Development of a manganese complex hyaluronic acid hydrogel encapsulating stimuli-responsive Gambogic acid nanoparticles for targeted Intratumoral delivery.

Gambogic acid is a natural compound with anticancer properties and is effective for many tumors. But its low water solubility and dose-dependent side effects limit its clinical application. This study aims to develop a novel drug delivery system for intratumoral delivery of gambogic acid. In our experimental study, we propose a new method for encapsulating gambogic acid nanoparticles using a manganese composite hyaluronic acid hydrogel as a carrier, designed for targeted drug delivery to tumors. The hydrogel delivery system is synthesized through the coordination of hyaluronic acid-dopamine (HA-DOPA) and manganese ions. The incorporation of manganese ions serves three purposes:1.To form cross-linked hydrogels, thereby improving the mechanical properties of HA-DOPA.2.To monitor the retention of hydrogels in vivo in real-time using magnetic resonance imaging (MRI).3.To activate the body's immune response. The experimental results show that the designed hydrogel has good biosafety, in vivo sustained release effect and imaging tracking ability. In the mouse CT26 model, the hydrogel drug-loaded group can better inhibit tumor growth. Further immunological analysis shows that the drug-loaded hydrogel group can stimulate the body's immune response, thereby better achieving anti-tumor effects. These findings indicate the potential of the developed manganese composite hyaluronic acid hydrogel as an effective and safe platform for intratumoral drug delivery. The amalgamation of biocompatibility, controlled drug release, and imaging prowess positions this system as a promising candidate for tumor treatment.

Design of a single-center, phase II trial to explore the efficacy and safety of 'R-ISV-RO' treatment in advanced tumors.

Background: The authors' preclinical study has confirmed that RO adjuvant (composed of TLR 7 agonists [imiquimod/R837] and OX40 agonists) injected into local lesions induces the regression of both primary tumor and distant metastasis. The authors propose to realize local control and exert abscopal effect through an 'R-ISV-RO' in situ strategy plus anti-PD-1 monoclonal antibody in advanced tumors. Methods: This study is a single-center, exploratory, phase II trial to evaluate the efficacy and safety of R-ISV-RO plus anti-PD-1 monoclonal antibody in advanced tumors. 30 patients with one or more measurable extracerebral lesions that are accessible for radiation or injection will be enrolled. The primary endpoint is the objective response rate of target lesions. Discussion/Conclusion: The efficacy and safety of the novel strategy will be further validated through this clinical trial. Clinical trial registration: ChiCTR2100053870 (www.chictr.org.cn/).

Imaging Features of Invasive Fungal Rhinosinusitis: A Systematic Review.

Fungal rhinosinusitis (FRS) includes non-invasive and invasive subtypes with the latter having significant morbidity and mortality. This systematic review aims to identify the imaging features most correlated with invasive fungal rhinosinusitis (IFRS) and present a checklist of these features to aid diagnosis. PubMed, Embase, CENTRAL, and Science Direct were searched from inception to May 2023, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Primary research articles published in English describing the imaging features of IFRS were included. The systematic review was conducted in accordance with the PRISMA guidelines. Forty-eight articles were identified for inclusion. Six studies examined radiological features in acute invasive fungal rhinosinusitis (AIFRS), and 9 studies of chronic invasive fungal rhinosinusitis (CIFRS). A majority of studies did not specify whether IFRS cases were acute or chronic. On CT, bony erosion and mucosal thickening were the most common features. Other features include nasal soft tissue thickening, nasal cavity opacification, opacification of the affected sinus, and perisinus soft tissue infiltration. Extra-sinus extension was commonly observed on MRI, most often invading intraorbitally and intracranially. Other sites of extra-sinus extension included the cavernous sinus, pterygopalatine fossa, infratemporal fossa, masticator space, and facial soft tissue. IFRS is a condition with potential for high morbidity and mortality. Several radiological features are highly suggestive of IFRS. Early identification of high-risk radiological features using a checklist may aid prompt diagnosis and early treatment. Future research investigating the radiological differentiation between IFRS and other significant pathology including bacterial orbital cellulitis would be beneficial.

Pantoprazole and Vonoprazan Performed Well in Preventing Peptic Ulcer Recurrence in Low-Dose Aspirin Users.

BACKGROUND: Low-dose aspirin (LDA) administration is associated with an elevated risk of recurring peptic ulcer (PU) and gastrointestinal (GI) hemorrhage. AIMS: This systematic review and Bayesian network meta-analysis aimed to comprehensively assess the effectiveness of diverse medications in preventing the recurrence of PU and GI hemorrhage in patients with a history of PU receiving long-term LDA therapy. METHODS: This systematic review and network meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and was registered on PROSPERO (CRD42023406550). We searched relevant studies in main databases from inception to March 2023. All statistical analyses were performed using R (version 4.1.3), with the "Gemtc" (version 1.0-1) package. The pooled risk ratio (RR), corresponding 95% credible interval (95% CrI), and the surface under the cumulative ranking curve (SUCRA) were calculated. RESULTS: 11 Randomized clinical trials (RCTs) were included. The analysis underscored pantoprazole was the most efficacious for reducing the risk of PU recurrence (RR [95% CrI] = 0.02 [0, 0.28]; SUCRA: 90.76%), followed by vonoprazan (RR [95% CrI] = 0.03 [0, 0.19]; SUCRA: 86.47%), comparing with the placebo group. Pantoprazole also performed well in preventing GI hemorrhage (RR [95% CrI] = 0.01[0, 0.42]; SUCRA: 87.12%) compared with Teprenone. CONCLUSIONS: For patients with a history of PU receiving LDA, pantoprazole and vonoprazan might be the optimal choices to prevent PU recurrence and GI hemorrhage.

Comment on Golcic et al. Evaluation of Systemic Treatment Options for Gastrointestinal Stromal Tumours. Cancers 2023, 15, 4081.

We carefully read the article written by Golcic et al. "Evaluation of Systemic Treatment Options for Gastrointestinal Stromal Tumours" [...].

CT synthesis from CBCT using a sequence-aware contrastive generative network.

Computerized tomography (CT) synthesis from cone-beam computerized tomography (CBCT) is a key step in adaptive radiotherapy. It uses a synthetic CT to calculate the dose to correct and adjust the radiotherapy plan in a timely manner. The cycle-consistent adversarial network (Cycle GAN) is commonly used in CT synthesis tasks but it has some defects: (a) the premise of the cycle consistency loss is that the conversion between domains is bijective, but the CBCT and CT conversion does not fully satisfy the bijective relationship, and (b) it does not take advantage of the complementary information between multiple sets of CBCTs for the same patient. To address these problems, we propose a novel framework named the sequence-aware contrastive generative network (SCGN) that introduces an attention sequence fusion module to improve the CBCT quality. In addition, it not only applies contrastive learning to the generative adversarial networks (GANs) to pay more attention to the anatomical structure of CBCT in feature extraction but also uses a new generator to improve the accuracy of the anatomical details. Experimental results on our datasets show that our method significantly outperforms the existing unsupervised CT synthesis methods.

Bivalent Gadolinium Ions Forming Injectable Hydrogels for Simultaneous In Situ Vaccination Therapy and Imaging of Soft Tissue Sarcoma.

Doxorubicin (DOX) is the classic soft tissue sarcomas (STS) first-line treatment drug, while dose-dependent myelosuppression and cardiotoxicity limit its application in clinic. This research intends to apply DOX, which is also an inducer of immunogenic cell death as a part for "in situ vaccination" and conjointly uses PD-1 inhibitors to enhance antitumor efficacy. In order to achieve the sustained vaccination effect and real-time monitoring of distribution in vivo, the in situ forming and injectable hydrogel platform with the function of visualization is established for local delivery. The hydrogel platform is synthesized by hyaluronic acid-dopamine coordinated with gadolinium ions (Gd2+ ). Gd2+ provides the ability of magnetic resonance imaging, meanwhile further cross-linking the hydrogel network. Experiments show excellent ability of sustained release and imaging tracking for the hydrogel platform. In mouse STS models, the "in situ vaccination" hydrogels show the best effect of inhibiting tumor growth. Further analysis of tumor tissues show that "in situ vaccination" group can increase T cell infiltration, promote M1-type macrophage polarization and block elevated PD-1/PD-L1 pathway caused by DOX. These results are expected to prove the potential for synthesized hydrogels to achieve a universal platform for "in situ vaccination" strategies on STS treatments.

Neglected intrapulmonary arteriovenous anastomoses: A comparative study of pulmonary right-to-left shunts in patients with patent foramen ovale.

Objective: Pulmonary right-to-left shunt (P-RLS) and patent foramen ovale right-to-left shunt (PFO-RLS) often appear in combination, and there are often differences and connections between them. Intrapulmonary arteriovenous anastomoses (IPAVAs), as part of P-RLS, are often overlooked because there are no technologies to detect and identify them. This study aimed to further clarify the incidence and characteristics of P-RLS with the help of contrast transesophageal echocardiography (c-TEE) and contrast transthoracic echocardiography (c-TTE), providing a reference for clinically relevant research and patent foramen ovale (PFO) management disposal decisions. Methods: We retrospectively investigated 414 subjects who came to our hospital for c-TEE from October 2021 to July 2022, and all subjects completed c-TTE simultaneously. 7 Patients who were newly diagnosed with an atrial septal defect were excluded. Eventually, 407 patients were included in this study. Among them, 157 patients with PFO (58 patients were treated with PFO closure subsequently) and 250 patients without PFO confirmed by c-TEE were finally enrolled. In the process, we observed and analysed the presence of P-RLS. Results: A total of 407 patients were included in the final analysis and divided into PFO group (N = 157) and non-PFO group (N = 250) according to the results of c-TEE. Whether at rest or after Valsalva maneuver, the incidence of P-RLS was significantly higher under c-TEE than under c-TTE in the two groups (P < 0.001). For both c-TTE and c-TEE, the incidence of P-RLS was slightly higher after Valsalva maneuver than at rest, but the difference was not significant (c-TTE: rest vs. Valsalva maneuver, P = 0.214; c-TEE: rest vs. Valsalva maneuver, P = 0.076). The Valsalva maneuver increased the incidence of P-RLS in the group without PFO, which was more significant in c-TEE (c-TTE: rest vs. Valsalva maneuver, P = 0.591; c-TEE: rest vs. Valsalva maneuver, P = 0.008). In both groups, the P-RLS semiquantitative grading was statistical significance under different states and examinations (P < 0.001). Conclusion: The vast majority of P-RLS are grade 1-2 and are derived from physiological IPAVAs. Even so, attention should be given to the differentiation between P-RLS and PFO-RLS. c-TEE is an effective method to detect P-RLS; however, the recruitments of c-TEE and Valsalva maneuver to P-RLS should be noted.

Calf muscle pump tensing as a novel maneuver to improve the diagnostic performance of detecting patent foramen ovale during transesophageal echocardiography.

Objective: The Valsalva maneuver is the most sensitive provocative maneuver for patent foramen ovale detection. However, nearly half of patients are unable to perform the Valsalva maneuver well. The aim of this study was to investigate the mechanism of action of calf muscle pump tensing (TENSE) as a novel patent foramen ovale (PFO) provocative maneuver and to evaluate the diagnostic value for PFO and the effect on right-to-left shunt volume compared with the Valsalva maneuver. Methods: This study prospectively investigated 171 patients who were highly suspected to have PFO clinically. Five patients with atrial septal defects newly diagnosed on transesophageal echocardiography (TEE) were excluded. 166 patients were injected with agitated saline under three provocative maneuvers: Valsalva maneuver, TENSE, and Valsalva + TENSE combined maneuver. The patients were divided into the effective Valsalva group (n = 93) and ineffective Valsalva group (n = 73) according to whether they could perform an effective Valsalva maneuver. TENSE consisted of the straightening of both lower limbs, and when the right atrium was filled with microbubbles, the patient performed instantaneous ankle dorsiflexion movements while maintaining dorsiflexion for 3-5 s. Results: Overall, the PFO detection rate of the Valsalva + TENSE combined maneuver (78 [50.1%]) was significantly higher than that of the Valsalva maneuver (51 [30.7%]) and TENSE maneuver (57 [34.3%]) (P < 0.001). In the patients who were able to perform an effective Valsalva maneuver, the PFO detection rate by TENSE was not significantly different from that by the Valsalva maneuver (Valsalva 37/93 [39.8%] vs. TENSE 31/93 [33.3%], P > 0.05), while for the patients who performed an ineffective Valsalva maneuver, the PFO detection rate by the TENSE maneuver was higher than that by the Valsalva maneuver (TENSE 26/73 [35.6%] vs. Valsalva14/73[19.2%], P = 0.017). Conclusion: TENSE is a simple and effective provocative maneuver in the diagnosis of PFO using TEE and can assist the Valsalva maneuver. For patients who cannot perform an effective Valsalva maneuver, TENSE can be an alternative to the Valsalva maneuver to some extent.

Nanomodified Switch Induced Precise and Moderate Activation of CAR-T Cells for Solid Tumors.

Chimeric antigen receptor (CAR)-T cell therapy is a transformative treatment against advanced malignancies. Unfortunately, once administrated in vivo, CAR-T cells become out of artificial control, and fierce response to CAR-T therapy may cause severe adverse events, represented by cytokine-release syndrome and on-target/off-tumor effects. Here, a nanomodified switch strategy is developed, leading to sustained and precise "on-tumor only" activation of CAR-T cells. Here, original gelatinase-responsive nanoparticles (NPs) are used to selectively deliver the heterodimerizing switch, which is the key component of switchable CAR with separated activation modules. The "NanoSwitch" is tumor-specific, thus inactivated switchable CAR-T cells do little harm to normal cells, even if the normal cells express the target of CAR-T. Owing to the sustained-release effect of NPs, the CAR-T cells are activated smoothly, avoiding sudden release of cytokine. These data introduce NanoSwitch as a universal and applicable solution to safety problems of CAR-T therapy regardless of the target.

Effectiveness of polyene phosphatidylcholine and its combination with other drugs in patients with liver diseases based on real-world research.

OBJECTIVES: Polyene phosphatidylcholine (PPC) is a widely used hepatoprotective drug. We aim to explore the effectiveness of PPC in patients with liver diseases based on real-world research, and compare with other hepatoprotective drugs. METHODS: This was a 'three-phase' retrospective study, including a descriptive study, a self-control case study, and a specific-disease cohort study. A total of 14,800 hospitalized patients were enrolled in phase I from 1 January 2015 to 1 January 2020, of which 793 patients using PPC alone were included for phase II and III. The major measurement of effectiveness analysis was the ALT level and its changes. Wilcoxon signed-rank test, Chi-square test, and Mann-Whitney U test were used. RESULTS: In patients without liver tumor, ALT level decreased after using PPC (p < 0.01), and the decrease in ALT level using PPC was greater than using glutathione or magnesium isoglycyrrhizinate alone (p = 0.044; p = 0.038). In patients without liver tumor but having abnormal liver function, the decrease in ALT level using PPC + glutathione was greater than using glutathione alone (p = 0.047). CONCLUSION: PPC had a beneficial effect on liver function in patients without liver tumor, and PPC could enhance the liver protective function of glutathione and magnesium isoglycyrrhizinate.

Outcomes With Multidisciplinary Cardiac Rehabilitation in Post-acute Systolic Heart Failure Patients-A Retrospective Propensity Score-Matched Study.

Background: Cardiac rehabilitation (CR) is recommended for patients with acute heart failure (HF). However, the results of outcome studies and meta-analyses on CR in post-acute care are varied. We aimed to assess the medium- to long-term impact of CR and ascertain the predictors of successful CR. Methods: In this propensity score-matched retrospective cohort study, records of consecutive patients who survived acute HF (left ventricular ejection fraction <40) and participated in a multidisciplinary HF rehabilitation program post-discharge between May 2014 and July 2019 were reviewed. Patients in the CR group had at least one exercise session within 3 months of discharge; the others were in the non-CR group. After propensity score matching, the primary (all-cause mortality) and secondary (HF readmission and life quality assessment) outcomes were analyzed. Results: Among 792 patients, 142 attended at least one session of phase II CR. After propensity score matching for covariates related to HF prognosis, 518 patients were included in the study (CR group, 137 patients). The all-cause mortality rate was 24.9% and the HF rehospitalization rate was 34.6% in the median 3.04-year follow-up. Cox proportional hazard analysis revealed that the CR group had a significant reduction in all-cause mortality compared to the non-CR group (hazard ratio [HR]: 0.490, 95% confidence interval [CI]: 0.308-0.778). A lower risk of the primary outcome with CR was observed in patients on renin-angiotensin-aldosterone system (RAAS) inhibitors, but was not seen in patients who were not prescribed this class of medications (interaction p = 0.014). Conclusions: Cardiac rehabilitation participation was associated with reduced all-cause mortality after acute systolic heart failure hospital discharge. Our finding that the benefit of CR was decreased in patients not prescribed RAAS inhibitors warrants further evaluation.

Perfluorooctane sulfonate induces suppression of testosterone biosynthesis via Sertoli cell-derived exosomal/miR-9-3p downregulating StAR expression in Leydig cells.

Perfluorooctane sulfonate (PFOS) is associated with male reproductive disorder, but the related mechanisms are still unclear. In this study, we used in vivo and in vitro models to explore the role of Sertoli cell-derived exosomes (SC-Exo)/miR-9-3p/StAR signaling pathway on PFOS-induced suppression of testosterone biosynthesis. Forty male ICR mice were orally administrated PFOS (0.5-10 mg/kg/bw) for 4 weeks. Bodyweight, organ index, sperm count, reproductive hormones were evaluated. Primary Sertoli cells and Leydig cells were used to delineate the molecular mechanisms that mediate the effects of PFOS on testosterone biosynthesis. Our results demonstrated that PFOS dose-dependently induced a decrease in sperm count, low levels of testosterone, and damage in testicular interstitium morphology. In vitro models, PFOS significantly increased miR-9-3p levels in Sertoli cells and SC-Exo, accompanied by a decrease in testosterone secretion and StAR expression in Leydig cells when Leydig cells were exposed to SC-Exo. Meanwhile, inhibition of SC-Exo or miR-9-3p by their inhibitors significantly rescued PFOS-induced decreases in testosterone secretion and the mRNA and protein expression of the StAR gene in Leydig cells. In summary, the present study highlights the role of the SC-Exo/miR-9-3p/StAR signaling pathway in PFOS-induced suppression of testosterone biosynthesis, advancing our understanding of molecular mechanisms for PFOS-induced male reproductive disorders.

Treatment Adherence to Nucleos(t)ide Analogs in Chinese Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma: A Single-Center Cross-Sectional Study.

PURPOSE: Chronic hepatitis B virus (HBV) infection is a crucial risk factor in the occurrence and development of hepatocellular carcinoma (HCC). Antiviral therapy is very important for patients with HBV-related HCC. To maintain undetectable level of HBV DNA, patients must take nucleos(t)ide analogues (NUCs) appropriately and regularly. We explored the adherence of Chinese patients with HBV-related HCC to antiviral treatment. PATIENTS AND METHODS: One-hundred and eighty-one patients were included in a cross-sectional study between August 2020 and February 2021. A structured questionnaire was used to interview patients, and a form was applied to collect data from electronic medical records. Medication adherence was measured using a visual analog scale. Data of the adherent group and non-adherent group were compared using Student's t-test and the chi-square test. Multivariate logistic regression analysis was employed to explore independent risk factors that affected adherence behavior. RESULTS: High adherence was reported in 46.4% of patients with HBV-related HCC. Patients with high adherence were more likely to be women (P = 0.02), shun alcohol (P = 0.01), take NUCs other than entecavir (P = 0.04), and pay attention to their titer of HBV DNA (P = 0.05). Sex, alcohol consumption, and taking entecavir were independent risk factors for low adherence (P < 0.05). The prevalence of virological breakthrough was lower in patients who adhered to NUC therapy than in those who did not, but the difference was not significant (P = 0.31). CONCLUSION: The adherence of patients with HBV-related HCC to NUC therapy was low. More attention should be paid to adherence of antiviral therapy in patients with HBV-related HCC.

CT synthesis from MRI using multi-cycle GAN for head-and-neck radiation therapy.

Magnetic Resonance Imaging (MRI) guided Radiation Therapy is a hot topic in the current studies of radiotherapy planning, which requires using MRI to generate synthetic Computed Tomography (sCT). Despite recent progress in image-to-image translation, it remains challenging to apply such techniques to generate high-quality medical images. This paper proposes a novel framework named Multi-Cycle GAN, which uses the Pseudo-Cycle Consistent module to control the consistency of generation and the domain control module to provide additional identical constraints. Besides, we design a new generator named Z-Net to improve the accuracy of anatomy details. Extensive experiments show that Multi-Cycle GAN outperforms state-of-the-art CT synthesis methods such as Cycle GAN, which improves MAE to 0.0416, ME to 0.0340, PSNR to 39.1053.

Human Microfibrillar-Associated Protein 4 (MFAP4) Gene Promoter: A TATA-Less Promoter That Is Regulated by Retinol and Coenzyme Q10 in Human Fibroblast Cells.

Elastic fibers are one of the major structural components of the extracellular matrix (ECM) in human connective tissues. Among these fibers, microfibrillar-associated protein 4 (MFAP4) is one of the most important microfibril-associated glycoproteins. MFAP4 has been found to bind with elastin microfibrils and interact directly with fibrillin-1, and then aid in elastic fiber formation. However, the regulations of the human MFAP4 gene are not so clear. Therefore, in this study, we firstly aimed to analyze and identify the promoter region of the human MFAP4 gene. The results indicate that the human MFAP4 promoter is a TATA-less promoter with tissue- and species-specific properties. Moreover, the promoter can be up-regulated by retinol and coenzyme Q10 (coQ10) in Detroit 551 cells.

The Interrelationship between Ventilatory Inefficiency and Left Ventricular Ejection Fraction in Terms of Cardiovascular Outcomes in Heart Failure Outpatients.

The relationship between left ventricular ejection fraction (LVEF) and cardiovascular (CV) outcome is documented in patients with low LVEF. Ventilatory inefficiency is an important prognostic predictor. We hypothesized that the presence of ventilatory inefficiency influences the prognostic predictability of LVEF in heart failure (HF) outpatients. In total, 169 HF outpatients underwent the cardiopulmonary exercise test (CPET) and were followed up for a median of 9.25 years. Subjects were divided into five groups of similar size according to baseline LVEF (≤39%, 40-58%, 59-68%, 69-74%, and ≥75%). The primary endpoints were CV mortality and first HF hospitalization. The Cox proportional hazard model was used for simple and multiple regression analyses to evaluate the interrelationship between LVEF and ventilatory inefficiency (ventilatory equivalent for carbon dioxide (VE/VCO2) at anaerobic threshold (AT) >34.3, optimized cut-point). Only LVEF and VE/VCO2 at AT were significant predictors of major CV events. The lower LVEF subgroup (LVEF ≤ 39%) was associated with an increased risk of CV events, relative to the LVEF ≥75% subgroup, except for patients with ventilatory inefficiency (p = 0.400). In conclusion, ventilatory inefficiency influenced the prognostic predictability of LVEF in reduced LVEF outpatients. Ventilatory inefficiency can be used as a therapeutic target in HF management.

Efficacy of Type 2 PRRSV vaccine against challenge with the Chinese lineage 1 (NADC30-like) PRRSVs in pigs.

The objective of the present study was to determine the cross-protection of Ingelvac PRRS MLV against challenge with the new lineage 1 PRRSV emerged in China in pigs. Two lineage 1 PRRSV strains (FJZ03 and FJWQ16 originated from recombination event between NADC30 and JXA1-like strain). We found that pigs vaccinated with the vaccine were protected against challenge with the FJZ03 as shown by fewer days of clinical fever, reduced lung pathology scores, lower PRRS virus load in the blood and developed broadly neutralizing antibodies with high titers to FJZ03. In contrast, vaccine provided limited protection against challenge with FJWQ16 with higher fever, lower antibody titers, lower neutralizing antibodies and higher viral loads in blood. These results demonstrate PRRSV-MLV provides incomplete protection against new lineage 1 PRRSVs.

Expression and characterization of albumin fusion protein canine IFNγ-CSA in baculovirus-insect cell expression system.

In this study, canine IFNγ was fused by a flexible linker with canine serum albumin to construct the fusion protein IFNγ-CSA for the purpose to design a long-acting canine IFNγ. The fusion protein was successfully expressed in baculovirus-infected Sf9 insect cells and was purified by salting-out and ion exchange chromatography. The IFNγ-CSA fusion possessed potent anti-viral assay against vesicular stomatitis virus in cultured cells. IFNγ-CSA was also stable at 37 °C up to 72 h compared with 8 h for IFNγ alone. In vivo pharmacokinetics demonstrated a significantly longer half-life for IFNγ-CSA (15.42 h) than for canine reIFNγ (1.51 h) in KM mice. These results indicate that IFNγ-CSA expression in the baculovirus system was successful and provide a promising long-acting cytokine for veterinary clinical applications.

Albumin fusion improves the pharmacokinetics and in vivo antitumor efficacy of canine interferon gamma.

Interferon (IFN)-γ plays an important role in antiviral, anti-proliferative, immunomodulatory and pro-inflammatory activities. However, the short therapeutic half-life of IFN-γ lessens its efficacy. Albumin fusion strategy is one of the most effective ways to improve the pharmacokinetic properties of cytokines. In this study, N- and C-terminal canine albumin fusions with canine IFN-γ were expressed in the baculovirus expression system. The fusion proteins stimulated Stat1 phosphorylation at levels similar to that of the recombinant IFN. The antiviral, anti-proliferative and promote apoptosis activity of CSA-IFN-γ was lower than IFN-γ-CSA and both were less than that of recombinant IFN-γ. In vivo pharmacokinetics demonstrated a significantly longer half-life for CSA-IFN-γ (21.73 h) than for IFN-γ-CSA (6.51 h) and canine reIFN-γ (2.22 h) in Wistar rats. CSA-IFN-γ was also more effective than IFN-γ-CSA and canine reIFN-γ at inhibiting growth of canine renal malignant histiocytosis in nude mice. Our results indicated that a canine serum albumin fusion at the N-terminus of IFN-γ prolongs its half-life and improves its in vivo antitumor activity.