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Lab on a Chip Jul 2024The recapitulation of tumor microenvironment is of great interest to preclinical screening of drugs. Compared with culture of cell lines, tumor organ slices can better...
The recapitulation of tumor microenvironment is of great interest to preclinical screening of drugs. Compared with culture of cell lines, tumor organ slices can better preserve the complex tumor architecture and phenotypic activity of native cells, but are limited by their exposure to fluid shear and gradual degradation under perfusion culture. Here, we established a decellularized liver matrix (DLM)-GelMA "sandwich" structure and a perfusion-based microfluidic platform to support long-term culture of tumor slices with excellent structural integrity and cell viability over 7 days. The DLM-GelMA was able to secrete cytokines and growth factors while providing shear protection to the tumor slice the sandwich structure, leading to the preservation of the tumor microenvironment where immune cells (CD3, CD8, CD68), tumor-associated fibroblasts (α-SMA), and extracellular matrix components (collagen I, fibronectin) were well maintained. Furthermore, this chip presented anti-tumor efficacy at cisplatin (20 μM) on tumor patients, demonstrating our platform's efficacy to design patient-specific treatment regimens. Taken together, the successful development of this DLM-GelMA sandwich structure on the chip could faithfully reflect the tumor microenvironment and immune response, accelerating the screening process of drug molecules and providing insights for practical medicine.
PubMed: 38953554
DOI: 10.1039/d4lc00278d -
Clinical Pharmacology in Drug... Jul 2024SERENE CD (NCT02065570) evaluated whether a higher adalimumab induction dose would improve patients with Crohn disease response and suggested a flat dose-response...
SERENE ER Analysis Part 1-SERENE CD: Exposure-Response Analysis of Higher Versus Standard Adalimumab Dosing Regimens for Patients With Moderately to Severely Active Crohn Disease.
SERENE CD (NCT02065570) evaluated whether a higher adalimumab induction dose would improve patients with Crohn disease response and suggested a flat dose-response relationship for efficacy in the induction study. We investigated exposure-response relationships in induction and maintenance studies considering patients' baseline characteristics. Adalimumab exposures were simulated using the established population pharmacokinetic model. Efficacy end points (clinical remission/endoscopic response) at Weeks 4, 12, and 56 were evaluated in exposure-response analyses using multivariable logistic regression. Analyses showed an increasing trend with heterogeneity between induction regimens, which suggested that average concentration has an impact on coprimary efficacy end points within each group, but data did not fit a single-response curve. Although higher concentrations within arms were associated with improved outcomes, increasing the concentration through a higher induction dose was not associated with increasing clinical remission/endoscopic response at Week 4/12. A model including inverse effective clearance eliminated heterogeneity and described trends across induction regimens with a single curve. In the maintenance study, the response rates at Week 56 showed no heterogeneity. In the induction study, patients with lower effective adalimumab clearance responded better, whereas in the maintenance study average concentration drove primary efficacy end points at Week 56. Research extending these findings to other indications is needed.
PubMed: 38953542
DOI: 10.1002/cpdd.1438 -
Melanoma Research Jun 2024Mucosal melanoma is a rare melanoma subtype, accounting for about 1% of all diagnosed melanomas. It is characterized by an aggressive phenotype with a poor prognosis and...
Mucosal melanoma is a rare melanoma subtype, accounting for about 1% of all diagnosed melanomas. It is characterized by an aggressive phenotype with a poor prognosis and a low response rate to approved treatments. We retrospectively analyzed the clinical features, treatments, and outcomes of patients diagnosed with mucosal melanoma treated with axitinib ± anti-programmed cell death protein 1 (PD-1) therapy at a single US referral center between 2018 and 2021. Radiologic response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), v1.1. Twenty-three patients were included in this study. In all, 78% were females with a median age of 62 years. The originating site of mucosal melanoma was the sinonasal (35%), genitourinary (35%), and gastrointestinal (30%) tracts. Sixty-five percent of patients had M1c or M1d disease and 0% had BRAF V600 mutations detected. The majority (96%) had prior treatment inclusive of anti-PD-1, with a median of 2 prior lines, and 78% of patients received a combination of axitinib and PD-1 and the median duration of treatment was 3.2 months. The overall response rate was 13% and the disease control rate was 26%. The median progression-free survival was 3.2 months, and the median overall survival was 8.2 months. Overall, the regimen was well tolerated with 39% of patients requiring dose reduction and 9% requiring treatment cessation. Axitinib with anti-PD-1 therapy has modest clinical activity in heavily pretreated patients with mucosal melanoma outside of Asia, including some with long-term benefits. This data supports the worldwide clinical trials evaluating this combination and the role of incorporating vascular endothelial growth factor-based therapy in the therapeutic paradigm for patients with mucosal melanoma.
PubMed: 38953532
DOI: 10.1097/CMR.0000000000000988 -
Journal of Periodontal Research Jul 2024To ascertain whether healthy lifestyles are associated with periodontal diseases in two large-scale surveys in the US (National Health and Nutrition Examination Survey -...
AIM
To ascertain whether healthy lifestyles are associated with periodontal diseases in two large-scale surveys in the US (National Health and Nutrition Examination Survey - NHANES) and the UK Biobank.
METHODS
9854 US adults and 111 679 UK adults were included in the analyses. A healthy lifestyle score (HLS), ranging between 0 and 5, was calculated based on the reported number of healthy behaviours, including never smoking, no heavy alcohol consumption, top third of leisure-time physical activity, higher dietary quality, and ideal sleep duration. The prevalence of periodontal diseases was the primary outcome in both surveys. In the NHANES, periodontal status was assessed through a full-mouth periodontal examination, while in the UKB, only self-reported periodontal status was available.
RESULTS
Multiple regression analyses confirmed that the presence of at least 2-3 healthy behaviours (vs. 0-1) was associated with lower odds of overall and severe periodontitis (ORs 0.5, 0.4-0.6; p < .001 and 0.5, 0.3-0.8; p = .003, respectively) in the NHANES, and of bleeding gums (OR = 0.9, 0.8-1.0; p = .092) and loose teeth (OR = 0.6, 0.5-0.7; p < .001) in UKB. This association increased when considering prevalence of 4-5 healthy behaviours (vs. 0-1) in both the NHANES (periodontitis: OR = 0.3, 0.2-0.4; p < .001; severe periodontitis: OR = 0.1, 0.01-0.2; p < .001) and the UKB (bleeding gums: OR = 0.8, 0.7-0.9; p < .001; loose teeth: OR = 0.5, 0.4-0.6; p < .001). Mediation analyses revealed how these protective associations could be partially mediated (1-14%) by differences in biomarkers of systemic inflammation (white blood cells and neutrophils count as well as C-reactive protein).
CONCLUSIONS
Adoption of healthy lifestyle behaviours is associated with a lower prevalence of periodontal diseases within two large population-based samples. This relationship exhibits a dose-response pattern, implying that greater adherence to healthy habits leads to a more significant protective effect against the odds of periodontal diseases. Additionally, our findings suggest that this protective effect is, in part, mediated by reductions in systemic inflammation.
PubMed: 38953498
DOI: 10.1111/jre.13320 -
International Nursing Review Jul 2024This study categorized quality-of-life trajectories among disaster victims in South Korea and identified the characteristics and predictors of each trajectory.
AIM
This study categorized quality-of-life trajectories among disaster victims in South Korea and identified the characteristics and predictors of each trajectory.
BACKGROUND
Disaster victims experience tremendous physical and mental distress, which has a long-term impact on their quality of life.
METHODS
We conducted a cross-sectional study using data obtained from the fourth Long-term Survey on the Change of Life of Disaster Victims conducted from 2017 to 2019. The study included 257 participants who experienced a typhoon, earthquake, or fire and completed the three-year follow-up. Latent transition analysis was used to identify the potential class of quality-of-life trajectories among disaster victims. Independent t tests, χ tests, and logistic regression were used to identify the predictors of quality-of-life trajectories.
RESULTS
Two latent quality-of-life classes were identified: persistent low-level and persistent high-level. Factors associated with the persistent high-level trajectory included higher education level, no injury/disease from the disaster, better subjective health status, higher social support, and lower social maladjustment.
DISCUSSION
Quality of life early after a disaster is maintained throughout subsequent years; early and active support following disasters is essential to promote its rapid improvement.
CONCLUSION
Targeted educational programs in disaster-prone areas are recommended to bolster resilience among individuals with lower education. Moreover, governmental and institutional efforts are needed to support victims who lack resources for disaster recovery.
IMPLICATIONS FOR NURSING AND HEALTH POLICY
There is a need to establish community-based social support systems and enhance nurses' disaster response capabilities to support vulnerable groups, with such interventions tailored to reflect disaster-affected victims' unique characteristics and needs, along with ongoing research and evaluation for continuous improvements to nursing practice and disaster response.
PubMed: 38953470
DOI: 10.1111/inr.13015 -
Clinical and Experimental Immunology Jul 2024The recent pandemic was caused by the emergence of a new human pathogen, SARS-CoV-2. While the rapid development of many vaccines provided an end to the immediate...
The recent pandemic was caused by the emergence of a new human pathogen, SARS-CoV-2. While the rapid development of many vaccines provided an end to the immediate crisis, there remains an urgent need to understand more about this new virus and what constitutes a beneficial immune response in terms of successful resolution of infection. Indeed, this is key for development of vaccines that provide long lasting protective immunity. The interferon lambda (IFNL) family of cytokines are produced early in response to infection and are generally considered anti-viral and beneficial. However, data regarding production of IFNL cytokines in COVID-19 patients is highly variable, and generally from underpowered studies. In this study, we measured all three IFNL1, IFNL2 and IFNL3 cytokines in plasma from a well characterised, large COVID-19 cohort (n=399) that included good representation from patients with a more indolent disease progression, and hence a beneficial immune response. While all three cytokines were produced, they differed in both the frequency of expression in patients, and the levels produced. IFNL3 was produced in almost all patients but neither protein level nor IFNL3/IFNL4 SNPs were associated with clinical outcome. In contrast, both IFNL1 and IFNL2 levels were significantly lower, or absent, in plasma of patients that had a more severe disease outcome. These data are consistent with the concept that early IFNL1 and IFNL2 cytokine production is protective against SARS-CoV-2 infection.
PubMed: 38953458
DOI: 10.1093/cei/uxae047 -
Journal of Medical Virology Jul 2024The genetic diversity of killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) genes influences the host's immune response to viral...
The genetic diversity of killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) genes influences the host's immune response to viral pathogens. This study aims to explore the impact of five single nucleotide polymorphisms (SNPs) in KIR3DL2 and HLA-A genes on hepatitis C virus (HCV) infection. A total of 2251 individuals were included in the case-control study. SNPs including KIR3DL2 rs11672983, rs3745902, rs1654644, and HLA-A rs3869062, rs12202296 were genotyped. By controlling various confounding factors using a modified logistic regression model, as well as incorporating stratified analysis, joint effects analysis, and multidimensional bioinformatics analysis, we analyzed the relationship between SNPs and HCV infection. The logistic regression analysis showed a correlation between KIR3DL2 rs11672983 AA, KIR3DL2 rs3745902 TT, and increased HCV susceptibility (p < 0.01). Stratified analysis indicated that KIR3DL2 rs1654644 and HLA-A rs3869062 also heightened HCV susceptibility in certain subgroups. A linear trend of rising HCV infection rates was observed when combining KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT (p = 0.007). Bioinformatics analysis suggested these SNPs' regulatory potential and their role in altering messenger RNA secondary structure, implying their functional relevance in HCV susceptibility. Our findings indicate that KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT are significantly associated with increased susceptibility to HCV infection.
Topics: Humans; Male; Polymorphism, Single Nucleotide; Female; Case-Control Studies; Hepatitis C; Middle Aged; Genetic Predisposition to Disease; Adult; Genotype; HLA-A Antigens; Hepacivirus; Receptors, KIR; Aged; Receptors, KIR3DL2
PubMed: 38953430
DOI: 10.1002/jmv.29776 -
British Journal of Clinical Pharmacology Jul 2024Cerebral hypometabolism occurs years prior to a diagnosis of neurodegenerative diseases and coincides with reduced cerebral perfusion and declining noradrenergic...
Effects on cerebral blood flow after single doses of the β agonist, clenbuterol, in healthy volunteers and patients with mild cognitive impairment or Parkinson's disease.
AIMS
Cerebral hypometabolism occurs years prior to a diagnosis of neurodegenerative diseases and coincides with reduced cerebral perfusion and declining noradrenergic transmission from the locus coeruleus. In pre-clinical models, β-adrenoceptor (β-AR) agonists increase cerebrocortical glucose metabolism, and may have therapeutic potential for neurodegenerative diseases. This study investigated the safety and effects on regional cerebral blood flow (rCBF) of the oral, brain-penetrant β-AR agonist, clenbuterol, in healthy volunteers (HV) and patients with mild cognitive impairment (MCI) or Parkinson's disease (PD).
METHODS
This study evaluated the safety and effects on cerebral activity of the oral, brain-penetrant, β-AR agonist clenbuterol (20-160 μg) in healthy volunteers and patients with MCI or PD. Regional CBF, which is tightly coupled to glucose metabolism, was measured by arterial spin labelling MRI in 32 subjects (25 HV and 8 MCI or PD) across five cohorts. In some cohorts, low doses of nadolol (1-5 mg), a β-AR antagonist with minimal brain penetration, were administered with clenbuterol to control peripheral β-AR responses.
RESULTS
Significant, dose-dependent increases in rCBF were seen in multiple brain regions, including hippocampus, amygdala and thalamus, following the administration of clenbuterol to HVs (mean changes from baseline in hippocampal rCBF of -1.7%, 7.3%, 22.9%, 28.4% 3 h after 20, 40, 80 and 160 μg clenbuterol, respectively). In patients with MCI or PD, increases in rCBF following 80 μg clenbuterol were observed both without and with 5 mg nadolol (in hippocampus, 18.6%/13.7% without/with nadolol). Clenbuterol was safe and well-tolerated in all subjects; known side effects of β-agonists, including increased heart rate and tremor, were mild in intensity and were blocked by low-dose nadolol.
CONCLUSIONS
The effects of clenbuterol on rCBF were evident both in the absence and presence of low-dose nadolol, suggesting central nervous system (CNS) involvement. Concomitant inhibition of the peripheral effects of clenbuterol by nadolol confirms that meaningful β-AR antagonism in the periphery was achieved without interrupting the central effects of clenbuterol on rCBF.
PubMed: 38953404
DOI: 10.1111/bcp.16160 -
Clinical Infectious Diseases : An... Jul 2024Screening for syphilis increasingly relies on positive treponemal rather than nontreponemal tests (rapid plasma reagin [RPR]). We compared ocular syphilis in patients...
BACKGROUND
Screening for syphilis increasingly relies on positive treponemal rather than nontreponemal tests (rapid plasma reagin [RPR]). We compared ocular syphilis in patients with nonreactive versus positive RPR.
METHODS
We conducted a retrospective observational cohort study of ocular syphilis treated at two New England hospitals 1996-2021 based on ophthalmologist-diagnosed eye findings and positive treponemal serology, regardless of RPR. We excluded patients with alternative diagnoses. We categorized RPR into nonreactive RPR, low-titer RPR (<1:8), and high-titer RPR (≥1:8) and compared early and long-term response to therapy.
RESULTS
Our sample included 115 patients with ocular syphilis (median follow-up 2.5 years): 25 (22%) nonreactive RPR, 21 (18%) low-titer RPR, 69 (60%) high-titer RPR. Compared with nonreactive and low-titer RPR, people with high-titer RPR were younger (mean 47 years, p<0.001), more likely male (93%, p<0.001) and more likely to be living with HIV (49%, p<0.001). People with nonreactive and low-titer RPR were less likely than high-titer RPR to have posterior/panuveitis (32% and 29% versus 75%, p<0.001) or abnormal CSF (26% and 35% versus 75%, p<0.001), and more likely to present with chronic eye findings (20% and 29% versus 1%, p<0.001). In long-term follow up, eye findings improved and did not recur in most patients (62% nonreactive, 68% low-titer, 96% high-titer RPR); improved but recurred in 29%, 11%, and 4%, respectively; and were stable in 10%, 21%, and 0%, respectively.
CONCLUSION
Patients with ocular syphilis and nonreactive RPR are similar to patients with low-titer RPR, and antibiotic therapy is beneficial in most.
PubMed: 38953389
DOI: 10.1093/cid/ciae354 -
Journal of Virology Jul 2024African swine fever virus causes a lethal hemorrhagic disease in domestic swine and wild boar for which currently licensed commercial vaccines are only available in...
UNLABELLED
African swine fever virus causes a lethal hemorrhagic disease in domestic swine and wild boar for which currently licensed commercial vaccines are only available in Vietnam. Development of subunit vaccines is complicated by the lack of information on protective antigens as well as suitable delivery systems. Our previous work showed that a pool of eight African swine fever virus genes vectored using an adenovirus prime and modified vaccinia virus boost could prevent fatal disease after challenge with a virulent genotype I isolate of the virus. Here, we identify antigens within this pool of eight that are essential for the observed protection and demonstrate that adenovirus-prime followed by adenovirus-boost can also induce protective immune responses against genotype I African swine fever virus. Immunization with a pool of adenoviruses expressing individual African swine fever virus genes partially tailored to genotype II virus did not protect against challenge with genotype II Georgia 2007/1 strain, suggesting that different antigens may be required to induce cross-protection for genetically distinct viruses.
IMPORTANCE
African swine fever virus causes a lethal hemorrhagic disease in domestic pigs and has killed millions of animals across Europe and Asia since 2007. Development of safe and effective subunit vaccines against African swine fever has been problematic due to the complexity of the virus and a poor understanding of protective immunity. In a previous study, we demonstrated that a complex combination of eight different virus genes delivered using two different viral vector vaccine platforms protected domestic pigs from fatal disease. In this study, we show that three of the eight genes are required for protection and that one viral vector is sufficient, significantly reducing the complexity of the vaccine. Unfortunately, this combination did not protect against the current outbreak strain of African swine fever virus, suggesting that more work to identify immunogenic and protective viral proteins is required to develop a truly effective African swine fever vaccine.
PubMed: 38953377
DOI: 10.1128/jvi.00622-24