BackgroundEmerging clinical data suggest that an immune checkpoint inhibitor in combination with an antiangiogenic agent is a reasonable strategy for multiple malignancies. We assessed the ...combination of camrelizumab with apatinib in pretreated advanced primary liver cancer (PLC, cohort A) from a multicohort phase Ib/II trial.MethodsPatients with PLC after prior systemic treatment(s) were administered camrelizumab (3 mg/kg, once every 2 weeks) plus apatinib (125, 250, 375, or 500 mg; once per day) in a 3+3 dose-escalation stage and subsequent expansion stage. The primary endpoints were tolerability and safety of study treatment.ResultsFrom April 2017 to July 2019, 28 patients (21 with hepatocellular carcinoma and 7 with intrahepatic cholangiocarcinoma) received camrelizumab plus apatinib. Two dose-limiting toxicities (both grade 3 diarrhea) were reported in the 500 mg cohort. Therefore, the 375 mg cohort was expanded. Of the 19 patients in the 375 mg cohort, dose reduction to 250 mg occurred in 8 patients within 2 months after treatment initiation. Of the 28 patients with PLC, 26 had grade ≥3 treatment-related adverse events, with hypertension being the most common (9/28). One treatment-related death occurred. The objective response rate was 10.7% (95% CI 2.3% to 28.2%). Median progression-free survival and overall survival were 3.7 months (95% CI 2.0 to 5.8) and 13.2 months (95% CI 8.9 to not reached), respectively.ConclusionThe combination of camrelizumab with apatinib had a manageable toxicity and promising antitumor activity in patients with advanced PLC. Apatinib at a dose of 250 mg is recommended as a combination therapy for further studies of advanced PLC treatment.Trial registration numbersNCT03092895.
Abstract Background The phase III Sorafenib Asia–Pacific (AP) trial—conducted in China, Taiwan and South Korea – confirmed that sorafenib improves overall survival (OS) and is safe for patients with ...advanced hepatocellular carcinoma (HCC). We performed a series of exploratory subset analyses to determine whether baseline status affected response to sorafenib. Methods In the Sorafenib AP trial, 226 patients with well-preserved liver function (>95% Child-Pugh A) were randomised 2:1 to sorafenib 400 mg bid or matching placebo. Subanalyses were based on aetiology (hepatitis B virus present/absent); tumour burden (macroscopic vascular invasion and/or extrahepatic spread present/absent); presence or absence of either lung or lymph node metastasis at baseline, Eastern Cooperative Oncology Group performance status (0, 1–2); serum concentrations of alanine aminotransferase/aspartate aminotransferase (normal, mildly elevated, moderately elevated), alpha-fetoprotein (normal/elevated) and total bilirubin (normal/elevated); and whether or not there was a history of hepatectomy or transarterial chemoembolisation/embolisation. Subgroup assessments included OS, time to progression (TTP), disease control rate and safety. Findings Sorafenib consistently improved both median OS and median TTP, compared with placebo (range of hazard ratios (HR), 0.32–0.87 and 0.31–0.75, respectively). The most common grade 3/4 adverse events were hand-foot skin reaction, diarrhoea and fatigue, the incidence of which was similar between subgroups. Interpretation The efficacy and safety profiles of sorafenib in the subpopulations described were comparable with those in the overall study population. These exploratory analyses suggest that sorafenib is effective for patients from the AP region with advanced HCC, irrespective of baseline status.
Summary Background Most cases of hepatocellular carcinoma occur in the Asia-Pacific region, where chronic hepatitis B infection is an important aetiological factor. Assessing the efficacy and safety ...of new therapeutic options in an Asia-Pacific population is thus important. We did a multinational phase III, randomised, double-blind, placebo-controlled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma. Methods Between Sept 20, 2005, and Jan 31, 2007, patients with hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A, were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period. Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread (or both), Eastern Cooperative Oncology Group performance status, and geographical region. Randomisation was done centrally and in a 2:1 ratio by means of an interactive voice-response system. There was no predefined primary endpoint; overall survival, time to progression (TTP), time to symptomatic progression (TTSP), disease control rate (DCR), and safety were assessed. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00492752. Findings 271 patients from 23 centres in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6·5 months (95% CI 5·56–7·56) in patients treated with sorafenib, compared with 4·2 months (3·75–5·46) in those who received placebo (hazard ratio HR 0·68 95% CI 0·50–0·93; p=0·014). Median TTP was 2·8 months (2·63–3·58) in the sorafenib group compared with 1·4 months (1·35–1·55) in the placebo group (HR 0·57 0·42–0·79; p=0·0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients 10·7%), diarrhoea (nine patients 6·0%), and fatigue (five patients 3·4%). The most common adverse events resulting in dose reductions were HFSR (17 patients 11·4%) and diarrhoea (11 patients 7·4%); these adverse events rarely led to discontinuation. Interpretation Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated. Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) trial, sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma. Funding Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, Inc.
Powdery mildew is one of the main problematic diseases in melon production, requiring the use of chemical pesticides with disease-resistant cultivars for control. However, the often rapid acquisition ...of fungicidal resistance by mildew pathogens makes this practice unsustainable. The identification of crop treatments that can enhance resistance to powdery mildew resistance is therefore important to reduce melon crop attrition. This study indicates that the application of Nano-Se can reduce the powdery mildew disease index by 21-45%. The Nano-Se treatment reduced reactive oxygen species (ROS) and malondialdehyde (MDA) accumulation, with increases in glutathione (GSH), proline and 1,1-Diphenyl-2-picrylhydrazyl radical (DPPH). Increases were also observed in the activities and transcriptional levels of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX) and peroxidase (POD). Assays with four different cultivars of melon with differing levels of mildew resistance demonstrated that relative to the control, the Nano-Se treatment resulted in larger responses to mildew infection, including increases in the levels of putrescine (PUT; 43-112%) and spermine (SPM; 36-118%), indoleacetic acid (IAA; 43-172%) and salicylic acid (SA; 24-73%), the activities of phenylalanine ammonium lyase (PAL), trans-cinnamate 4-hydroxylase (C4H) and 4-coumarate: Co A ligase (4CL) of the phenylpropanoid pathway (22-38%, 24-126% and 19-64%, respectively). Key genes in the polyamine and phenylpropanoid pathway were also upregulated. These results indicate that the foliar application of Nano-Se improved melon defenses against powdery mildew infection, with a significant reduction in mildew disease development.
The novel coronavirus COVID-19, has caused a worldwide pandemic, impairing several human organs and systems. Whether COVID-19 affects human thyroid function remains unknown.
Eighty-four hospitalized ...COVID-19 patients in the First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou, China) were retrospectively enrolled in this study, among which 22 cases had complete records of thyroid hormones. In addition, 91 other patients with pneumonia and 807 healthy subjects were included as controls.
We found that levels of total triiodothyronine (TT3) and thyroid stimulating hormone (TSH) were lower in COVID-19 patients than healthy group (p < 0.001). Besides, TSH level in COVID-19 patients was obviously lower than non-COVID-19 patients (p < 0.001). Within the group of COVID-19, 61.9% (52/84) patients presented with thyroid function abnormalities and the proportion of thyroid dysfunction was higher in severe cases than mild/moderate cases (74.6 vs. 23.8%, p < 0.001). Patients with thyroid dysfunction tended to have longer viral nucleic acid cleaning time (14.1 ± 9.4 vs. 10.6 ± 8.3 days, p = 0.088). To note, thyroid dysfunction was also associated with decreased lymphocytes (p < 0.001) and increased CRP (p = 0.002). The correlation between TT3 and TSH level seemed to be positive rather than negative in the early stage, and gradually turned to be negatively related over time.
Thyroid function abnormalities are common in COVID-19 patients, especially in severe cases. This might be partially explained by nonthyroidal illness syndrome.
Black phosphorus (BP) has attracted extensive attention due to its unique optical and electrical properties. However, BP is easily oxidized in the air, which significantly limits its application. In ...this study, BP is successful doped into sol-gel glass, it shows excellent chemical stability in atmospheric environment for five months. In addition, as a kind of inorganic matrix, optical damage threshold of BP-doped sol-gel glass reaches as high as 51.69 GW/cm 2 , which is six times higher than that of plastic polymer. Saturable absorption parameters of the BP are maintained after five months in the air. The BP-doped sol-gel glass is inserted into erbium-doped fiber (EDF) laser to realize passively Q-switched and mode locked operation. Compared to most Q-switched EDF lasers based on broadband absorbers, the single pulse energy is one of the highest values (315.99 nJ). Overall, these data evidently provide a practical solution to stabilize BP in the air by embedding it in the silica, and also open the way for extensive applications of BP.
In this letter, a Q-switched linear-cavity Er-doped fiber laser was prepared using a reflective molybdenum disulfide saturable absorber mirror (MoS 2 -SAM). MoS 2 -SAM with high uniformity and ...compactness was prepared using Langmuir-Blodgett (LB) technology. Films as thin as single molecule can be fabricated by LB technology under suitable conditions and thus, the nonsaturable losses of absorbers can be decreased. The modulation depth of MoS 2 -SAM is 9.8%. By inserting MoS 2 -SAM in Er-doped fiber lasers, a stable passive Q-switched operation was achieved with repetition rate ranging from 46.21 to 215.45 kHz and pulse duration ranging from 1316 to 319 ns. Under a maximum pump power of 500 mW, the laser still works stably with an average output power of 7.37 mW and a signal-to-noise ratio of 58 dB. Notably, the minimum pulse width is as narrow as 319 ns. This shows that LB method is a practical method to improve the performance of saturable absorbers.
We report a stable, tunable and non-volatile converse magnetoelectric effect (ME) in a new type of FeAl/PIN-PMN-PT heterostructure at room temperature, with a giant electrical modulation of ...magnetization for which the maximum relative magnetization change (ΔM/M) is up to 66%. The 109° ferroelastic domain switching in the PIN-PMN-PT and coupling with the ferromagnetic (FM) film via uniaxial anisotropy originating from the PIN-PMN-PT (011) surface are the key roles in converse ME effect. We also propose here a new, four-state memory through which it is possible to modify the remanent magnetism state by adjusting the electric field. This work represents a helpful approach to securing electric-writing magnetic-reading with low energy consumption for future high-density information storage applications.
(1) Background: This study aimed to establish a nomogram model for predicting the overall survival (OS) of medullary thyroid carcinoma (MTC) patients based on the Surveillance, Epidemiology, and End ...Results (SEER) database. (2) Methods: Patients with MTC in the SEER database from 2004 to 2015 were included and divided into a modeling group and an internal validation group. We also selected MTC patients from our center from 2007 to 2019 to establish an external validation group. Univariate and multivariate Cox regression analyses were used to screen for significant independent variables and to establish a nomogram model. Kaplan-Meier (K-M) curves were plotted to evaluate the influence of the predictors. The C-indexes, areas under the curves (AUCs), and calibration curves were plotted to validate the predictive effect of the model. (3) Results: A total of 1981 MTC patients from the SEER database and 85 MTC patients from our center were included. The univariate and multivariate Cox regression analyses showed that age, tumor size, N stage, and M stage were significant factors, and a nomogram model was established. The C-index of the modeling group was 0.792, and the AUCs were 0.811, 0.825, and 0.824. The C-index of the internal validation group was 0.793, and the AUCs were 0.847, 0.846, and 0.796. The C-index of the external validation group was 0.871, and the AUCs were 0.911 and 0.827. The calibration curves indicated that the prediction ability was reliable. (4) Conclusions: A nomogram model based on age, tumor size, N stage, and M stage was able to predict the OS of MTC patients.
Liquid chromatography tandem mass spectrometry (LC-MS/MS) has gradually become a promising alternative to ligand binding assay for the bioanalysis of biotherapeutic molecules, due to its rapid method ...development and high accuracy. In this study, we established a new LC-MS/MS method for the determination of the anti-sclerostin monoclonal antibody (SHR-1222) in cynomolgus monkey serum, and compared it to a previous electrochemiluminescence method. The antibody was quantified by detecting the surrogate peptide obtained by trypsin digestion. The surrogate peptide was carefully selected by investigating its uniqueness, stability and MS response. The quantitative range of the proposed method was 2.00–500 μg/mL, and this verified method was successfully applied to the toxicokinetic assessment of SHR-1222 in cynomolgus monkey serum. It was found that the concentrations of SHR-1222 in cynomolgus monkeys displayed an excellent agreement between the LC-MS/MS and electrochemiluminescence methods (ratios of drug exposure, 0.8–1.0). Notably, two monkeys in the 60 mg/kg dose group had abnormal profiles with a low detection value of SHR-1222 in their individual sample. Combining the high-level anti-drug antibodies (ADAs) in these samples and the consistent quantitative results of the two methods, we found that the decreased concentration of SHR-1222 was due to the accelerated clearance mediated by ADAs rather than the interference of ADAs to the detection platform. Taken together, we successfully developed an accurate, efficient and cost-effective LC-MS/MS method for the quantification of SHR-1222 in serum samples, which could serve as a powerful tool to improve the preclinical development of antibody drugs.
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•LC-MS/MS method was established for the quantification of an anti-sclerostin monoclonal antibody.•The LC-MS/MS was compared with one previous MSD-ECL method.•ADA-tolerant LC-MS/MS method explained the mechanism of outliers in PK profiles.•LC-MS/MS method exhibited superior accuracy, efficiency and cost-effectiveness.
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