Effect of emulsifiers on the properties of corn starch films incorporated with Zanthoxylum bungeanum essential oil.

The use of natural and safe ingredients in green food packaging material is a hot research topic. This study investigated the effect of different emulsifiers on starch film properties. Three types of emulsifiers, including Tween 80 as a small-molecule surfactant, sodium caseinate (CAS), whey protein isolate (WPI), and gelatin (GE) as macromolecule emulsifiers, whey protein isolate fibril (WPIF) as a particle emulsifier, were utilized to prepare Zanthoxylum bungeanum essential oil (ZBO) emulsions. The mechanical, physical, thermal, antibacterial properties, microstructure and essential oil release of starch films were investigated. CAS-ZBO nanoemulsion exhibited the smallest particle size of 198.6 ± 2.2 nm. The film properties changed with different emulsifiers. CAS-ZBO film showed the highest tensile strength value. CAS-ZBO and WPIF-ZBO films exhibited lower water vapor permeability than Tween-ZBO. CAS-ZBO film showed good dispersion of essential oil, the slowest release rate of essential oils in all food simulants, and the best antibacterial effect against Staphylococcus aureus and Listeria monocytogenes. The films composed of CAS-ZBO nanoemulsion, corn starch, and glycerol are considered more suitable for food packaging. This work indicated that natural macromolecule emulsifiers of CAS and WPIF are expected to be used in green food packaging material to offer better film properties.

Valuation of EQ-5D-5L health states from cancer patients' perspective: a feasibility study.

OBJECTIVES: To assess the feasibility of estimating an EQ-5D-5L value set using a small study design in cancer patients and to compare the EQ-5D-5L values based on the preferences of cancer patients with those of the general public. METHODS: Patients with clinically diagnosed cancers were recruited from two hospitals in Shanghai, China. In face-to-face interviews using the EQ-PVT survey, health states were valued by cancer patients using both cTTO and DCE methods. cTTO data was modelled alone or jointly with DCE data. Forty-eight models using different model specifications (cross-attribute level effect [CALE] and additive models), random/fixed effects model assumptions, data heteroscedasticity and censoring were estimated. The best performed model was identified in terms of monotonicity of estimated model coefficients and out-of-sample prediction accuracy. RESULTS: Data collected from 221 cancer patients who participated in the study were included. The hybrid CALE model using both TTO and DCE data performed best in terms of prediction accuracy (Lin's concordance coefficient = 0.989; root mean squared error = 0.058) and suggested that pain/discomfort and anxiety/depression were the most undesirable health problems. Compared to values based on general Chinese public's health preferences, the values based on cancer patients' preferences were much higher and lower for health states characterized by extreme mobility problems and severe/extreme pain or discomfort, respectively. CONCLUSION: This study demonstrated the feasibility of using a small design to develop EQ-5D-5L value sets based on cancer patients' health preferences. Since there were signs of differences between preferences of patients and general population, it may be valuable to develop patient-specific value sets and use them in clinical decision making and economic evaluations.

Cost-effectiveness of sacituzumab govitecan versus chemotherapy in advanced or metastatic triple-negative breast cancer.

PURPOSE: The ASCENT trial demonstrated the efficacy of sacituzumab govitecan for the treatment of advanced or metastatic triple-negative breast cancer (TNBC). The current study evaluated the cost-effectiveness of receiving sacituzumab govitecan compared with standard of care chemotherapy from the United States payer perspective. METHODS: A partitioned survival approach was used to project the disease course of advanced or metastatic TNBC. Two survival modes were applied to analyze two groups of patients. The survival data were gathered from the ASCENT trial. Direct medical costs were derived from the data of Centers for Medicare & Medicaid Services. Utility data was collected from the published literature. The incremental cost-utility ratio (ICUR) was the primary outcome that measured the cost-effectiveness of therapy regimen. One-way sensitivity and probabilistic sensitivity analysis were implemented to explore the uncertainty and validate the stability of results. RESULTS: In the base-case, the ICUR of sacituzumab govitecan versus chemotherapy is $ 778,771.9/QALY and $ 702,281/QALY for full population group and brain metastatic-negative (BMN) group with the setting of classic survival mode. And in the setting of cure survival mode, the ICUR is $ 506,504.5/QALY for the full population group and $ 274,232.0/QALY for BMN population group. One-way sensitivity analyses revealed that the unit cost of sacituzumab govitecan and body weight were key roles that lower the ICUR value. Probabilistic sensitivity analyses also showed that reducing the unit price of sacituzumab govitecan can improve the likelihood of becoming cost-effective. CONCLUSION: The cost-effectiveness analysis suggested that from a US payer perspective, sacituzumab govitecan at current price is unlikely to be a preferred option for patients with advanced or metastatic TNBC at a threshold of $ 150,000/QALY.

Atezolizumab plus platinum-based chemotherapy as first-line therapy for metastatic urothelial cancer: A cost-effectiveness analysis.

Purpose: According to the IMvigor130 trial, adding atezolizumab to platinum-based chemotherapy was effective in the treatment of metastatic urothelial cancer (mUC). Based on the perspective of the United States and China, the current study evaluated cost-effectiveness of atezolizumab plus chemotherapy for mUC patients in the first-line setting. Methods: A partitioned survival model was adopted for mUC patients. The survival data were derived from the IMvigor130 trial. Direct cost values were collected from the Centers for Medicare and Medicaid Services (CMS), Chinese Drug Bidding Database, and published literatures. The utility and toxicity data were gathered from related research studies and IMvigor130 trial. The incremental cost-utility ratios (ICURs) and incremental cost-effectiveness ratios (ICERs) were calculated and analyzed. Scenario analyses and sensitivity analyses were performed to observe the outputs and uncertainties. Results: The base-case analysis showed that the ICUR of atezolizumab plus chemotherapy versus chemotherapy in American and Chinese settings is $ 737,371 /QALY and $ 385,384 /QALY, respectively. One-way sensitivity analyses showed that the ICUR ranged from $ 555,372/QALY to $ 828,205/QALY for the United States. Also, the range was from $ 303,099/QALY to $ 433,849/QALY in the Chinese setting. A probabilistic sensitivity analysis showed the likelihood that atezolizumab plus chemotherapy becoming the preferred strategy was a little low even if the price reduction strategy was applied. Conclusion: Adding atezolizumab to chemotherapy improved survival time, but it is not a cost-saving option compared to chemotherapy for metastatic urothelial cancer patients in the American and Chinese settings.

Budget Impact Analysis of the Introduction of a Trastuzumab Biosimilar for HER2-Positive Breast Cancer in China.

BACKGROUND AND OBJECTIVE: Biosimilars provide the possibility to reduce the high expenditure on biologic drugs and expand access to effective but less expensive treatments. Biosimilars of trastuzumab showed significant cost savings from the payer's perspective in the USA and Europe. After 2020, with the first approval of a trastuzumab biosimilar in China, it became feasible for biosimilar switching for trastuzumab. However, the economic impact of switching to a trastuzumab biosimilar was not evaluated. A budget impact model was constructed from a payer's perspective of China to demonstrate the economic impact of the introduction of a biosimilar trastuzumab in the treatment of human epidermal growth factor receptor 2-positive breast cancer. METHODS: This budget impact model was based on disease incidence to estimate the net budget impact using epidemiological data from the literature, financial reports from manufacturers on the market shares of originator trastuzumab (Herceptin®) or the biosimilar, and localized direct costs. The budget impact was estimated for 5 years after the introduction of the first-approved trastuzumab biosimilar in China. Furthermore, two scenarios were simulated in this study to estimate the budget impact of biosimilars within: (1) real-world practice and (2) the policy of volume-based procurement. RESULTS: Analyses of the base-case and scenario results implied that adoption of a trastuzumab biosimilar would lead to an expenditure decrease. The average total cost savings over 5 years was estimated to be US$46,651,348, with a range from $10,306,611 in year 1 to $60,821,822 in year 5. The cost savings could benefit an additional 654-3858 patients with breast cancer. If utilizing costs from real-world practice, the introduction of a trastuzumab biosimilar could help an additional 2237-13,203 patients get access to human epidermal growth factor receptor 2-positive targeted therapy. When volume-based procurement was carried out after year 4, $672,366,180 could be saved annually. CONCLUSIONS: This budget impact analysis emphasized the positive effects of adopting a trastuzumab biosimilar in the healthcare system of China. However, cost savings still have a large potential to decrease by regulating pricing and by the procurement policy of biosimilars.

Protein disulfide isomerases (PDIs) negatively regulate ebolavirus structural glycoprotein expression in the endoplasmic reticulum (ER) via the autophagy-lysosomal pathway.

Zaire ebolavirus (EBOV) causes a severe hemorrhagic fever in humans and non-human primates with high morbidity and mortality. EBOV infection is dependent on its structural glycoprotein (GP), but high levels of GP expression also trigger cell rounding, detachment, and downregulation of many surface molecules that is thought to contribute to its high pathogenicity. Thus, EBOV has evolved an RNA editing mechanism to reduce its GP expression and increase its fitness. We now report that the GP expression is also suppressed at the protein level in cells by protein disulfide isomerases (PDIs). Although PDIs promote oxidative protein folding by catalyzing correct disulfide formation in the endoplasmic reticulum (ER), PDIA3/ERp57 adversely triggered the GP misfolding by targeting GP cysteine residues and activated the unfolded protein response (UPR). Abnormally folded GP was targeted by ER-associated protein degradation (ERAD) machinery and, unexpectedly, was degraded via the macroautophagy/autophagy-lysosomal pathway, but not the proteasomal pathway. PDIA3 also decreased the GP expression from other ebolavirus species but increased the GP expression from Marburg virus (MARV), which is consistent with the observation that MARV-GP does not cause cell rounding and detachment, and MARV does not regulate its GP expression via RNA editing during infection. Furthermore, five other PDIs also had a similar inhibitory activity to EBOV-GP. Thus, PDIs negatively regulate ebolavirus glycoprotein expression, which balances the viral life cycle by maximizing their infection but minimizing their cellular effect. We suggest that ebolaviruses hijack the host protein folding and ERAD machinery to increase their fitness via reticulophagy during infection.Abbreviations: 3-MA: 3-methyladenine; 4-PBA: 4-phenylbutyrate; ACTB: ß-actin; ATF: activating transcription factor; ATG: autophagy-related; BafA1: bafilomycin A1; BDBV: Bundibugyo ebolavirus; CALR: calreticulin; CANX: calnexin; CHX: cycloheximide; CMA: chaperone-mediated autophagy; ConA: concanamycin A; CRISPR: clusters of regularly interspaced short palindromic repeats; Cas9: CRISPR-associated protein 9; dsRNA: double-stranded RNA; EBOV: Zaire ebolavirus; EDEM: ER degradation enhancing alpha-mannosidase like protein; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; Env: envelope glycoprotein; ER: endoplasmic reticulum; ERAD: ER-associated protein degradation; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; GP: glycoprotein; HA: hemagglutinin; HDAC6: histone deacetylase 6; HMM: high-molecular-mass; HIV-1: human immunodeficiency virus type 1; HSPA5/BiP: heat shock protein family A (Hsp70) member 5; IAV: influenza A virus; IP: immunoprecipitation; KIF: kifenesine; Lac: lactacystin; LAMP: lysosomal associated membrane protein; MAN1B1/ERManI: mannosidase alpha class 1B member 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MARV: Marburg virus; MLD: mucin-like domain; NHK/SERPINA1: alpha1-antitrypsin variant null (Hong Kong); NTZ: nitazoxanide; PDI: protein disulfide isomerase; RAVV: Ravn virus; RESTV: Reston ebolavirus; SARS-CoV: severe acute respiratory syndrome coronavirus; SBOV: Sudan ebolavirus; sGP: soluble GP; SQSTM1/p62: sequestosome 1; ssGP: small soluble GP; TAFV: Taï Forest ebolavirus; TIZ: tizoxanide; TGN: thapsigargin; TLD: TXN (thioredoxin)-like domain; Ub: ubiquitin; UPR: unfolded protein response; VLP: virus-like particle; VSV: vesicular stomatitis virus; WB: Western blotting; WT: wild-type; XBP1: X-box binding protein 1.

HIV-1 Nef interacts with the cyclin K/CDK13 complex to antagonize SERINC5 for optimal viral infectivity.

HIV-1-negative factor (Nef) protein antagonizes serine incorporator 5 (SERINC5) by redirecting this potent restriction factor to the endosomes and lysosomes for degradation. However, the precise mechanism remains unclear. Using affinity purification/mass spectrometry, we identify cyclin K (CycK) and cyclin-dependent kinase 13 (CDK13) as a Nef-associated kinase complex. CycK/CDK13 phosphorylates the serine at position 360 (S360) in SERINC5, which is required for Nef downregulation of SERINC5 from the cell surface and its counteractivity of the SERINC5 antiviral activity. To understand the role of S360 phosphorylation, we generate chimeric proteins between CD8 and SERINC5 to study their response to Nef. Nef not only downregulates but, importantly, also binds to this chimera in an S360-dependent manner. Thus, S360 phosphorylation increases interactions between Nef and SERINC5 and initiates the destruction of SERINC5 by the endocytic machinery.

Economic burden of patients with advanced non-small-cell lung cancer receiving nivolumab versus chemotherapy in China.

Aim: As new treatment patterns are gradually being used in patients with non-small-cell lung cancer, it is necessary to have a better understanding of real-world data on clinical practices and their potential impact on healthcare resource utilization (HCRU). Patients & methods: A retrospective observational study was conducted with electronic medical records from Shanghai Chest Hospital. Hospitalized patients treated with nivolumab or second-line chemotherapy were included. Results: A total of 296 patients were included in this study, of whom 187 were treated with nivolumab. About 74.33% received nivolumab monotherapy at different doses. The mean cost of nivolumab was $3334.14 (±86.69). Nivolumab decreased inpatient days to 1.9545 days with a more stable cost and HCRU per cycle. Conclusion: Nivolumab is expensive but it reduces other HCRU.

The Differences in the Safety and Tolerability of Immune Checkpoint Inhibitors as Treatment for Non-Small Cell Lung Cancer and Melanoma: Network Meta-Analysis and Systematic Review.

Background: Immune checkpoint inhibitors (ICIs) have evolved for the treatment of solid tumors. In addition to the efficacy of ICIs for cancer, the adverse events (AEs) of ICIs are also noteworthy for gradually more extensive clinical use. Objective: To conduct a systematic review and network meta-analysis to evaluate the treatment-related AEs that occurred in clinical trials using different kinds of ICIs, to explore the differences in AEs among ICIs for treating non-small cell lung cancer (NSCLC) and melanoma, and to compare select immune-related AEs. Methods: PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and other available sources were systematically searched for published reports up to January 1, 2019. Two reviewers independently selected reports about phase II/III randomized controlled trials to compare among ICIs and between ICIs and chemotherapy. After the bias assessment of all included trials, a Bayesian network meta-analysis was performed. The primary outcomes were any-grade and high-grade treatment-related AEs from all ICIs. The secondary outcomes were AEs in patients with NSCLC and melanoma and the presence of the select AEs pneumonitis/pneumonia and colitis. Results: Eighteen randomized controlled trials containing 11,223 patients with NSCLC or melanoma were included. A total network meta-analysis was conducted. The meta-analysis showed that atezolizumab 1,200 mg and pembrolizumab 2 mg/kg every 3 weeks were generally more tolerable than other ICIs. ICI combined with chemotherapy might suggest a higher risk of treatment-related AEs than monotherapy with a single ICI, except durvalumab and ipilimumab. In the NSCLC subgroup, pembrolizumab was associated with a higher risk of high-grade AEs than nivolumab. In addition, ICIs (nivolumab, atezolizumab, and avelumab) led to a lower risk of any/high-grade treatment-related AEs than traditional chemotherapy and ICI combination chemotherapy. However, ICIs did not present preferable safety and tolerability compared to chemotherapy in treating melanoma. Compared with chemotherapy, nivolumab, durvalumab, two ICIs, and ICI combined chemotherapy led to more pneumonitis/pneumonia. However, when treating NSCLC, different types of ICIs did not differ significantly regarding the incidence of pneumonitis/pneumonia. A combination of nivolumab and ipilimumab had the highest risk for colitis, while pembrolizumab and atezolizumab had a lower possibility than the other ICIs. Conclusion: Atezolizumab 1,200 mg and pembrolizumab 2 mg/kg every 3 weeks were ordinarily safer than other ICIs. When treating NSCLC, nivolumab had the lowest risk; when treating melanoma, pembrolizumab had the lowest toxicity.

The retroviral accessory proteins S2, Nef, and glycoMA use similar mechanisms for antagonizing the host restriction factor SERINC5.

Serine incorporator 5 (SERINC5) is a recently identified restriction factor that blocks virus entry but is antagonized by three unrelated retroviral accessory proteins. The S2 protein from equine infectious anemia virus (EIAV) has been reported to reduce SERINC5 expression at steady-state levels likely via the endocytic pathway; however, the precise mechanism is still unclear. Here, we investigated how EIAV S2 protein down-regulates SERINC5 compared with down-regulation induced by Nef from HIV-1 and glycoMA proteins from murine leukemia virus (MLV). Using bimolecular fluorescence complementation (BiFC) assay and immunoprecipitation (IP), we detected an interaction between S2 and SERINC5. We found that this interaction relies on the S2 myristoylation site, indicating that it may occur on the plasma membrane. S2 internalized SERINC5 via receptor-mediated endocytosis and targeted it to endosomes and lysosomes, resulting in a ubiquitination-dependent decrease in SERINC5 expression at steady-state levels. Both BiFC and IP detected a glycoMA-SERINC5 interaction, but a Nef-SERINC5 interaction was detected only by BiFC. Moreover, S2 and glycoMA down-regulated SERINC5 more effectively than did Nef. We further show that unlike Nef, both S2 and glycoMA effectively down-regulate SERINC2 and also SERINC5 from Xenopus tropicalis (xSERINC5). Moreover, we detected expression of the equine SERINC5 (eSERINC5) protein and observed that its expression is much weaker than expression levels of SERINC5 from other species. Nonetheless, eSERINC5 had a strong antiviral activity that was effectively counteracted by S2. We conclude that HIV-1, EIAV, and MLV share a similar mechanism to antagonize viral restriction by host SERINC5.

Poxviruses Evade Cytosolic Sensing through Disruption of an mTORC1-mTORC2 Regulatory Circuit.

Viruses employ elaborate strategies to coopt the cellular processes they require to replicate while simultaneously thwarting host antiviral responses. In many instances, how this is accomplished remains poorly understood. Here, we identify a protein, F17 encoded by cytoplasmically replicating poxviruses, that binds and sequesters Raptor and Rictor, regulators of mammalian target of rapamycin complexes mTORC1 and mTORC2, respectively. This disrupts mTORC1-mTORC2 crosstalk that coordinates host responses to poxvirus infection. During infection with poxvirus lacking F17, cGAS accumulates together with endoplasmic reticulum vesicles around the Golgi, where activated STING puncta form, leading to interferon-stimulated gene expression. By contrast, poxvirus expressing F17 dysregulates mTOR, which localizes to the Golgi and blocks these antiviral responses in part through mTOR-dependent cGAS degradation. Ancestral conservation of Raptor/Rictor across eukaryotes, along with expression of F17 across poxviruses, suggests that mTOR dysregulation forms a conserved poxvirus strategy to counter cytosolic sensing while maintaining the metabolic benefits of mTOR activity.

HIV-1 counteracts an innate restriction by amyloid precursor protein resulting in neurodegeneration.

While beta-amyloid (Aß), a classic hallmark of Alzheimer's disease (AD) and dementia, has long been known to be elevated in the human immunodeficiency virus type 1 (HIV-1)-infected brain, why and how Aß is produced, along with its contribution to HIV-associated neurocognitive disorder (HAND) remains ill-defined. Here, we reveal that the membrane-associated amyloid precursor protein (APP) is highly expressed in macrophages and microglia, and acts as an innate restriction against HIV-1. APP binds the HIV-1 Gag polyprotein, retains it in lipid rafts and blocks HIV-1 virion production and spread. To escape this restriction, Gag promotes secretase-dependent cleavage of APP, resulting in the overproduction of toxic Aß isoforms. This Gag-mediated Aß production results in increased degeneration of primary cortical neurons, and can be prevented by γ-secretase inhibitor treatment. Interfering with HIV-1's evasion of APP-mediated restriction also suppresses HIV-1 spread, offering a potential strategy to both treat infection and prevent HAND.

Distinct functions of diaphanous-related formins regulate HIV-1 uncoating and transport.

Diaphanous (Dia)-related formins (DRFs) coordinate cytoskeletal remodeling by controlling actin nucleation and microtubule (MT) stabilization to facilitate processes such as cell polarization and migration; yet the full extent of their activities remains unknown. Here, we uncover two discrete roles and functions of DRFs during early human immunodeficiency virus type 1 (HIV-1) infection. Independent of their actin regulatory activities, Dia1 and Dia2 facilitated HIV-1-induced MT stabilization and the intracellular motility of virus particles. However, DRFs also bound in vitro assembled capsid-nucleocapsid complexes and promoted the disassembly of HIV-1 capsid (CA) shell. This process, also known as "uncoating," is among the most poorly understood stages in the viral lifecycle. Domain analysis and structure modeling revealed that regions of Dia2 that bound viral CA and mediated uncoating as well as early infection contained coiled-coil domains, and that these activities were genetically separable from effects on MT stabilization. Our findings reveal that HIV-1 exploits discrete functions of DRFs to coordinate critical steps in early infection and identifies Dia family members as regulators of the poorly understood process of HIV-1 uncoating.

Recombinant rabies viruses expressing GM-CSF or flagellin are effective vaccines for both intramuscular and oral immunizations.

Our previous studies indicated that recombinant rabies viruses (rRABV) expressing chemokines or cytokines (including GM-CSF) could enhance the immunogenicity by recruiting and/or activating dendritic cells (DC). In this study, bacterial flagellin was cloned into the RABV genome and recombinant virus LBNSE-Flagellin was rescued. To compare the immunogenicity of LBNSE-Flagellin with recombinant virus expressing GMCSF (LBNSE-GMCSF), mice were immunized with each of these rRABVs by intramuscular (i.m.) or oral route. The parent virus (LBNSE) without expression of any foreign molecules was included for comparison. The i.m.-immunized mice were bled at three weeks after the immunization for the measurement of virus neutralizing antibody (VNA) and then challenged with 50 LD50 challenge virus standard (CVS-24). Orally immunized mice were boosted after three weeks and then bled and challenged one week after the booster immunization. It was found that both LBNSE-GMCSF and LBNSE-Flagellin recruited/activated more DCs and B cells in the periphery, stimulated higher levels of adaptive immune responses (VNA), and protected more mice against challenge infection than the parent virus LBNSE in both the i.m. and the orally immunized groups. Together, these studies suggest that recombinant RABV expressing GM-CSF or flagellin are more immunogenic than the parent virus in both i.m. and oral immunizations.