Efficacy and safety of abrocitinib for moderate-to-severe atopic dermatitis in adolescents and adults: Meta-analysis

Objective: This study aims to investigate the safety and efficacy of abrocitinib in treating moderate-to-severe AD in adolescents and adults.Methods: Pubmed, Cochrane, Embase, and Web of science data base were searched from inception to 9 August 2022. All randomized controlled trials (RCTs) evaluating the efficacy and safety of abrocitinib in moderate to severe AD were included in the meta-analysis.Results: This meta-analysis comprised 7 studies and found that 100 mg or 200 mg of abrocitinib significantly improved IGA {[RR = 2.44, 95% CI (1.93–3.08)] [RR = 3.16, 95% CI (2.52–3.96)]} and EASI-75{[RR = 2.18, 95%CI (1.78–2.67)] [RR = 3.04, 95%CI (2.22–4.16)]} responses compared to placebo. Following that, the population was divided into adolescent and adult groups. The abrocitinib improved IGA, EASI-75 responses, and it was still superior to placebo in both the adolescent and the adult groups. PP-NRS4 response index demonstrated that abrocitinib had a greater effect than placebo at 100 mg [RR = 2.22, 95% CI 1.80–2.72] and 200 mg [RR = 3.28, 95% CI 2.59–4.17]. Abrocitinib improved PSAAD, POEM, DLQI, CDLQI, and HADS more than a placebo.Conclusion: In conclusion, this meta-analysis preliminarily demonstrated that abrocitinib had higher efficacy and safety in the treatment of moderate-to-severe AD in adolescents and adults. In addition, abrocitinib could rapidly relieve itching, and effectively improve symptoms and signs, with a greater effect at the dosage of 200 mg than 100 mg

Antibody responses following vaccination versus infection in a porcine circovirus-type 2 (PCV2) disease model show distinct differences in virus neutralization and epitope recognition

Porcine circovirus associated disease (PCVAD) encompasses a group of syndromes linked to infection with porcine circovirus type 2 (PCV2). Based on the hypothesis that the immune responses to vaccination versus infection are quantitatively and qualitatively different, the objective of this study was to evaluate immunity, virus replication and disease protection in pigs vaccinated with PCV2 capsid protein (CP) and during infection. The disease model included dual infection with PCV2 and porcine reproductive and respiratory syndrome virus (PRRSV), a virus known to enhance disease progression and severity. The principal effect of PRRSV infection was to increase peak PCV2 viremia by almost 40-fold; however, PCV2 failed to show a reciprocal effect on PRRSV. In vaccinated pigs, there was no evidence of disease or PCV2 replication following dual virus challenge. Immunity following vaccination favored PCV2 neutralizing activity; whereas, PCV2 infection and disease produced high levels of non-neutralizing antibody, primarily directed against a polypeptide in the C-terminal region of CP. These results support the notion that the magnitude of the total antibody response cannot be used as a measure of protective immunity. Furthermore, protection versus disease lies in the immunodominance of specific epitopes. Epitope specificity should be taken into consideration when designing PCV2 vaccines

Alterations in tumor necrosis factor signaling pathways are associated with cytotoxicity and resistance to taxanes: a study in isogenic resistant tumor cells

INTRODUCTION: The taxanes paclitaxel and docetaxel are widely used in the treatment of breast, ovarian, and other cancers. Although their cytotoxicity has been attributed to cell-cycle arrest through stabilization of microtubules, the mechanisms by which tumor cells die remains unclear. Paclitaxel has been shown to induce soluble tumor necrosis factor alpha (sTNF-α) production in macrophages, but the involvement of TNF production in taxane cytotoxicity or resistance in tumor cells has not been established. Our study aimed to correlate alterations in the TNF pathway with taxane cytotoxicity and the acquisition of taxane resistance. METHODS: MCF-7 cells or isogenic drug-resistant variants (developed by selection for surviving cells in increasing concentrations of paclitaxel or docetaxel) were assessed for sTNF-α production in the absence or presence of taxanes by enzyme-linked immunosorbent assay (ELISA) and for sensitivity to docetaxel or sTNF-α by using a clonogenic assay (in the absence or presence of TNFR1 or TNFR2 neutralizing antibodies). Nuclear factor (NF)-κB activity was also measured with ELISA, whereas gene-expression changes associated with docetaxel resistance in MCF-7 and A2780 cells were determined with microarray analysis and quantitative reverse transcription polymerase chain reaction (RTqPCR). RESULTS: MCF-7 and A2780 cells increased production of sTNF-α in the presence of taxanes, whereas docetaxel-resistant variants of MCF-7 produced high levels of sTNF-α, although only within a particular drug-concentration threshold (between 3 and 45 nM). Increased production of sTNF-α was NF-κB dependent and correlated with decreased sensitivity to sTNF-α, decreased levels of TNFR1, and increased survival through TNFR2 and NF-κB activation. The NF-κB inhibitor SN-50 reestablished sensitivity to docetaxel in docetaxel-resistant MCF-7 cells. Gene-expression analysis of wild-type and docetaxel-resistant MCF-7, MDA-MB-231, and A2780 cells identified changes in the expression of TNF-α-related genes consistent with reduced TNF-induced cytotoxicity and activation of NF-κB survival pathways. CONCLUSIONS: We report for the first time that taxanes can promote dose-dependent sTNF-α production in tumor cells at clinically relevant concentrations, which can contribute to their cytotoxicity. Defects in the TNF cytotoxicity pathway or activation of TNF-dependent NF-κB survival genes may, in contrast, contribute to taxane resistance in tumor cells. These findings may be of strong clinical significance

Co-sensitization and cross-reactivity of Blomia tropicalis with two Dermatophagoides species in Guangzhou, China

Around 85.50% of patients were sensitized to Der p, 85.37% of patients were sensitized to Der f, and 71.54% of patients were sensitized to Blo t. Further, 70.14% of patients were co-sensitized to Blo t, Der p, and Der f, and only seven patients were sensitized solely to Blo t. With increasing sIgE levels for Blo t, the positive rates of severe-level (class 5-6) co-sensitization to Der p or Der f significantly increased. Blo t was moderately associated with Der p and Der f, with correlation coefficients of 0.6998 and 0.6782, respectively. Der p and Der f inhibited IgE binding to Blo t more strongly than Blo t inhibited IgE binding to Der p or Der f in the patient groups CBlo t  < CDer p and CBlo t  < CDer f .Open Project of State Key Laboratory of Respiratory Disease [SKLRD-OP-201803, SKLRD-OP-201809]; Science and Technology Innovation Committee Project of Guangzhou [201831802]; Bureau of traditional Chinese Medicine Scientific Research Project of Guangdong [20192048]; National Natural Science Foundation of China [81601394, 81802076, 81871736]Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Single dose combination nanovaccine provides protection against influenza A virus in young and aged mice

Immunosenescence poses a formidable challenge in designing effective influenza vaccines for aging populations. While approved vaccines against influenza viruses exist, their efficacy in older adults is significantly decreased due to the diminished capabilities of innate and adaptive immune responses. In this work, the ability of a combination nanovaccine containing both recombinant hemagglutinin and nucleoprotein to provide protection against seasonal influenza virus infection was examined in young and aged mice. Vaccine formulations combining two nanoadjuvants, polyanhydride nanoparticles and pentablock copolymer micelles, were shown to enhance protection against challenge compared to each adjuvant alone in young mice. Nanoparticles were shown to enhance in vitro activation of dendritic cells isolated from aged mice, while both nanoadjuvants did not induce proinflammatory cytokine secretion which may be detrimental in aged individuals. In addition, the combination nanovaccine platform was shown to induce demonstrable antibody titers in both young and aged mice that correlated with the maintenance of body weight post-challenge. Collectively, these data demonstrate that the combination nanovaccine platform is a promising technology for influenza vaccines for older adults

Full-Length Genome Sequences of Senecavirus A from Recent Idiopathic Vesicular Disease Outbreaks in U.S. Swine

Since July 2015, vesicular lesions affecting growing pigs and sows accompanied with neonatal mortality have been reported in multiple U.S. states. Senecavirus A has been consistently detected from these cases. The complete genome sequences of 3 recent U.S. Senecavirus A isolates were determined to further characterize this virus

Novel Senecavirus A in Swine with Vesicular Disease, United States, July 2015

To the Editor: Senecavirus A (SVA; formerly known as Seneca Valley virus [SVV] belongs to the genus Senecavirus, family Picornaviridae (1,2). SVA was first isolated in 2001 as a contaminant of the PER.C6 cell line and designated as SVV-001 (1,3). Since its discovery, SVA has been infrequently detected in swine with idiopathic vesicular disease (IVD) (4–6), which clinically resembles foot-and-mouth disease, swine vesicular disease, vesicular exanthema of swine, and vesicular stomatitis. The virus has also been retrospectively detected in previous cases with various clinical conditions in the United States during 1988–2001 (7). However, the clinical significance of SVA in swine could not be determined (7,8)

B Cell-Related Circulating MicroRNAs With the Potential Value of Biomarkers in the Differential Diagnosis, and Distinguishment Between the Disease Activity and Lupus Nephritis for Systemic Lupus Erythematosus

Our understanding of circulating microRNAs (miRNAs) related to systemic lupus erythematosus (SLE) remains very limited. In this study, we screened SLE-specific miRNAs in plasma from 42 B cell-related miRNAs by using miRNA PCR Array. The selected miRNAs were first confirmed in plasma samples from 50 SLE patients, 16 rheumatoid arthritis (RA) patients, and 20 healthy donors using qRT-PCR. We then investigated the relationship between expressions of the selected miRNAs and SLE clinical indicators. As a result, 14 miRNAs (miR-103, miR-150, miR-20a, miR-223, miR-27a, miR-15b, miR-16, miR-181a, miR-19b, miR-22, miR-23a, miR-25, miR-92a, and miR-93) were significantly decreased in the plasma of SLE patients compared with healthy controls (P &lt; 0.05) and could act as the diagnostic signature to distinguish SLE patients from healthy donors. Six miRNAs (miR-92a, miR-27a, miR-19b, miR-23a, miR-223, and miR-16) expressed in plasma were significantly lower in SLE patients than in RA patients (P &lt; 0.05), revealing the potentially diagnostic signature to distinguish SLE patients from RA patients. Furthermore, the downregulated expression of miR-19b, miR-25, miR-93, and miR-15b was associated with SLE disease activity (P &lt; 0.05) while miR-15b and miR-22 expressions were significantly lower in SLE patients with low estimate glomerular filtration rate (eGFR &lt; 60 ml/min/1.73 m2) (P &lt; 0.05). The diagnostic potential of miR-15b for SLE disease activity and lupus nephritis (LN) with low eGFR was validated on an independent validation set with 69 SLE patients and a cross-validation set with 80 SLE patients. In summary, the signature of circulating miRNAs will provide novel biomarkers for the diagnosis of SLE and evaluation of disease activity and LN

Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance

<p>Abstract</p> <p>Background</p> <p>Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance <it>in vitro </it>occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated with the enhanced expression and activity of specific drug transporters. To address these issues, MCF-7 cells were selected for survival in increasing concentrations of doxorubicin (MCF-7_DOX-2), epirubicin (MCF-7_EPI), paclitaxel (MCF-7_TAX-2), or docetaxel (MCF-7_TXT). During selection cells were assessed for drug sensitivity, drug uptake, and the expression of various drug transporters.</p> <p>Results</p> <p>In all cases, resistance was only achieved when selection reached a specific threshold dose, which was well within the clinical range. A reduction in drug uptake was temporally correlated with the acquisition of drug resistance for all cell lines, but further increases in drug resistance at doses above threshold were unrelated to changes in cellular drug uptake. Elevated expression of one or more drug transporters was seen at or above the threshold dose, but the identity, number, and temporal pattern of drug transporter induction varied with the drug used as selection agent. The pan drug transporter inhibitor cyclosporin A was able to partially or completely restore drug accumulation in the drug-resistant cell lines, but had only partial to no effect on drug sensitivity. The inability of cyclosporin A to restore drug sensitivity suggests the presence of additional mechanisms of drug resistance.</p> <p>Conclusion</p> <p>This study indicates that drug resistance is achieved in breast tumour cells only upon exposure to concentrations of drug at or above a specific selection dose. While changes in drug accumulation and the expression of drug transporters does occur at the threshold dose, the magnitude of resistance cannot be attributed solely to changes in drug accumulation or the activity of drug transporters. The identities of these additional drug-transporter-independent mechanisms are discussed, including their likely clinical relevance.</p