Cost-effectiveness analysis of toripalimab for metastatic or recurrent triple-negative breast cancer

BackgroundToliparibizumab in combination with nab-paclitaxel (T+N) has excellent efficacy inmetastatic or recurrent triple-negative breast cancer (TNBC), but the optimal choice of sequence of therapy is unclear given the trade-offs between quality of life and cost. Cost-effectiveness analyses can quantify these tradeoffs, leading to more informed decisions. Our objective was to assess the societal cost-effectiveness of the T+N regimen for metastatic or recurrent TNBC.MethodsClinical data were extracted from a multicenter, randomized, double-blind trial, TORCHLIGHT (NCT04085276). Patients were randomized into the T+N group or placebo plus nab-paclitaxel (P+N) group. 531 patients from 53 study locations were randomly assigned (T+N, n=353; P+N, n=178) into intend to treat (ITT) population; 200 and 100 patients, respectively had programmed death protein 1 (PD-L1) positive TNBC. A Markov model was established with a 21-day cycle length. Costs were acquired from local hospitals, effect parameters included quality-adjusted life year (QALY) and incremental cost-effectiveness ratio (ICER).ResultsThe cost differences were 47,538.3 CNY in ITT population (T+N, 143,725.67 CNY; P+N group, 96,187.37 CNY) and 29,258.84 CNY in PD-L1+ subgroup (T+N, 100,128.28 CNY; P+N group, 70,869.45 CNY). Meanwhile, the IEs were 0.03409 in the ITT population (T+N, 0.55323 QALY; P+N, 0.51914 QALY) and 0.03409 in the PD-L1+ subgroup (T+N, 0.42327 QALY; P+N, 0.37628 QALY). The ICERs between T+N and P+N groups were 1,394,548.41 CNY/QALY in the ITT population and 622,663.98 CNY/QALY in the PD-L1+ subgroup. We also analyzed the cost-effectiveness of toripalimab could be received in the Chinese medical insurance catalog. If toripalimab could be reimbursed at an 80% rate, the cost differences were changed to 16,598.99 CNY in ITT population (T+N, 112,786.36 CNY; P+N group, 96,187.37 CNY) and 7,704.58 CNY in PD-L1+ subgroup (T+N, 78,574.03 CNY; P+N group, 70,869.45 CNY). Meanwhile, the IEs remained unchanged. The ICERs between T+N and P+N groups were changed to 486,935.82 CNY/QALY in the ITT population and 163,962.96 CNY/QALY in the PD-L1+ subgroup. Sensitivity analyses indicated the stability of the model and the impact of utility.ConclusionAt current drug prices, the T+N group is not more cost-effective than the P+N group, but after incorporating toripalimab into medical insurance, the T+N group will be more cost-effective for patients with PD-L1+ metastatic or recurrent triple-negative breast cancer

Silver Nanoparticles Induce Tight Junction Disruption and Astrocyte Neurotoxicity in a Rat Blood-Brain Barrier Primary Triple Coculture Model

BACKGROUND: Silver nanoparticles (Ag-NPs) can enter the brain and induce neurotoxicity. However, the toxicity of Ag-NPs on the blood-brain barrier (BBB) and the underlying mechanism(s) of action on the BBB and the brain are not well understood. METHOD: To investigate Ag-NP suspension (Ag-NPS)-induced toxicity, a triple coculture BBB model of rat brain microvascular endothelial cells, pericytes, and astrocytes was established. The BBB permeability and tight junction protein expression in response to Ag-NPS, NP-released Ag ions, and polystyrene-NP exposure were investigated. Ultrastructural changes of the microvascular endothelial cells, pericytes, and astrocytes were observed using transmission electron microscopy (TEM). Global gene expression of astrocytes was measured using a DNA microarray. RESULTS: A triple coculture BBB model of primary rat brain microvascular endothelial cells, pericytes, and astrocytes was established, with the transendothelial electrical resistance values \u3e200 Ω·cm2. After Ag-NPS exposure for 24 hours, the BBB permeability was significantly increased and expression of the tight junction (TJ) protein ZO-1 was decreased. Discontinuous TJs were also observed between microvascular endothelial cells. After Ag-NPS exposure, severe mitochondrial shrinkage, vacuolations, endoplasmic reticulum expansion, and Ag-NPs were observed in astrocytes by TEM. Global gene expression analysis showed that three genes were upregulated and 20 genes were downregulated in astrocytes treated with Ag-NPS. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the 23 genes were associated with metabolic processes, biosynthetic processes, response to stimuli, cell death, the MAPK pathway, and so on. No GO term and KEGG pathways were changed in the released-ion or polystyrene-NP groups. Ag-NPS inhibited the antioxidant defense of the astrocytes by increasing thioredoxin interacting protein, which inhibits the Trx system, and decreasing Nr4a1 and Dusp1. Meanwhile, Ag-NPS induced inflammation and apoptosis through modulation of the MAPK pathway or B-cell lymphoma-2 expression or mTOR activity in astrocytes. CONCLUSION: These results draw our attention to the importance of Ag-NP-induced toxicity on the neurovascular unit and provide a better understanding of its toxicological mechanisms on astrocytes

Parathyroid Hormone-Related Protein (1-40) Enhances Calcium Uptake in Rat Enterocytes Through PTHR1 Receptor and Protein Kinase Cα/β Signaling

Background/Aims: Parathyroid hormone-related protein (PTHrP) is implicated in regulating calcium homeostasis in vertebrates, including sea bream, chick, and mammals. However, the molecular mechanism underlying the function of PTHrP in regulating calcium transport is still not fully investigated. This study aimed to investigate the effect of PTHrP on the calcium uptake and its underlying molecular mechanism in rat enterocytes. Methods: The rat intestinal epithelial cell line (IEC-6) was used. Calcium uptake was determined by using the fluo-4 acetoxymethyl ester fluorescence method. The expression levels of RNAs and proteins was assessed by RT-PCR and Western-blot, respectively. Results: PTHrP (1-40) induced rapid calcium uptake in enterocytes in a dose-dependent manner. PTHrP (1-40) up-regulated parathyroid hormone 1 receptor (PTHR1) protein but not 1,25D3-MARRS receptor. Pre-treatment of anti- PTHR1 antibody abolished the PTHrP (1-40)-induced calcium uptake. PTHrP (1-40) significantly up-regulated four transcellular calcium transporter proteins, potential vanilloid member 6 (TRPV6), calbindin-D9k (CaBP-D9k), sodium-calcium exchanger 1 (NCX1) and plasma membrane calcium ATPase 1 (PMCA1), in a dose- and time-dependent manner. Pre-treatment with TRPV6 or CaBP-D9k antibodies or knockout of rat TRPV6 or CaBP-D9k markedly inhibited PTHrP (1-40)-induced calcium uptake, whereas inhibition of NCX or PMCA1 by antibodies or inhibitors had no effect on PTHrP(1-40)-induced calcium uptake. Furthermore, PTHrP (1-40) treatment up-regulated protein levels of protein kinase C (PKC α/β) and protein kinase A (PKA). Pretreatment of PKC α/β inhibitor (but not PKA inhibitor) inhibited PTHrP (1-40)-induced calcium uptake. Conclusion: PTHrP (1-40) stimulates calcium uptake via PTHR1 receptor and PKC α/β signaling pathway in rat enterocytes, and calcium transporters TRPV6 and CaBP-D9k are necessary for this stimulatory effect

Ameliorative effects of eosinophil deficiency on immune response, endoplasmic reticulum stress, apoptosis, and autophagy in fungus-induced allergic lung inflammation

Abstract Background Respiratory fungal exposure is known to be associated with various allergic pulmonary disorders. Eosinophils have been implicated in tissue homeostasis of allergic inflammation as both destructive effector cells and immune regulators. What contributions eosinophils have in Aspergillus fumigatus (Af)-induced allergic lung inflammation is worthy of investigating. Methods We established the Af-exposed animal asthmatic model using eosinophil-deficient mice, ∆dblGATA1 mice. Airway inflammation was assessed by histopathological examination and total cell count of bronchoalveolar lavage fluid (BALF). The protein level in BALF and lung mRNA level of type 2 cytokines IL-4, IL-5, and IL-13 were detected by ELISA and qRT-PCR. We further studied the involvement of endoplasmic reticulum (ER) stress, apoptosis, and autophagy by western blots, qRT-PCR, immunofluorescence, TUNEL, or immunohistochemistry. RNA-Seq analysis was utilized to analyze the whole transcriptome of Af-exposed ∆dblGATA1 mice. Results Hematoxylin and eosin (HE) staining and periodic acid–Schiff staining (PAS) showed that airway inflammation and mucus production were alleviated in Af-challenged ∆dblGATA1 mice compared with wild-type controls. The protein and mRNA expressions of IL-4, IL-5, and IL-13 were reduced in the BALF and lung tissues in Af-exposed ∆dblGATA1 mice. The results demonstrated that the significantly increased ER stress markers (GRP78 and CHOP) and apoptosis executioner caspase proteases (cleaved caspase-3 and cleaved caspase-7) in Af-exposed wild-type mice were all downregulated remarkably in the lungs of ∆dblGATA1 mice with Af challenge. In addition, the lung autophagy in Af-exposed ∆dblGATA1 mice was found elevated partially, manifesting as higher expression of LC3-II/LC3-I and beclin1, lower p62, and downregulated Akt/mTOR pathway compared with Af-exposed wild-type mice. Additionally, lung RNA-seq analysis of Af-exposed ∆dblGATA1 mice showed that biological processes about chemotaxis of lymphocytes, neutrophils, or eosinophils were enriched but without statistical significance. Conclusions In summary, eosinophils play an essential role in the pathogenesis of Af-exposed allergic lung inflammation, whose deficiency may have relation to the attenuation of type 2 immune response, alleviation of ER stress and apoptosis, and increase of autophagy. These findings suggest that anti-eosinophils therapy may provide a promising direction for fungal-induced allergic pulmonary diseases

Data Redundancy Mitigation in V2X based Collective Perceptions

Collective perception is a new paradigm to extend the limited horizon of individual vehicles. Incorporating with the recent vehicle-2-x (V2X) technology, connected and autonomous vehicles (CAVs) can periodically share their sensory information, given that traffic management authorities and other road participants can benefit from these information enormously. Apart from the benefits, employing collective perception could result in a certain level of transmission redundancy, because the same object might fall in the visible region of multiple CAVs, hence wasting the already scarce network resources. In this paper, we analytically study the data redundancy issue in highway scenarios, showing that the redundant transmissions could result in heavy loads on the network under medium to dense traffic. We then propose a probabilistic data selection scheme to suppress redundant transmissions. The scheme allows CAVs adaptively adjust the transmission probability of each tracked objects based on the position, vehicular density and road geometry information. Simulation results confirm that our approach can reduce at most 60% communication overhead in the meanwhile maintain the system reliability at desired levels

Uneven aftershock distribution of Wenchuan Ms8.0 earthquake and possible mechanism

The aftershock activity of Wenchuan Ms8.0 earthquake showed different spatial and temporal distributions along two different segments of the Longmenshan fault. This difference was likely the result of segmentation of the earthquake rupture process, which in turn may be the result of the fault’s segmentation in its long-term geotectonic condition