purpose of this paper is to investigate the possible mechanisms of resistance to chemotherapy in melanoma from the perspective of molecular biology and to discuss the strategies to overcome them. Cisplatin, a DNA-damaging compound that triggers apoptotic cell death, is commonly used in the treatment of malignant melanoma. However, most patients develop mechanisms of acquired resistance and about 25% of them do not achieve tumor regression at all, due to intrinsic resistance to therapy. In the current study, we reported the tumor xenografts of the human A375 melanoma, after 40-weeks' consecutive therapy with cisplatin that developed resistance as a result of EphB4 overexpression. Moreover, the expression of phospho-AKT and phospho-ERK were significantly increased in cisplatin-resistant tumors. In addition, combined of cisplatin with EphB4 selective inhibitor could abrogate this acquired mechanism of drug resistance due to an enhanced apoptotic effect in cisplatin-resistant xenografts. In summary, these results help to understand the mechanisms of acquired resistance to chemotherapy and provide important information for clinical treatment strategies.

Quantitative assessment of the association between XPC Lys939Gln polymorphism and cutaneous melanoma risk.

Previous studies evaluating the association between XPC Lys939Gln polymorphism and cutaneous melanoma risk reported conflicting findings. We searched PubMed and Embase databases up to May 16, 2013 to identify eligible studies on the association between XPC Lys939Gln polymorphism and cutaneous melanoma risk. Finally, a total of seven case-control studies including 3,971 cases of cutaneous melanoma and 5,873 controls were included in the meta-analysis. Statistical analysis was performed with STATA version 11.0. Odds ratios (ORs) with 95 % confidence intervals (95 % CIs) were used to assess the strength of the association. Overall, there was no association between XPC Lys939Gln polymorphism and cutaneous melanoma risk under all five genetic models (Gln vs. Lys: OR = 1.11, 95 % CI = 0.98-1.26, P = 0.10; GlnGln vs. LysLys: OR = 1.26, 95 % CI = 0.98-1.61, P = 0.07; LysGln vs. LysLys: OR = 1.04, 95 % CI = 0.88-1.22, P = 0.64; GlnGln/LysGln vs. LysLys: OR = 1.10, 95 % CI = 0.92-1.31, P = 0.29; GlnGln vs. LysLys/LysGln: OR = 1.19, 95 % CI = 0.99-1.43, P = 0.06). Subgroup analysis in Caucasians showed that there was an obvious association between XPC Lys939Gln polymorphism and cutaneous melanoma risk in Caucasians (GlnGln vs. LysLys/LysGln: OR = 1.12, 95 % CI = 1.00-1.25, P = 0.05). Sensitivity analysis by omitting one study in turns showed that the significance of the pooled ORs was not stable. In addition, there was some evidence of publication bias in the meta-analysis, and meta-analyses of the studies with large sample size did not find the obvious association between XPC Lys939Gln polymorphism and cutaneous melanoma risk in Caucasians. Therefore, there is little evidence for the association between XPC Lys939Gln polymorphism and cutaneous melanoma risk.

Research on tumorigenicity of cinnamaldehyde in melanoma cell lines and its mechanism.

Melanoma is a highly malignant tumor originating from melanocytes. This disease is characterized by inconspicuous onset, high malignancy, and poor prognosis. The aim of this study is to explore the effect of cinnamaldehyde on melanoma tumorigenicity and its mechanism. Melanoma cells were subcutaneously injected into a nude mouse to establish the tumour model. A comparison was made for the difference in formation and growth of melanoma cell tumor between normal saline and cinnamaldehyde. A comparison was also made for the number of new vessels between the normal saline group (the control group) and the cinnamaldehyde group (the experimental group) through immumohistochemical staining. The western blot was used to detect the difference in expression levels of vascularization related proteins. The results indicated that the volume of tumors formed and the number of new vessels in melanoma cells of the cinnamaldehyde group decreased significantly compared with those in the cells of the normal saline group. A further study indicated that the expression of hypoxia-inducible factor-a (HIF-α) and vascular endothelial growth factor (VEGF) in the melanoma of the cinnamaldehyde group decreased significantly. In conclusion, cinnamaldehyde plays a certain role in inhibiting the occurrence and progression of melanoma and its action mechanism may be manifested by inhibiting expression of VEGF and HIF-α, thus blood vessel simulation and formation of new blood vessels of melanoma cells, and growth of tumors accordingly.

Anti-tumor effect of polysaccharides from Scutellaria barbata D. Don on the 95-D xenograft model via inhibition of the C-met pathway.

Polysaccharides isolated from Scutellaria barbata (PSB) have been reported to have anti-tumor effects. To investigate the underlying mechanism, a highly invasive, metastatic and phospho-c-Met overexpression lung carcinoma cell, 95-D cell line was used. The results showed that in vitro, PSB not only could inhibit the proliferation of 95-D cell line (IC(50) = 35.2 µg/mL), but also down-regulated the expression of phospho-c-Met and its downstream signaling molecules including phospho-Erk and phospho-Akt. In vivo, PSB inhibited tumor growth in the 95-D subcutaneous xenograft model in a dose-dependent manner; after once-daily intraperitoneal injection for 3 weeks, tumor growth inhibition T/C ratio for 100 and 200 mg/kg treatments was 42.72% and 13.6%, respectively. In the end of the in vivo study, tumor tissues were harvested for further evaluation of the phosphorylation level of c-Met, AKT, and ERK. Ex vivo results demonstrated that the phosphorylation of c-Met and its downstream signaling molecules were also significantly inhibited by PSB. Immunohistochemistry analysis showed dose-dependent inhibition of tumor cell proliferation (Ki67) and reduction of microvessel density (CD31). In summary, the results indicated that PSB exerted anti-tumor growth activity on human lung cancer 95-D in vitro and in vivo by directly regulating the c-Met signaling pathway and the anti-tumor effects were mainly based on its anti-proliferation and anti-angiogenesis action.

Meta-analysis of changes in thiol-disulfide homeostasis during preeclampsia.

The present study systematically assessed alterations in thiol-disulfide homeostasis among women with preeclampsia (PE) through meta-analysis. This was conducted as such changes are believed to be associated with the oxidative stress underlying this condition. A comprehensive search of Medline, Web of Science, and Embase databases was conducted from their inception until 22 March 2023, to identify studies comparing levels of native thiol, total thiol, and disulfide between pregnant women with PE and those without PE. Results were pooled using a random-effects model to account for study heterogeneity. The analysis included a total of 631 women diagnosed with PE and 668 healthy pregnant women, encompassing 13 case-control studies and 1 prospective study. Pooled outcomes revealed that women with PE had significantly lower blood levels of native thiol, (mean difference [MD] -51.42 umol/L; 95% confidence interval [CI] -79.75 to -23.10 umol/L; P < 0.001; I2 = 0% and total thiol (MD -65.56 umol/L; 95% CI -104.97 to -26.15 umol/L; P = 0.001; I2 = 0%) compared to the control group. In contrast, no significant difference was observed in blood disulfide levels between the two groups (MD -1.10 umol/L; 95% CI -4.41 to -2.21 umol/L; P = 0.51; I2 = 0%). Subgroup analyses indicated that the results were consistent across studies matched by gestational age and body mass index, as well as those with varying quality scores (P for subgroup differences all > 0.05). In conclusion, women with PE are associated with significantly reduced blood levels of native and total thiols but show no change in blood disulfide levels, suggesting a state of reduced antioxidants in PE.

Polysaccharides from waste Zingiber mioga leaves: Ultrasonic-microwave-assisted extraction, characterization, antioxidant and anticoagulant potentials.

Zingiber mioga is a highly economic crop that is used to produce vegetables, spices and herbal pharmaceuticals. Its edible flower bud contributes most to the economic value, but the big leaves were discarded as agricultural waste, which urgently needs to be exploited. In this work, polysaccharides from waste Z. mioga leaves (PWZMLs) were extracted using ultrasonic-microwave-assisted extraction (UMAE). After purification and characterization, the antioxidation and anticoagulation of PWZMLs were evaluated to appraise the potential in cardiovascular protection. Under the liquid-solid ratio of 26: 1 mL/g, after ultrasonication at 495 W for 10 min, followed by microwaving at 490 W for 5 min, the yield of PWZMLs achieved to 6.22 ± 0.14 %, notably higher (P < 0.01) than other methods, and ultrasound contributed more to the yield than microwave. Various analyses confirmed that PWZMLs were negatively charged polysaccharides with galacturonic acid the dominant uronic acid. PWZMLs exerted excellent antioxidant capacity, especially for scavenging 1, 1-diphenyl-2-picrylhydrazyl radical. PWZMLs also elicited promising anticoagulant property, particularly for prolonging activated partial thromboplastin time and lowering fibrinogen, which were almost equivalent to heparin at the same concentration. PWZMLs contained two polysaccharide fractions (199.53 and 275.42 kDa) that could synergistically contribute to the pronounced antioxidant and anticoagulant activities. The PWZMLs extracted with optimized UMAE have great potential in cardiovascular protection.

5-ALA-PDT induced ferroptosis in keloid fibroblasts via ROS, accompanied by downregulation of xCT, GPX4.

Keloids display many cancerous properties, including uncontrolled and invasive growth, high rates of recurrence as well as similar bioenergetics. 5-aminolevulinic acid-based photodynamic therapy (5-ALA-PDT) is an effective treatment that performs cytotoxic effects by producing reactive oxygen species (ROS), which is linked to lipid peroxidation and ferroptosis. Herein, we explored underlying mechanisms of 5-ALA-PDT against keloids. We identified that 5-ALA-PDT led to elevated levels of ROS and lipid peroxidation in keloid fibroblasts, accompanied by downregulation of xCT and GPX4, which are associated with anti-oxidation effects and ferroptosis inhibition. These results may indicate that 5-ALA-PDT treatment increases ROS while inhibiting xCT and GPX4, thus promoting lipid peroxidation to induce ferroptosis in keloid fibroblasts.

First-in-human phase I/Ib study of QL1706 (PSB205), a bifunctional PD1/CTLA4 dual blocker, in patients with advanced solid tumors.

BACKGROUND: QL1706 (PSB205) is a single bifunctional MabPair (a novel technical platform) product consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1), with a shorter elimination half-life (t1/2) for CTLA-4. We report results from a phase I/Ib study of QL1706 in patients with advanced solid tumors who failed standard therapies. METHODS: In the phase I study, QL1706 was administered intravenously once every 3 weeks at one of five doses ranging from 0.3 to 10 mg/kg, and the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of QL1706 were investigated. In the phase Ib study, QL1706 was administered at the RP2D intravenously every 3 weeks, and the preliminary efficacies in non-small cell lung cancer (NSCLC), nasopharyngeal carcinoma (NPC), cervical cancer (CC), and other solid tumors were evaluated. RESULTS: Between March 2020 and July 2021, 518 patients with advanced solid tumors were enrolled (phase I, n = 99; phase Ib, n = 419). For all patients, the three most common treatment-related adverse events (TRAEs) were rash (19.7%), hypothyroidism (13.5%), and pruritus (13.3%). The TRAEs and immune-related adverse events (irAEs) of grade ≥ 3 occurred in 16.0% and 8.1% of patients, respectively. In phase I, 2 of 6 patients in the 10mg/kg group experienced dose-limiting toxicities (DLTs) (grade 3 thrombocytopenia and grade 4 immune-mediated nephritis), so the maximum tolerated dose (MTD) was reached at 10 mg/kg. The RP2D was determined to be 5 mg/kg based on comprehensive analysis of tolerability, PK/PD, and efficacy. For all patients who received QL1706 at the RP2D, the objective response rate (ORR) and median duration of response were 16.9% (79/468) and 11.7 months (8.3-not reached [NR]), respectively; and the ORRs were 14.0% (17/121) in NSCLC, 24.5% (27/110) in NPC, 27.3% (15/55) in CC, 7.4% (2/27) in colorectal cancer, 23.1% (6/26) in small cell lung cancer. For immunotherapy-naive patients, QL1706 exhibited promising antitumor activities, especially in NSCLC, NPC, and CC, with ORRs of 24.2%, 38.7%, and 28.3%, respectively. CONCLUSIONS: QL1706 was well tolerated and demonstrated promising antitumor activity in solid tumors, especially in NSCLC, NPC, and CC patients. It is currently being evaluated in randomized phase II (NCT05576272, NCT05179317) and phase III (NCT05446883, NCT05487391) trials. Trial Registration ClinicalTrials.gov Identifier: NCT04296994 and NCT05171790.