Nonclinical immunogenicity risk assessment for knobs-into-holes bispecific IgG1 antibodies.

Bispecific antibodies, including bispecific IgG, are emerging as an important new class of antibody therapeutics. As a result, we, as well as others, have developed engineering strategies designed to facilitate the efficient production of bispecific IgG for clinical development. For example, we have extensively used knobs-into-holes (KIH) mutations to facilitate the heterodimerization of antibody heavy chains and more recently Fab mutations to promote cognate heavy/light chain pairing for efficient in vivo assembly of bispecific IgG in single host cells. A panel of related monospecific and bispecific IgG1 antibodies was constructed and assessed for immunogenicity risk by comparison with benchmark antibodies with known low (Avastin and Herceptin) or high (bococizumab and ATR-107) clinical incidence of anti-drug antibodies. Assay methods used include dendritic cell internalization, T cell proliferation, and T cell epitope identification by in silico prediction and MHC-associated peptide proteomics. Data from each method were considered independently and then together for an overall integrated immunogenicity risk assessment. In toto, these data suggest that the KIH mutations and in vitro assembly of half antibodies do not represent a major risk for immunogenicity of bispecific IgG1, nor do the Fab mutations used for efficient in vivo assembly of bispecifics in single host cells. Comparable or slightly higher immunogenicity risk assessment data were obtained for research-grade preparations of trastuzumab and bevacizumab versus Herceptin and Avastin, respectively. These data provide experimental support for the common practice of using research-grade preparations of IgG1 as surrogates for immunogenicity risk assessment of their corresponding pharmaceutical counterparts.

Effects of different light intensity on leaf color changes in a Chinese cabbage yellow cotyledon mutant.

Leaf color is one of the most important phenotypic features in horticultural crops and directly related to the contents of photosynthetic pigments. Most leaf color mutants are determined by the altered chlorophyll or carotenoid, which can be affected by light quality and intensity. Our previous study obtained a Chinese cabbage yellow cotyledon mutant that exhibited obvious yellow phenotypes in the cotyledons and the new leaves. However, the underlying mechanisms in the formation of yellow cotyledons and leaves remain unclear. In this study, the Chinese cabbage yellow cotyledon mutant 19YC-2 exhibited obvious difference in leaf color and abnormal chloroplast ultrastructure compared to the normal green cotyledon line 19GC-2. Remarkably, low-intensity light treatment caused turn-green leaves and a significant decrease in carotenoid content in 19YC-2. RNA-seq analysis revealed that the pathways of photosynthesis antenna proteins and carotenoid biosynthesis were significantly enriched during the process of leaf color changes, and many differentially expressed genes related to the two pathways were identified to respond to different light intensities. Remarkably, BrPDS and BrLCYE genes related to carotenoid biosynthesis showed significantly higher expression in 19YC-2 than that in 19GC-2, which was positively related to the higher carotenoid content in 19YC-2. In addition, several differentially expressed transcription factors were also identified and highly correlated to the changes in carotenoid content, suggesting that they may participate in the regulatory pathway of carotenoid biosynthesis. These findings provide insights into the molecular mechanisms of leaf color changes in yellow cotyledon mutant 19YC-2 of Chinese cabbage.

Copper-Catalyzed Domino-Double Annulation of o-Aminobenzamides with 2-Iodoisothiocyanates for the Synthesis of 12H-Benzo[4,5]thiazolo[2,3-b]quinazolin-12-ones.

A facile and efficient copper-catalyzed domino-double annulation strategy was developed from easily accessible o-aminobenzamides and 2-iodoisothiocyanates, which affords a direct pathway for the synthesis of tetracyclic fused 12H-benzo[4,5]thiazolo[2,3-b]quinazolin-12-ones in moderate to good yields without the addition of ligands, bases, and external oxidants. The reaction involves a C-N bond cleavage and the formation of a C-N/C-S bond in one step with the advantages of using an inexpensive copper catalyst and easy operation. Mechanistic studies suggest that this transformation proceeds via intermolecular condensation of o-aminobenzamides with 2-iodoisothiocyanates, followed by an intramolecular Ullmann-type cross-coupling cyclization reaction.

Palladium-Copper-Catalyzed Oxidative Intermolecular [2 + 2 + 2] Coupling-Annulation: Regioselective Synthesis of Multiaryl-Substituted Benzenes.

A palladium-catalyzed intermolecular [2 + 2 + 2] oxidative coupling-annulation of terminal alkenes and alkynes using copper(II) as the oxidant has been developed through direct C-C bond formation. These reactions provide effective access to multiaryl-substituted benzenes with high regioselectivity in the absence of any ligands. The features of this protocol are broad substrate scope, and high atom and step economy. The aggregation-induced emission properties of selected products were further investigated. These synthesized multiaryl-substituted benzenes may be worth exploring for further applications in the fields of advanced functional materials or drugs.

Structure- and machine learning-guided engineering demonstrate that a non-canonical disulfide in an anti-PD-1 rabbit antibody does not impede antibody developability.

Rabbits produce robust antibody responses and have unique features in their antibody repertoire that make them an attractive alternative to rodents for in vivo discovery. However, the frequent occurrence of a non-canonical disulfide bond between complementarity-determining region (CDR) H1 (C35a) and CDRH2 (C50) is often seen as a liability for therapeutic antibody development, despite limited reports of its effect on antibody binding, function, and stability. Here, we describe the discovery and humanization of a human-mouse cross-reactive anti-programmed cell death 1 (PD-1) monoclonal rabbit antibody, termed h1340.CC, which possesses this non-canonical disulfide bond. Initial removal of the non-canonical disulfide resulted in a loss of PD-1 affinity and cross-reactivity, which led us to explore protein engineering approaches to recover these. First, guided by the sequence of a related clone and the crystal structure of h1340.CC in complex with PD-1, we generated variant h1340.SA.LV with a potency and cross-reactivity similar to h1340.CC, but only partially recovered affinity. Side-by-side developability assessment of both h1340.CC and h1340.SA.LV indicate that they possess similar, favorable properties. Next, and prompted by recent developments in machine learning (ML)-guided protein engineering, we used an unbiased ML- and structure-guided approach to rapidly and efficiently generate a different variant with recovered affinity. Our case study thus indicates that, while the non-canonical inter-CDR disulfide bond found in rabbit antibodies does not necessarily constitute an obstacle to therapeutic antibody development, combining structure- and ML-guided approaches can provide a fast and efficient way to improve antibody properties and remove potential liabilities.

Serum amyloid beta 42 levels correlated with metabolic syndrome and its components.

Introduction: Beta-amyloid accumulation in the brain appears to be a key initiating event in Alzheimer's disease (AD), and factors associated with increased deposition of beta-amyloid are of great interest. Enhanced deposition of amyloid-ß peptides is due to an imbalance between their production and elimination. Previous studies show that diminished levels of CSF amyloid beta 42 (Aß42) is a biomarker in AD; however, the role of serum Aß42 in AD is contradictory. BMI and obesity have been reported to be related to increased serum Aß42 levels. Therefore, we aimed to investigate the relation between metabolic syndrome (MetS), its clinical measures (abdominal obesity, high glucose, high triglyceride, low high-density lipoprotein cholesterol level, and hypertension), and serum Aß42 levels. Methods: A total of 1261 subjects, aged 18-89 years in Chengdu, China, were enrolled from January 2020 to January 2021 to explore the correlation of serum Aß42 levels with body mass index (BMI), blood lipids, and blood pressure. Furthermore, as the risk of MetS is closely related to age, 1,212 participants (N = 49 with age ≥ 80 years old were excluded) were analyzed for the correlation of serum Aß42 level and MetS clinical measures. Results: The results showed that log-transformed serum Aß42 level was positively correlated with BMI (R = 0.29; p < 0.001), log-transformed triglyceride (R = 0.14; p < 0.001), and diastolic blood pressure (DBP) (R = 0.12; p < 0.001) and negatively correlated with high-density lipoprotein (HDL-c) (R = -0.18; p < 0.001). After adjusting for age, sex, and other covariates, elevated serum Aß42 level was correlated with higher values of BMI (ßmodel1 = 2.694, ßmodel2 = 2.703) and DBP (ßmodel1 = 0.541, ßmodel2 = 0.546) but a lower level of HDL-c (ßmodel2 = -1.741). Furthermore, serum Aß42 level was positively correlated with MetS and its clinical measures, including BMI and DBP, and negatively correlated with HDL-c level in the Han Chinese population. However, the level of serum Aß42 did not show a significant correlation with high glucose or high triglyceride. Discussion: These observations indicate that MetS and its components are associated with higher levels of serum Aß42 and hence limit the potential of serum Aß42 as a suitable diagnostic biomarker for AD. As such, we recommend serum Aß42 serve as a direct risk biomarker for MetS rather than for AD.

Preliminary study on early diagnosis of Alzheimer's disease in APP/PS1 transgenic mice using multimodal magnetic resonance imaging.

Alzheimer's disease (AD) has an insidious onset and lacks clear early diagnostic markers, and by the time overt dementia symptoms appear, the disease is already in the mid-to-late stages. The search for early diagnostic markers of AD may open a critical window for Alzheimer's treatment and facilitate early intervention to slow the progression of AD. In this study, we aimed to explore the imaging markers for early diagnosis of AD through the combined application of structural magnetic resonance imaging (sMRI), resting-state functional magnetic resonance imaging (rs-fMRI), and 1H-magnetic resonance spectroscopy (1H-MRS) multimodal magnetic resonance imaging (MRI) techniques at the animal experimental level, with the aim to provide a certain reference for early clinical diagnosis of AD. First, sMRI scans were performed on 4-month-old amyloid beta precursor protein/presenilin 1 (APP/PS1) transgenic AD model mice and wild type mice of the same litter using a 7.0 T animal MRI scanner to analyze the differential brain regions with structural changes in the gray matter of the brain by voxel-based morphometry (VBM). Next, rs-fMRI scans were performed to analyze the differential brain regions between groups for local spontaneous brain activity and functional connectivity (FC) between brain regions. Finally, 1H-MRS scans were performed to quantify and analyze intergroup differences in the relative concentrations of different metabolites within regions of interest (cortex and hippocampus). Compared with wild type mice, the volume of the left hippocampus, and right olfactory bulb of APP/PS1 transgenic AD model mice were reduced, the functional activity of the bilateral hippocampus, right piriform cortex and right caudate putamen was reduced, the functional network connectivity of the hippocampus was impaired, and the relative content of N-acetylaspartate (NAA)in the hippocampus was decreased. In addition, this study found that imaging changes in olfactory-related brain regions were closely associated with AD diagnosis, and these findings may provide some reference for the early diagnosis of AD.

Effectiveness of a novel rat model of off-target PLA2R1 knockout to renal impairment.

Phospholipase A2 receptor 1 (PLA2R1) plays a crucial role in various diseases, including membranous nephropathy. However, the precise implications of PLA2R1 deficiency remain poorly understood. In this study, we created PLA2R1 knockout rats to explore potential consequences resulting from the loss of the PLA2R1 gene. Unexpectedly, our PLA2R1 knockout rats exhibited symptoms resembling those of chronic kidney disease after an 8-week observation period. Notably, several rats developed persistent proteinuria, a hallmark of renal dysfunction. Immunohistochemical and immunofluorescence analyses revealed insignificant glomerular fibrosis, reduced podocyte count, and augmented glomerular expression of complement C3 (C3) compared to immunoglobin A (IgA) and immunoglobin G(IgG) in the rat model. These findings suggest that the loss of PLA2R1 may contribute to the pathogenesis of membranous nephropathy and related conditions. Our knockout rat model provides a valuable tool for investigating the underlying pathology of PLA2R1-associated diseases, and may facilitate the development of targeted therapies for membranous nephropathy and other related disorders.

Filter Lifespan, Treatment Effect, and Influencing Factors of Continuous Renal Replacement Therapy for Severe Burn Patients.

Continuous renal replacement therapy (CRRT) is often disrupted due to various factors, such as patient-related issues, vascular access complications, treatment plans, and medical staff factors. This unexpected interruption is referred to as non-selective filter stoppage and can result in additional treatment expenses. This study conducted a retrospectively analyzed 501 CRRT filters used in 62 patients with severe burns, lifespan and therapeutic effect of all filters were mainly analyzed, used logistic regression analysis was performed to identify risk factors associated with non-selective cessation filters. Out of 493 filters, 279 cases received heparin (56.60%), the median lifespan of the filter was 14.08 h (25th, 75th quantile: 7.30, 21.50); 128 cases were treated with nafamostat mesylate (26.00%), and the median lifespan of the filter was 16.42 h (10.49, 22.76); 86 cases were treated with sodium citrate (17.40%), and the median lifespan of the filter was 31.06 h (19.25, 48.75). In addition, significant differences were observed in the electrolyte index, renal function index, and procalcitonin levels before and after treatment with a single filter (P < .001). Multivariate logistic regression showed that the risk of non-selective cessation of sodium citrate anticoagulants was lower than that of heparin anticoagulation. Overall, CRRT is progressively becoming more prevalent in the treatment of patients with severe burns. The lifespan of individual filters and total patient treatment duration showed a consistent upward trend. The filter's lifespan was notably greater during sodium citrate anticoagulation when compared to nafamostat mesylate and heparin, meanwhile notably reducing the risk of non-selective cessation. Therefore, we recommend sodium citrate for anticoagulation in patients without any contraindications.

Architecture of the baculovirus nucleocapsid revealed by cryo-EM.

Baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) has been widely used as a bioinsecticide and a protein expression vector. Despite their importance, very little is known about the structure of most baculovirus proteins. Here, we show a 3.2 Å resolution structure of helical cylindrical body of the AcMNPV nucleocapsid, composed of VP39, as well as 4.3 Å resolution structures of both the head and the base of the nucleocapsid composed of over 100 protein subunits. AcMNPV VP39 demonstrates some features of the HK97-like fold and utilizes disulfide-bonds and a set of interactions at its C-termini to mediate nucleocapsid assembly and stability. At both ends of the nucleocapsid, the VP39 cylinder is constricted by an outer shell ring composed of proteins AC104, AC142 and AC109. AC101(BV/ODV-C42) and AC144(ODV-EC27) form a C14 symmetric inner layer at both capsid head and base. In the base, these proteins interact with a 7-fold symmetric capsid plug, while a portal-like structure is seen in the central portion of head. Additionally, we propose an application of AlphaFold2 for model building in intermediate resolution density.

Fire acupuncture for anti-LGI1 antibody autoimmune encephalitis: a case report.

Autoimmune encephalitis, a class of encephalitis, is clinically characterized by multifocal or diffuse brain injury, including aberrant mental behavior, convulsions, and near-event memory impairment. In this article, we describe a female patient with autoimmune encephalitis who tested positive for leucine-rich glioma inactivated 1 (LGI1) antibodies and had hippocampal inflammatory edema in the lesion area. During the first 3 months of her illness, the patient primarily experienced memory loss, the onset of rigid twitching in her extremities that lasted for 1 min while in remission, and incontinence. After gamma globulin administration, methylprednisolone shock, and other symptomatic therapies during hospitalization, the patient's psychiatric symptoms and seizures improved considerably; however, she did not fully recover her memory. After receiving fire acupuncture for 6 months, the patient's understanding, orientation, and calculation skills improved considerably. Her memory and mental state were also improved at the follow-up visit. In this case, the use of fire acupuncture for the treatment of autoimmune encephalitis resulted in favorable outcomes with important benefits for conditions affecting the central nervous system; however, more convincing data are required to support the effectiveness of this treatment method.

Acupuncture with twirling reinforcing and reducing manipulation shows a control of hypertension and regulation of blood pressure-related target brain regions in spontaneously hypertensive rat: a preliminary resting-state functional MRI study.

Aim: To observe the effects of acupuncture manipulations on blood pressure and brain function in spontaneously hypertensive rats and elucidate the anti-hypertensive effect of the manipulations' central mechanism. Methods: This study used acupuncture twirling reinforcing, acupuncture twirling reducing, and acupuncture twirling uniform reinforcing-reducing manipulations to act on the bilateral TaiChong point of rats. The depth of acupuncture was 1.5-2 mm, and twisting was performed at a frequency of 60 times/min within ±360° for 3 min, followed by the needle being retained for 17 min. Functional magnetic resonance imaging was performed at the end of the intervention. Regional homogeneity and amplitude of low-frequency fluctuations were used to assess the differences in brain regions in each group of rats, and the core brain region (left hypothalamus) among the differential brain regions was selected as the seed for functional connectivity analysis. Results: (1) The anti-hypertensive effect was achieved by acupuncture manipulations, and the anti-hypertensive effect of twirling reducing manipulation on spontaneously hypertensive rats was better than that of twirling uniform reinforcing-reducing and twirling reinforcing manipulations. (2) After regional homogeneity and amplitude of low-frequency fluctuations analyses, the hypothalamus, the brain region related to blood pressure, was activated in the twirling uniform reinforcing-reducing manipulation group; the corpus callosum and cerebellum were activated in the twirling reinforcing manipulation group; and the hypothalamus, olfactory bulb, corpus callosum, brainstem, globus pallidum, and striatum were activated in the twirling reducing manipulation group. (3) According to the functional connectivity analysis, different acupuncture manipulations increased the functional connections between seed points and the brainstem, olfactory bulb, and cerebellum, etc. Conclusion: These results suggest that acupuncture manipulations achieved the hypotensive effect and the twirling reducing manipulation had a better hypotensive effect on spontaneously hypertensive rats than twirling uniform reinforcing-reducing and twirling reinforcing manipulations; the central mechanism of the anti-hypertensive effect of twirling reinforcing and reducing manipulation may be related to the activation of brain regions associated with blood pressure regulation and the functional connections between them. Furthermore, brain regions involved in motor control, cognition, and hearing were also activated. We hypothesize that activation of these brain regions may help prevent or mitigate the onset and progression of hypertensive brain damage.

Interface designing of efficient Z-scheme Ti-ZnFe2O4/In2O3 photoanode toward boosting photoelectrochemical water oxidation.

Ti-ZnFe2O4 photoanode has attracted extensive attention in photoelectrochemical (PEC) water oxidation due to its narrow band gap and good photostability. However, its low efficiency limits its development. Herein, we designed and constructed direct Z-scheme Ti-ZnFe2O4/In2O3 (Ti-ZFO/In2O3) photoanode. Under the interface electric field, photogenerated holes with stronger oxidation capacity on In2O3 are retained to participate in the water oxidation reaction, and the photocurrent density of Ti-ZFO/In2O3 is much higher than that of pure Ti-ZFO, reaching 2.2 mA/cm2 at 1.23 V vs. RHE. Kelvin Probe, steady-state photovoltage spectroscopy (SPV), transient photovoltage spectroscopy (TPV) and in-situ double beam strategy were used to demonstrate the Z-scheme charge transfer mechanism of Ti-ZFO/In2O3 photoanode. Our work provides an effective scheme and technical means for further understanding the mechanism of interfacial charge transfer.

Electroacupuncture and manual acupuncture at LR3 and ST36 have attenuating effects on hypertension and subsequent cognitive dysfunction in spontaneously hypertensive rats: A preliminary resting-state functional magnetic resonance imaging study.

Introduction: Chronic hypertension may have a contributory role toward cognitive impairment. Acupuncture exerts protective effects on cognitive functions while controlling the blood pressure. However, the neural mechanism underlying the dual attenuating effect of acupuncture remains unclear. In this study, we investigated the effects of electroacupuncture (EA) and manual acupuncture (MA) on the functional activity of the brain regions of spontaneously hypertensive rats (SHRs) by through resting-state functional magnetic resonance imaging (rs-fMRI). We also evaluated the differences in these functional activities between the EA and MA groups. Methods: We randomly assigned 30 SHRs into the EA, MA, and model (SHR) groups. Wistar Kyoto rats (n = 10) were used as normal control (WKY). The interventions were administered once every alternate day for 12 weeks. The systolic blood pressure of all rats was recorded every 2 weeks until the end of the intervention. After the intervention, rs-fMRI scanning was performed to access the whole brain data of rats randomly selected from each group evenly. The amplitude of low frequency fluctuation (ALFF) analysis, regional homogeneity (ReHo) analysis, and functional connectivity (FC) analysis were also conducted. The Morris water maze (MWM) test was conducted to evaluate the learning and memory of the rats. Hematoxylin-eosin staining and Nissl staining were performed to observe histopathological changes in the key brain regions. Results: We demonstrated that, when compared with the SHR group, the EA and MA groups had significantly lower blood pressure and better performance for behavioral test indices, and that the effect of EA was better than that of MA. ALFF and ReHo analyses revealed enhancement of the neuronal activity of some functionally impaired brain areas in the EA and MA groups. The main callback brain regions included the hypothalamus, entorhinal cortex, brain stem, prelimbic cortex, cingulate cortex, corpus callosum, and cerebellum. The FC analysis demonstrated that EA and MA enhanced the functional connectivity between the seeds and brain regions such as the brain stem, entorhinal cortex, hippocampus, prelimbic cortex, and cerebellum. The pathological test of the entorhinal cortex also verified the protective effect of acupuncture on the neuronal functional activity. Discussion: Our findings suggested that EA and MA exhibited attenuating effects on hypertension and cognitive dysfunction by enhancing the functional activities in the corresponding brain regions. Moreover, EA activated more callback brain regions and functional connectivity than MA, which may explain why the effect of EA was better than that of MA.

Efficacy and Safety of Tyrosine Kinase Inhibitors Alone or Combination with Programmed Death-1 Inhibitors in Treating of Hepatitis C-Related Hepatocellular Carcinoma.

Background: Tyrosine kinase inhibitors (TKI) combined with programmed cell death-1 (PD-1) inhibitor is a potential treatment modality for patients with HCV-related unresectable hepatocellular carcinoma (uHCC). Methods: The participants of the present work included the patients having HCV-related uHCC who were treated with TKI monotherapy (TKI group) or TKI combined with PD-1 inhibitors therapy (combination group) in our center between June 2018 and June 2021. In addition, the patients were classified into RNA-positive and RNA-negative groups based on whether or not the baseline HCV RNA was detectable. The overall survival (OS) was used as the primary efficacy endpoint, while progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were used as secondary endpoints. The adverse events were recorded and evaluated. Results: Among the 67 patients contained this work, 43 patients were classified into the TKI group, while 24 patients formed the combination group. In relative to the TKI group, the combination group presented notably better median OS (21 months vs 13 months, p = 0.043) and median PFS (8 months vs 5 months, p = 0.005). No evident differences were observed between the two groups in terms of the DCR (58.1% vs 79.2%, p = 0.080), ORR (13.9% vs 25.0%, p = 0.425) and the incidence of grade 3-4 adverse events (34.8% vs 33.3%, p = 1.000). In addition, there existed no obvious difference between the RNA-positive group and RNA-negative group in terms of median OS (14 months vs 19 months, p = 0.578) and median PFS (4 months vs 6 months, p = 0.238). Conclusion: The patients having HCV-related uHCC after being treated with the TKI and PD-1 inhibitor combination therapy exhibited a better prognosis and manageable toxicity compared to the patients who underwent TKI monotherapy.

A multi-center retrospective study on the efficacy and safety of regorafenib vs. regorafenib combined with PD-1 inhibitors as a second-line therapy in patients with advanced hepatocellular carcinoma.

Background: At present, there are no definitive optimal treatment options for patients with hepatocellular carcinoma (HCC) following first-line treatment failure. To maximize the survival benefit of patients, we compared the combination therapy of regorafenib and programmed death-1 (PD-1) inhibitors with regorafenib monotherapy as a second-line treatment for patients with advanced HCC. Methods: Our multicenter retrospective study evaluated consecutive patients with advanced HCC who received regorafenib plus PD-1 inhibitors or regorafenib alone as a later-line therapy from May 2019 to January 2022. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria, and safety was assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results: A total of 133 patients were included in the study (regardless of first-line treatment), including 94 who received regorafenib plus PD-1 inhibitors and 39 who received regorafenib. The regorafenib plus PD-1 inhibitors group had a significantly higher ORR (25.53% vs. 10.26%, P=0.015), higher DCR (87.23% vs. 66.67%, P=0.006), and longer PFS (median 9.0 vs. 4.0 months, P<0.0001) than the regorafenib group. Meanwhile, the median OS (mOS) did not differ between the regorafenib plus PD-1 and regorafenib monotherapy groups {mOS, 14.0 months [95% confidence interval (CI), 14.0-16.0 months] vs. 12.0 months (95% CI, 10.0-22.0 months)}. There was no notable difference in the total incidence of treatment-related adverse effects (TRAEs) (71.79% vs. 78.72%, P=0.39) and the incidence of grade 3/4 serious adverse effects (5.13% vs. 18.09%, P=0.19) between the regorafenib monotherapy group and PD-1 inhibitors combination group. Conclusions: Compared with regorafenib alone, regorafenib combined with PD-1 inhibitors therapy increased PFS, ORR but did not improve OS, and can be used an option in second-line HCC therapy, regardless of first-line treatments. Regorafenib combined with PD-1 inhibitors is recommended as early as a second-line therapy to benefit patients. The combination regimen was as safe as regorafenib monotherapy for treatment of HCC in patients with compensated liver disease [Child-Turcotte-Pugh (CTP) A/B].

Comparison of hepatitis B virus reactivation in hepatocellular carcinoma patients who received tyrosine kinase inhibitor alone or together with programmed cell death protein-1 inhibitors.

BACKGROUND AND AIMS: Programmed cell death protein-1 (PD-1) inhibitors plus tyrosine kinase inhibitor (TKI) have dramatically improved survival of patients with advanced hepatocellular carcinoma (HCC). However, the risk of hepatitis B virus (HBV) reactivation from these antitumor medications remains unclear. METHODS: Patients receiving TKI monotherapy (TKI group) or TKI combined with PD-1 inhibitors (combination group) were included. The primary endpoint was HBV reactivation as defined by an increase in HBV DNA titer by at least 1 log (tenfold) from baseline. The secondary endpoints included tumor progression and overall survival. RESULTS: Four hundred and ninety-nine patients met the inclusion criteria, including 296 patients in the TKI group and 203 patients in the combination group. The 3-, 6- and 12-month cumulative incidence rates of HBV reactivation in the TKI group vs. combination group were 7.8%, 12.8% and 21.3% vs. 9.9%, 19.2% and 30.0%, respectively (p = 0.02). The Cox proportional hazard model indicated that combination therapy (HR 1.41, 95% CI 1.00-1.99, p = 0.05), ALT > 40 U/ml (HR 1.50, 95% CI 1.05-2.16, p = 0.03), and tumor size > 5 cm (HR 1.58, 95% CI 1.10-2.28, p = 0.01) were independent risk factors for HBV reactivation. Compared with the HBV reactivation group, the progression-free survival and overall survival of patients in the HBV non-reactivation group were significantly prolonged (p < 0.001 and p = 0.001). CONCLUSIONS: Patients who received TKI combined with PD-1 inhibitors had a greater risk for HBV reactivation, and those with HBV reactivation had a higher rate of tumor progression and shorter survival time, than those receiving TKI alone.

Validation of different personalized risk models of chemotherapy-induced nausea and vomiting: results of a randomized, double-blind, phase III trial of fosaprepitant for cancer patients treated with high-dose cisplatin.

BACKGROUND: Highly emetogenic chemotherapy induces emesis in cancer patients without prophylaxis. The purpose of this study was to evaluate the efficacy and safety of a fosaprepitant-based triple antiemetic regimen for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with solid malignant tumors, determine risk factors and externally validate different personalized risk models for CINV. METHODS: This phase III trial was designed to test the non-inferiority of fosaprepitant toward aprepitant in cancer patients who were to receive the first cycle of single-day cisplatin chemotherapy. The primary endpoint was complete response (CR) during the overall phase (OP) with a non-inferiority margin of 10.0%. Logistic regression models were used to assess the risk factors of CR and no nausea. To validate the personalized risk models, the accuracy of the risk scoring systems was determined by measuring the specificity, sensitivity and area under the receiver operating characteristic (ROC) curve (AUC), while the predictive accuracy of the nomogram was measured using concordance index (C-index). RESULTS: A total of 720 patients were randomly assigned. CR during the OP in the fosaprepitant group was not inferior to that in the aprepitant group (78.1% vs. 77.7%, P = 0.765) with a between-group difference of 0.4% (95% CI, -5.7% to 6.6%). Female sex, higher cisplatin dose (≥ 70 mg/m2 ), no history of drinking and larger body surface area (BSA) were significantly associated with nausea. The AUC for the acute and delayed CINV risk indexes was 0.68 (95% CI: 0.66-0.71) and 0.66 (95% CI: 0.61-0.70), respectively, and the C-index for nomogram CINV prediction was 0.59 (95% CI, 0.54-0.64). Using appropriate cutoff points, the three models could stratify patients with high- or low-risk CINV. No nausea and CR rate were significantly higher in the low-risk group than in the high-risk group (P < 0.001). CONCLUSIONS: Fosaprepitant-based triple prophylaxis demonstrated non-inferior control for preventing CINV in patients treated with cisplatin-base chemotherapy. Female cancer patients without a history of alcohol consumption, with larger BSA and received high-dose cisplatin might be more vulnerable to CINV. Three personalized prediction models were well-validated and could be used to optimize antiemetic therapy for individual patients.

TKI or TKI combined with PD-1 inhibitors as second-line treatment for HCC patients after sorafenib failure.

Background: Tyrosine kinase inhibitors (TKI) in combination with programmed cell death-1 (PD-1) inhibitors become the potential treatment modality for patients undergoing unresectable hepatocellular carcinoma (uHCC) in the first-line setting. However, the efficacy and safety of this combination regimen in patients after sorafenib failure remains unclear. Methods: Participants in this study included patients with uHCC after sorafenib failure who received TKI monotherapy (TKI group) or TKI combined with PD-1 inhibitors therapy (combination group) in our center from July 2018 to July 2021. The overall survival (OS) was used to be the primary efficacy endpoint, while progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were applied to be secondary endpoints. In addition, the adverse events are recorded and evaluated. Results: Among the 92 patients contained in this work, 50 patients were categorized into the TKI group, while 42 patients were in the combination group. There existed no evident differences between the two groups concerning the ORR (8.0% vs. 9.5%, p = 1.000). However, the DCR in the combined group was better in relative to that in the TKI group (71.4% vs. 50.0%, p = 0.037). In comparison with the TKI group, it was found that the combination group presented notably better median PFS (8.1 months vs. 4.7 months, p = 0.005) and median OS (21.9 months vs. 16.6 months, p = 0.042). According to multivariate analysis, PFS (HR 0.5, 95% CI: 0.3-0.8, p = 0.005) and OS (HR 0.5, 95% CI: 0.3-1.0, p = 0.051) were improved in the combination group in relative to the TKI group after the adjustment for some risk factors. Additionally, the incidence rates of grade ≥1 adverse event in the TKI group and the combination group were 96.0% and 97.6%, respectively. The most normal adverse event in the TKI group was neutropenia (n = 24,48.0%) and the combination group was hypoalbuminemia (n = 23,54.8%). All of these adverse events improved after symptomatic treatment, and no new toxic events were found to occur. Conclusion: TKI combined with PD-1 inhibitors showed better prognosis with manageable toxicity in uHCC patients after sorafenib failure compared with TKI monotherapy.