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EMBO Reports Jul 2024Signals emanating from the T-cell receptor (TCR), co-stimulatory receptors, and cytokine receptors each influence CD8 T-cell fate. Understanding how these signals...
Signals emanating from the T-cell receptor (TCR), co-stimulatory receptors, and cytokine receptors each influence CD8 T-cell fate. Understanding how these signals respond to homeostatic and microenvironmental cues can reveal new ways to therapeutically direct T-cell function. Through forward genetic screening in mice, we discover that loss-of-function mutations in LDL receptor-related protein 10 (Lrp10) cause naive and central memory CD8 T cells to accumulate in peripheral lymphoid organs. Lrp10 encodes a conserved cell surface protein of unknown immunological function. T-cell activation induces Lrp10 expression, which post-translationally suppresses IL7 receptor (IL7R) levels. Accordingly, Lrp10 deletion enhances T-cell homeostatic expansion through IL7R signaling. Lrp10-deficient mice are also intrinsically resistant to syngeneic tumors. This phenotype depends on dense tumor infiltration of CD8 T cells, which display increased memory cell characteristics, reduced terminal exhaustion, and augmented responses to immune checkpoint inhibition. Here, we present Lrp10 as a new negative regulator of CD8 T-cell homeostasis and a host factor that controls tumor resistance with implications for immunotherapy.
PubMed: 38956225
DOI: 10.1038/s44319-024-00191-w -
Scientific Reports Jul 2024To improve the efficacy of organic solar cells (OSCs), novel small acceptor molecules (CTD1-CTD7) were designed by modification at the terminal acceptors of reference...
To improve the efficacy of organic solar cells (OSCs), novel small acceptor molecules (CTD1-CTD7) were designed by modification at the terminal acceptors of reference compound CTR. The optoelectronic properties of the investigated compounds (CTD1-CTD7) were accomplished by employing density functional theory (DFT) in combination with time-dependent density functional theory (TD-DFT). The M06 functional along with a 6-311G(d,p) basis set was utilized for calculating various parameters such as: frontier molecular orbitals (FMO), absorption maxima (λ), binding energy (E), transition density matrix (TDM), density of states (DOS), and open circuit voltage (V) of entitled chromophores. A red shift in the absorption spectra of all designed chromophores (CTD1-CTD7) was observed as compared to CTR, accompanied by low excitation energy. Particularly, CTD4 was characterized by the highest λ value of 685.791 nm and the lowest transition energy value of 1.801 eV which might be ascribed to the robust electron-withdrawing end-capped acceptor group. The observed reduced binding energy (Eb) was linked to an elevated rate of exciton dissociation and substantial charge transfer from central core in HOMO towards terminal acceptors in LUMO. These results were further supported by the outcomes from TDM and DOS analyses. Among all entitled chromophores, CTD4 exhibited bathochromic shift (685.791 nm), minimum HOMO/LUMO band gap of 2.347 eV with greater CT. Thus, it can be concluded that by employing molecular engineering with efficient acceptor moieties, the efficiency of photovoltaic materials could be improved.
PubMed: 38956211
DOI: 10.1038/s41598-024-65459-6 -
Scientific Reports Jul 2024Coronary artery bypass surgery can result in endothelial dysfunction due to ischemia/reperfusion (IR) injury. Previous studies have demonstrated that DuraGraft helps...
Coronary artery bypass surgery can result in endothelial dysfunction due to ischemia/reperfusion (IR) injury. Previous studies have demonstrated that DuraGraft helps maintain endothelial integrity of saphenous vein grafts during ischemic conditions. In this study, we investigated the potential of DuraGraft to mitigate endothelial dysfunction in arterial grafts after IR injury using an aortic transplantation model. Lewis rats (n = 7-9/group) were divided in three groups. Aortic arches from the control group were prepared and rings were immediately placed in organ baths, while the aortic arches of IR and IR + DuraGraft rats were preserved in saline or DuraGraft, respectively, for 1 h before being transplanted heterotopically. After 1 h after reperfusion, the grafts were explanted, rings were prepared, and mounted in organ baths. Our results demonstrated that the maximum endothelium-dependent vasorelaxation to acetylcholine was significantly impaired in the IR group compared to the control group, but DuraGraft improved it (control: 89 ± 2%; IR: 24 ± 1%; IR + DuraGraft: 48 ± 1%, p < 0.05). Immunohistochemical analysis revealed decreased intercellular adhesion molecule-1, 4-hydroxy-2-nonenal, caspase-3 and caspase-8 expression, while endothelial cell adhesion molecule-1 immunoreactivity was increased in the IR + DuraGraft grafts compared to the IR-group. DuraGraft mitigates endothelial dysfunction following IR injury in a rat bypass model. Its protective effect may be attributed, at least in part, to its ability to reduce the inflammatory response, oxidative stress, and apoptosis.
Topics: Animals; Rats; Endothelium, Vascular; Reperfusion Injury; Rats, Inbred Lew; Male; Coronary Artery Bypass; Oxidative Stress; Intercellular Adhesion Molecule-1; Disease Models, Animal; Aldehydes; Caspase 3; Vasodilation; Apoptosis; Acetylcholine
PubMed: 38956161
DOI: 10.1038/s41598-024-66056-3 -
Scientific Reports Jul 2024Analyze the relationship between genetic variations in the MTHFR gene at SNPs (rs1801131 and rs1801133) and the therapy outcomes for Iraqi patients with rheumatoid...
Analyze the relationship between genetic variations in the MTHFR gene at SNPs (rs1801131 and rs1801133) and the therapy outcomes for Iraqi patients with rheumatoid arthritis (RA). The study was conducted on a cohort of 95 RA Iraqi patients. Based on their treatment response, the cohort was divided into two groups: the responder (47 patients) and the nonresponder (48 patients), identified after at least three months of methotrexate (MTX) treatment. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was employed to analyze the MTHFR variations, specifically at rs1801133 and rs1801131. Overall, rs1801131 followed both codominant and dominate models, in which in the codominant model, GG [OR (95% CI) 0.11 (0.022-0.553)] and TG [OR (95% CI) 0.106 (0.021-0.528)] predict responders compared to the TT genotype; meanwhile, for the dominate model, the presence of both GG and TG genotypes [OR (95% CI) 0.108 (0.023-0.507)] together predict responders compared to the TT genotype. The AG haplotype was significantly associated with responders [OR (95% CI): 0.388 (0.208-0.723)], while the GT haplotype was associated marginally with nonresponders [OR (95% CI) 1.980 (0.965-4.064)]. In the final multivariate analysis, GG/TG genotypes were independently related to responders after adjustment for patients, disease, and treatment characteristics, while TT genotypes were associated with nonresponders. The Iraqi RA patients showed genetic polymorphism in MTHFR gene rs1801131 with T carrier allele associated with nonresponders to MTX therapy. The rs1801131 followed both codominant and dominant models. The G-carried allele for rs1801131 showed an independent association with responder to MTX therapy after adjustment for patients, disease, and treatment characteristics.
Topics: Humans; Methylenetetrahydrofolate Reductase (NADPH2); Arthritis, Rheumatoid; Methotrexate; Male; Female; Polymorphism, Single Nucleotide; Iraq; Middle Aged; Adult; Treatment Outcome; Antirheumatic Agents; Genotype
PubMed: 38956106
DOI: 10.1038/s41598-024-65199-7 -
Nature Communications Jul 2024Diabetes involves the death or dysfunction of pancreatic β-cells. Analysis of bulk sequencing from human samples and studies using in vitro and in vivo models suggest...
Diabetes involves the death or dysfunction of pancreatic β-cells. Analysis of bulk sequencing from human samples and studies using in vitro and in vivo models suggest that endoplasmic reticulum and inflammatory signaling play an important role in diabetes progression. To better characterize cell type-specific stress response, we perform multiplexed single-cell RNA sequencing to define the transcriptional signature of primary human islet cells exposed to endoplasmic reticulum and inflammatory stress. Through comprehensive pair-wise analysis of stress responses across pancreatic endocrine and exocrine cell types, we define changes in gene expression for each cell type under different diabetes-associated stressors. We find that β-, α-, and ductal cells have the greatest transcriptional response. We utilize stem cell-derived islets to study islet health through the candidate gene CIB1, which was upregulated under stress in primary human islets. Our findings provide insights into cell type-specific responses to diabetes-associated stress and establish a resource to identify targets for diabetes therapeutics.
Topics: Humans; Endoplasmic Reticulum Stress; Islets of Langerhans; Insulin-Secreting Cells; Calcium-Binding Proteins; Single-Cell Analysis; Glucagon-Secreting Cells; Sequence Analysis, RNA; Transcriptome; Stress, Physiological
PubMed: 38956087
DOI: 10.1038/s41467-024-49724-w -
Rheumatology and Therapy Jul 2024Some retrospective data sources, such as electronic health records in the USA, report composite outcome measures not fully validated in psoriatic arthritis (PsA)....
INTRODUCTION
Some retrospective data sources, such as electronic health records in the USA, report composite outcome measures not fully validated in psoriatic arthritis (PsA). However, they often contain global assessments, such as a Physician Global Assessment (PhGA) and Patient Global Assessment (PatGA), along with patient-reported pain scores, which individually are considered validated in PsA. This research described the performance characteristics of a 3-item global assessment and pain (GAP) composite endpoint using data from the ixekizumab phase 3 PsA clinical trial program.
METHODS
Discrimination of GAP was assessed by comparing placebo to active treatment arms. The magnitude of treatment effect and responsiveness were compared to Disease Activity Index for PsA (DAPSA), clinical DAPSA, DAPSA28, and Psoriatic Arthritis Disease Activity Score (PASDAS) using effect size (ES) and standardized response mean (SRM), respectively. Construct validity was evaluated through correlation among the composite endpoints, and with other physician- and patient-reported outcomes. Change in GAP was compared in patients who reached low disease activity (LDA) levels based on DAPSA, cDAPSA, and PASDAS vs those who did not.
RESULTS
GAP discriminated between active treatment and placebo with statistically significant separation as early as week 1. The largest ES/SRM was seen with GAP (2.29/1.74) and PASDAS (2.47/1.68). GAP had the strongest correlation with PASDAS (0.81-0.92) and showed moderate correlations with patient-assessed physical function, low correlations with physician-assessed skin and nail psoriasis, and low to moderate correlation with physician-assessed enthesitis. A significantly greater improvement in GAP was seen in the groups achieving LDA states compared to those not (p < 0.001).
CONCLUSION
The GAP composite, an abbreviated endpoint comprising measures common in electronic health records, has promising performance characteristics and could be used to address important clinical questions regarding outcomes and impact of PsA in existing datasets. CLINTRIALS.
GOV IDENTIFIER
NCT01695239; NCT02349295.
PubMed: 38955921
DOI: 10.1007/s40744-024-00690-1 -
Journal of Microbiology and... Apr 2024Secretin PilQ is an antigenically conserved outer membrane protein that is present in most meningococci and PorA is a major protein that elicits bactericidal immune...
Secretin PilQ is an antigenically conserved outer membrane protein that is present in most meningococci and PorA is a major protein that elicits bactericidal immune response in humans following natural disease and immunization. In the present study, BALB/c mice were immunized subcutaneously with rPilQ406-770 or rPorA together with Freund's adjuvant (FA). Serum antibody responses to serogroup A and B whole cells or purified proteins and functional activity of antibodies were determined by ELISA and serum bactericidal assay (SBA), respectively. Serum IgG responses were significantly increased in the immunized group with rPilQ406-770 or rPorA together with FA compared to control groups. IgG antibody response of mice immunized with rPilQ406-770 was significantly more than mice immunized with rPorA (OD at 450 nm was 1.6 versus 0.83). The booster injections were effective in increasing the responses of antirPilQ406-770 or anti-rPorA IgG significantly. Antisera produced against rPilQ406-770 or rPorA demonstrated strong surface reactivity to serogroup B in comparison with control groups. Antisera raised against rPorA or rPilQ406-770 and FA demonstrated SBA titers from 1/1024 to 1/2048 against serogroup B. The strongest bactericidal activity was detected in sera from mice immunized with rPilQ406-770 mixed with FA. These results suggest that rPilQ406-770 is a potential vaccine candidate for serogroup B
PubMed: 38955797
DOI: 10.4014/jmb.2401.01018 -
Allergology International : Official... Jul 2024Allergen immunotherapy (AIT), including SCIT and SLIT, is a treatment that involves the administration of allergens to which patients with allergic diseases have been... (Review)
Review
Allergen immunotherapy (AIT), including SCIT and SLIT, is a treatment that involves the administration of allergens to which patients with allergic diseases have been sensitized. HDM-SCIT for asthma is indicated in cases of HDM-sensitized allergic asthma with normal lung function. HDM-SCIT improves asthma symptoms and AHR, and decreases the medication dose. Importantly, AIT can improve other allergic diseases complicated by asthma, such as allergic rhinitis, which can also contribute to the improvement of asthma symptoms. Several studies have suggested that HDM-SLIT also attenuates the risk of asthma exacerbations, and improves lung function in asthma cases with allergic rhinitis. Furthermore, AIT can modify the natural course of allergic diseases, including asthma. For example, the effects of AIT are maintained for at least several years after treatment discontinuation. AIT can prevent the onset of asthma when introduced in allergic rhinitis, and can also inhibit or reduce new allergen sensitizations. Recent data have suggested that AIT may suppress non-targeted allergen-induced immune responses in addition to targeted allergen-induced responses, and suppress infections of the lower respiratory tract by enhancing IFN responses.
PubMed: 38955611
DOI: 10.1016/j.alit.2024.05.005 -
Annals of the Rheumatic Diseases Jul 2024To report long-term safety and tolerability of olokizumab (OKZ) in combination with methotrexate (MTX) in subjects with active rheumatoid arthritis (RA), using pooled...
OBJECTIVE
To report long-term safety and tolerability of olokizumab (OKZ) in combination with methotrexate (MTX) in subjects with active rheumatoid arthritis (RA), using pooled data from three randomised clinical trials (RCT) followed by open-label extension (OLE) study.
METHODS
Cumulative data from three phase 3 core trials and their OLE were analysed. Safety variables assessed included treatment-emergent adverse events (AEs), serious AEs (SAEs), AEs of special interest and laboratory results. Efficacy assessments included ACR20/50/70 responses, Disease Activity Score 28 (C-reactive protein) <3.2, CDAI remission and low disease activity (LDA), SDAI remission and LDA, HAQ-DI decrease of 0.22 unit and Boolean 2.0 remission.
RESULTS
A total of 2304 patients received OKZ in combination with MTX either once every 2 weeks or once every 4 weeks. Event rates per 100 patient-years in OKZ every 2 weeks and OKZ every 4 weeks, respectively, were 9.57 and 9.13 for SAEs; 2.95 and 2.34 for serious infections; 0.09 and 0.05 for gastrointestinal perforations; 0.58 and 0.83 for major adverse cardiovascular events; and 0.45 and 0.50 for malignancies. No increase in the rate of any AE was observed over 106 weeks of treatment. The evaluation of laboratory variables demonstrated the expected changes, like neutropenia, elevation of liver enzymes and blood lipids. Clinical response rates remained stable during the OLE.
CONCLUSION
The long-term safety and tolerability of OKZ in combination with MTX remained stable. The efficacy of OKZ was maintained through week 106. These findings support OKZ as a treatment option for patients with active RA.
PubMed: 38955475
DOI: 10.1136/ard-2023-225473 -
International Journal of Hyperthermia :... 2024Cryoablation (Cryo) is a minimally invasive treatment for tumors. Cryo can activate the body's immune response, although it is typically weak. The immune response...
BACKGROUND
Cryoablation (Cryo) is a minimally invasive treatment for tumors. Cryo can activate the body's immune response, although it is typically weak. The immune response induced by Cryo in hepatocellular carcinoma (HCC) is poorly understood. PD-1 and CTLA-4 monoclonal antibodies are immune checkpoint inhibitors used in immunotherapy for tumors. The combined use of these antibodies with Cryo may enhance the immune effect.
METHODS
A Balb/c mouse model of HCC was established and treated with Cryo, immune checkpoint blockade (ICB), or Cryo + ICB (combination therapy). The growth trend of right untreated tumors and survival time of mice were determined. The expression of apoptosis-related proteins was detected by Western blot (WB) assay. The percentages of immune cells and immunosuppressive cells were analyzed by flow cytometry. The numbers of infiltrating T lymphocytes were checked by immunohistochemistry, and the levels of T-cell-associated cytokines were detected by Quantitative real-time Polymerase Chain Reaction (qRT-PCR) assays and Enzyme-Linked Immunosorbent Assays (ELISA) assays.
RESULTS
Cryo + ICB inhibited the growth of right untreated tumors, promoted tumor cell apoptosis, and prolonged the survival time of mice. Local T-cell infiltration in right tumor tissues increased after the combination therapy, while the number of immunosuppressive cells was significantly reduced. In addition, the combination therapy may induce the production of multiple Th1-type cytokines but reduce the production of Th2-type cytokines.
CONCLUSIONS
Cryo can activate CD8 and CD4 T-cell immune responses. Cryo + ICB can relieve the immunosuppressive tumor microenvironment and shift the Th1/Th2 balance toward Th1 dominance, further enhancing the Cryo-induced T-cell immune response and resulting in a stronger antitumor immune response.
Topics: Animals; Carcinoma, Hepatocellular; Mice; Liver Neoplasms; Cryosurgery; Mice, Inbred BALB C; Immune Checkpoint Inhibitors; Disease Models, Animal; Cell Line, Tumor
PubMed: 38955354
DOI: 10.1080/02656736.2024.2373319