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BACKGROUND: This randomized, parallel-controlled, double-blinded, phase III equivalence study evaluated the equivalence of a proposed pertuzumab biosimilar QL1209 to the pertuzumab (Perjeta®) each with trastuzumab and docetaxel in neoadjuvant treatment of early or locally advanced breast cancer patients with HER2-positive, ER/PR-negative. METHODS: Eligible patients were randomly (1:1) assigned to receive 4 cycles of neoadjuvant QL1209 or pertuzumab each with trastuzumab and docetaxel, and adjuvant treatment. The primary endpoint was total pathologic complete response (tpCR), with equivalence margins of 0.76 to 1.32. RESULTS: Among the 585 patients enrolled, 257 and 259 patients were assigned to the QL1209 and pertuzumab groups, respectively. The tpCR rates were comparable in the QL1209 (109/255, 42.75%; 90% CI 37.65 to 47.84) and pertuzumab (117/259, 45.17%; 90% CI 40.09 to 50.26) groups. The tpCR risk ratio was 0.95 (90% CI, 0.80 to 1.11), and the 90% CI fell within the predefined equivalence margin. The most common grade ≥3 treatment-related adverse event was decreased neutrophil count (10. 9% vs. 12.7%) in the QL1209 and pertuzumab groups. CONCLUSIONS: QL1209 demonstrated equivalent efficacy and comparable safety profile to the reference pertuzumab in neoadjuvant treatment of HER2-positive, ER/PR-negative, early, or locally advanced breast cancer. TRIAL REGISTRATION: Chinadrugtrials.org CTR20201073; ClinicalTrials.gov NCT04629846.
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OBJECTIVE: QL1604 is a highly selective, humanized monoclonal antibody against programmed death protein 1. We assessed the efficacy and safety of QL1604 plus chemotherapy as first-line treatment in patients with advanced cervical cancer. METHODS: This was a multicenter, open-label, single-arm, phase II study. Patients with advanced cervical cancer and not previously treated with systemic chemotherapy were enrolled to receive QL1604 plus paclitaxel and cisplatin/carboplatin on day 1 of each 21-day cycle for up to 6 cycles, followed by QL1604 maintenance treatment. RESULTS: Forty-six patients were enrolled and the median follow-up duration was 16.5 months. An 84.8% of patients had recurrent disease and 13.0% had stage IVB disease. The objective response rate (ORR) per Response Evaluation Criteria in Advanced Solid Tumors (RECIST) v1.1 was 58.7% (27/46). The immune ORR per immune RECIST was 60.9% (28/46). The median duration of response was 9.6 months (95% confidence interval [CI]=5.5-not estimable). The median progression-free survival was 8.1 months (95% CI=5.7-14.0). Forty-five (97.8%) patients experienced treatment-related adverse events (TRAEs). The most common grade≥3 TRAEs (>30%) were neutrophil count decrease (50.0%), anemia (32.6%), and white blood cell count decrease (30.4%). CONCLUSION: QL1604 plus paclitaxel-cisplatin/carboplatin showed promising antitumor activity and manageable safety profile as first-line treatment in patients with advanced cervical cancer. Programmed cell death protein 1 inhibitor plus chemotherapy may be a potential treatment option for the patient population who have contraindications or can't tolerate bevacizumab, which needs to be further verified in phase III confirmatory study. Trial RegistrationClinicalTrials.gov Identifier: NCT04864782.
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BACKGROUND: Adolescent nicotine and tobacco product use remains common despite declining smoking rates in the United States, likely due to the emergence of novel products. Concurrent use of multiple products may increase the risk of nicotine dependency and subsequent substance use. AIM: To identify patterns and trends of dual and poly nicotine and tobacco use among adolescents in the US and explore associations of dual and poly nicotine and tobacco use with sociodemographic factors. METHODS: 12 years of annual National Youth Tobacco Survey data (2011-2022) from 242,637 respondents were used to examine prevalence trends of different combinations of nicotine or tobacco product use among adolescents in the US using weighted point estimates for each year. Poisson regression models examined sociodemographic factors associated with different patterns of dual and poly-product use from 2011 to 2022. RESULTS: Overall, the prevalence of dual (i.e. at least two products) and poly (i.e. at least three products) use decreased between 2011 and 2021 (from 9.5 % to 2.8 % and from 5.1 % to 1.1 %, respectively), but showed signs of increase between 2021 and 2022 (3.7 % for dual and 1.7 % for poly use). The most common combinations included a combustible product with either a novel or noncombustible product. The risk for dual and poly-product use was higher among non-Hispanic Whites, males, and high school students. CONCLUSIONS: Previously declining trends in the prevalence of tobacco/nicotine dual and poly use may have been reversed. Close monitoring and targeted tobacco control policies are essential to tackle multiple product use among adolescents.
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Sistemas Eletrônicos de Liberação de Nicotina , Produtos do Tabaco , Tabagismo , Masculino , Adolescente , Humanos , Estados Unidos/epidemiologia , Nicotina , Uso de Tabaco/epidemiologia , Fumar/epidemiologia , Tabagismo/epidemiologiaRESUMO
Background: QL1604 is a humanized immunoglobulin G4 monoclonal antibody against programmed cell death protein 1. This first-in-human, open-label phase I study aimed to investigate the safety and tolerability and to identify the recommended doses of QL1604 for future studies. Pharmacokinetics/pharmacodynamics (PK/PD) and preliminary antitumor activity were also assessed. Methods: Patients with advanced or metastatic solid tumors who failed or had no standard therapies available were recruited. In the dose-escalation phase, patients were treated with QL1604 at 0.3 mg/kg, 1 mg/kg, 3 mg/kg, and 10 mg/kg intravenously once every 2 weeks (Q2W) in an accelerated titration with a traditional 3 + 3 design, followed by a dose-expansion phase at 3 mg/kg Q2W, 3 mg/kg once every 3 weeks (Q3W), 10 mg/kg Q2W and a fixed dose of 200 mg Q3W. Dose-limiting toxicities (DLTs) were assessed during the first 28 days after the first dose of study drug. Adverse events (AEs) were graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, and antitumor activity of QL1604 was evaluated by investigators on the basis of Response Evaluation Criteria in Solid Tumors version 1.1. Results: A total of 35 patients with advanced or metastatic solid tumors were enrolled. DLTs were reported in one patient at the dose level of 3 mg/kg Q2W (grade 3 immune-mediated myositis and myasthenia gravis), and maximum tolerated dose was not reached. The most frequent treatment-related AEs (≥10%) were fatigue (37.1%), anemia (22.9%), increased blood thyroid-stimulating hormone (17.1%), increased aspartate aminotransferase (AST) (17.1%), increased alanine aminotransferase (ALT) (14.3%), decreased white blood cell (WBC) count (11.4%), rash (14.3%), and pruritus (14.3%). AEs leading to discontinuation of QL1604 occurred in three of the 35 patients (8.6%). Partial responses (PRs) occurred in seven patients, resulting in an objective response rate of 20.0% (7/35). Single dose of QL1604 exhibited a dose-dependent increase in the exposure ranging from 0.3 mg/kg to 10 mg/kg. Mean receptor occupancy (RO) for QL1604 at the dose of 3 mg/kg (Q2W and Q3W) and 200 mg (Q3W) was greater than 80% during cycle 1 after one infusion. Conclusion: QL1604 monotherapy exhibited favorable safety, PK, and signal of antitumor activity in patients with advanced or metastatic solid tumors, and the results supported further clinical studies of QL1604. On the basis of the safety, PK, and RO data, the recommended dosage for further clinical trials is 3 mg/kg or a fixed dose of 200 mg given every 3 weeks. Clinical Trial Registration: https://classic.clinicaltrials.gov/ct2/show/NCT05649761?term=QL1604&draw=2&rank=1, identifier NCT05649761.
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Miosite , Segunda Neoplasia Primária , Neoplasias , Humanos , Neoplasias/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Critérios de Avaliação de Resposta em Tumores Sólidos , Miosite/induzido quimicamenteRESUMO
Background: Patients undergoing video-assisted thoracoscopic surgery (VATS) frequently suffered postoperative acute and chronic pains. In recent years, intrathoracic intercostal nerve block (INB) is regularly used thanks to its safety and accuracy, especially under the circumstance of lacking ultrasound or in face of the contraindications of the thoracic paravertebral block (TPVB). However, clinical evidence of comparing TPVB and INB for pain management after VATS has been limited and the observation of the chronic pain has been less than clear. Methods: A total of 180 patients undergoing VATS were randomly divided into three groups: A single multi-point paravertebral nerve block (Group P), intrathoracic intercostal nerve block (Group I), and general anesthesia without any regional block (Group C). Postoperative acute pain was scored at rest and coughing by the Visual Analog Scale (VAS) for recording 24h, 48h and 72h after VATS. All patients were interviewed 1, 3 and 6 months after the surgery to investigate both the incidence and intensity of chronic pains. Results: There were significantly less incidence and intensity of acute pain in Group P and Group I, compared to those in Group C. The patients in Group I showed the least incidence and intensity of chronic pain after 3 months compared with those in Group P and Group C. There are 89 of 98 patients suffering pains after 1 month, which grew into chronic pains after 3 months and 78 of them still suffered chronic pains even after 6 months. Conclusion: The intrathoracic INB offers excellent relief from acute and chronic pains, which does as effectively as TPVB. Besides, one-month postoperative pain could increase the risk of a chronic one.
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Cordyceps militaris is a well-known traditional Chinese medicine. Studies have demonstrated that the polysaccharides of C. militaris have various bioactivities. However, their mechanisms of action remain unclear. We previously purified a water-soluble polysaccharide CM1 from C. militaris and found that it has a cholesterol efflux improving capacity. This study further investigates the effect of CM1 in anti-atherosclerosis and its underlying mechanism in apolipoprotein E-deficient mice. Our data indicated that CM1 significantly decreased the total cholesterol and triglyceride in the plasma of mice, and decreased lipid deposition and formation of atherosclerotic plaque in a dose-dependent manner. Integrated bioinformatics analysis revealed that CM1 interacted with multiple signaling pathways, including those involved in lipid metabolism, inflammatory response, oxidoreductase activity and fluid shear stress, to exert its anti-atherosclerotic effect. Molecular technology analysis showed that CM1 enhanced the expression of proteins involved in lipid metabolism, reduced the expression of intercellular adhesion molecule-1 and tumor necrosis factor-α in the aorta, and decreased the content of oxidative products by enhancing the activities of antioxidant enzymes. Microarray analysis and biochemical data indicated that CM1 can improve lipid metabolism, reduce inflammation and oxidative stress. Taken together, CM1 could be used for the treatment of hyperlipidemia and atherosclerotic cardiovascular diseases.
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Aterosclerose/tratamento farmacológico , Cordyceps/química , Polissacarídeos/farmacologia , Animais , Antioxidantes/farmacologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aterosclerose/metabolismo , Biologia Computacional , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
PURPOSE: We aimed to introduce an explainable machine learning technology to help clinicians understand the risk factors for neonatal postoperative mortality at different levels. METHODS: A total of 1481 neonatal surgeries performed between May 2016 and December 2019 at a children's hospital were included in this study. Perioperative variables, including vital signs during surgery, were collected and used to predict postoperative mortality. Several widely used machine learning methods were trained and evaluated on split datasets. The model with the best performance was explained by SHAP (SHapley Additive exPlanations) at different levels. RESULTS: The random forest model achieved the best performance with an area under the receiver operating characteristic curve of 0.72 in the validation set. TreeExplainer of SHAP was used to identify the risk factors for neonatal postoperative mortality. The explainable machine learning model not only explains the risk factors identified by traditional statistical analysis but also identifies additional risk factors. The visualization of feature contributions at different levels by SHAP makes the "black-box" machine learning model easily understood by clinicians and families. Based on this explanation, vital signs during surgery play an important role in eventual survival. CONCLUSIONS: The explainable machine learning model not only exhibited good performance in predicting neonatal surgical mortality but also helped clinicians understand each risk factor and each individual case.
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Aprendizado de Máquina , Tecnologia , Criança , Humanos , Recém-Nascido , Período Pós-Operatório , Curva ROC , Fatores de RiscoRESUMO
One novel alkali-extracted polysaccharide, CM3-SII, was obtained from the fruiting body of C. militaris via column chromatography. Its structural characteristics were investigated via chemical and spectroscopic methods. The backbone of CM3-SII was composed of â4)-ß-D-Manp(1â, â6)-ß-D-Manp(1â, and â6)-α-D-Manp(1â glycosyls, and branching at the O-4 positions of â6)-ß-D-Manp(1â glycosyls with ß-D-Galp, (1â2) linked-ß-D-Galf, and â2,6)-α-D-Manp(1â residues. Furthermore, O-6 and O-2 positions of the â2,6)-α-D-Manp(1â residues were substituted with methyl and ß-D-Galp, respectively. This polysaccharide significantly enhanced the intracellular protein expression of low-density lipoprotein receptor and proprotein convertase subtilisin/kexin type 9 (PCSK9) via regulating sterol regulatory element-binding protein 2 in hepatoma Huh7 cells. Of note, CM3-SII significantly decreased PCSK9 secretion at the concentration of 200 µg/mL. Collectively, CM3-SII is different from the previously reported alkali-extracted polysaccharides isolated from the fruiting body of C. militaris, and it may have potential application in hypolipidemia or as a pharmaceutical additive.
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Cordyceps/química , Polissacarídeos , Pró-Proteína Convertase 9/metabolismo , Receptores de LDL/metabolismo , Linhagem Celular Tumoral , Humanos , Inibidores de PCSK9 , Polissacarídeos/isolamento & purificação , Polissacarídeos/farmacologiaRESUMO
A novel glucan PSPP-1 (18.3 kDa) was purified from the foot tuber of purple sweet potato Ipomoea Batatas (L.) Lam. Its backbone was composed of â4)-α-d-Glcp(1â glycosyl, and branching at the O-2, O-3, and O-6 positions with α-d-Glcp(1â residues. X-ray diffraction experiment showed that PSPP-1 existed as an amorphous form. Its microstructure was detected via scanning electron microscopy. Its particle size was mainly concentrated at 230 nm in water. Congo red and circular dichroism experiments showed there was no triple-helix conformation. Atomic force microscopy data suggested that its height and width ranged from 1.0 to 6.1 nm and 65 to 210 nm, respectively; its maximum ring diameter and chain length was â¼800 nm and â¼7.0 µm, respectively. Furthermore, it exhibited inhibitory activities on HepG2, LOVO, and MCF-7 cells. Collectively, our data are useful for understanding the structural characteristics of sweet potato polysaccharides, and their application in foods and pharmaceutical areas.
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Antocianinas/química , Antineoplásicos/farmacologia , Glucanos/química , Ipomoea batatas/metabolismo , Extratos Vegetais/farmacologia , Varredura Diferencial de Calorimetria , Linhagem Celular Tumoral , Dicroísmo Circular , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Técnicas In Vitro , Células MCF-7 , Espectroscopia de Ressonância Magnética , Microscopia de Força Atômica , Microscopia Eletrônica de Varredura , Peso Molecular , Tamanho da Partícula , Polissacarídeos/química , Relação Estrutura-Atividade , Termogravimetria , Água/química , Difração de Raios XRESUMO
LXRα agonists have attracted significant attention due to their potential biological activities on promoting cholesterol efflux. This study was designed to investigate whether setosphapyrone C and D have potential lipid-lowering capacity and the underlying mechanisms in vitro. Our data showed that setosphapyrone C and D had weak cytotoxicity compared to the liver X receptor α (LXRα) agonist T0901317. In RAW 264.7 macrophages, setosphapyrone C and D significantly enhanced [3H]-cholesterol efflux by ~ 21.3% and 32.4%, respectively; furthermore, setosphapyrone C and D enhanced the protein levels of ATP-binding cassette transporter (ABC) A1 and LXRα by 58% and 69%, and 60% and 70% (8 µM), respectively; however, they had no effect on the protein levels of ABCG1 and scavenger receptor B type 1; additionally, they had minor effect on the mRNA expression of lipogenic genes. Of note, setosphapyrone C and D significantly enhanced LXRα/ABCA1pathway in mice primary macrophages. In BRL cells, setosphapyrone C and D significantly improved the protein levels of ABCA1 and ABCG1; setosphapyrone D significantly enhanced the protein expression of low-density lipoprotein. Collectively, setosphapyrone C and D with weak cytotoxicity exhibited effective lipid-lowering effect via enhancing LXRα/ABC pathways. Setosphapyrones possess potential application for the treatment of hyperlipidemic diseases.
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Colesterol/metabolismo , Hipolipemiantes/farmacologia , Receptores X do Fígado/agonistas , Macrófagos/efeitos dos fármacos , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Hidrocarbonetos Fluorados/farmacologia , Receptores X do Fígado/metabolismo , Macrófagos/metabolismo , Camundongos , Células RAW 264.7 , Sulfonamidas/farmacologiaRESUMO
Glioblastoma multiforme is the most common primary central nervous system malignancy, accounting for half of all intracranial primary tumors. In this study we constructed a multifunctional chlorotoxin fusion protein E-CHP that combines enhanced green fluorescent protein (E), glioma-targeting peptide chlorotoxin (C), destabilizing lipid membrane peptide riHA2 (H), and C-terminal and mouse double minute domains of p53 (P). E-CHP was expressed in Escherichia coli and purified by His affinity chromatography. Fluorescence microscopy observation showed that E-CHP could effectively target glioma cells; real-time quantitative PCR revealed that E-CHP increased miR-374a expression; and the dual luciferase reporter assay showed that tumor necrosis factor alpha-induced protein (TNFAIP)8 is a direct target of miR-374a. E-CHP and miR-374a inhibited the proliferation and migration of glioma cells, and Western blot analysis indicated that they suppressed TNFAIP8 expression in glioma cells and promoted the expression of caspase-3 and -8. Finally, E-CHP and miR-374a stimulated the apoptosis of glioma cells, as determined by flow cytometry analysis. These results suggest that miR-374a is a new candidate target for glioma therapy, whereas E-CHP fusion protein has the potential to be developed as a multifunctional carrier for targeted drug delivery and therapy.
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Chemotherapy is the main postsurgical and adjuvant therapy for glioma, and intrinsic or acquired temozolomide (TMZ) resistance may result in poor prognosis. The miR-181 family was discovered to play an important role in regulating biological functions in glioma, and miR-181b is less expressed in human gliomas as a tumor-suppressive miRNA. The aim of this study was to explore the molecular mechanism of miR-181b-5p and its target gene on modulating TMZ chemosensitivity in glioma cells. The enhanced chemosensitivity effect of miR-181b-5p to TMZ in glioma cells U87MG and U251 was detected by MTT method. Dual luciferase reporter assay, quantitative real-time PCR (qRT-PCR) and Western blotting were performed to demonstrate that miR-181b-5p directly targets Bcl-2 to reduce the expression. Transwell and ï¬ow cytometry assays showed that combination of miR-181b-5p and TMZ exerted stronger effects on inhibiting U87MG cells proliferation, migration and invasion as well as promoting apoptosis and S phase arrest than miR-181b-5p and TMZ alone. The same tendency was observed in the upregulation of apoptosis-related protein Bax and downregulation of cycle-related proteins CyclinD1 and CDK4. In vivo experiments indicated that miR-181b-5p could enhance the tumor-suppressive effect of TMZ. In conclusion, our findings indicate that upregulation of miR-181b-5p targets Bcl-2 directly and may function as an important modifier to sensitize glioma cells to TMZ.