Electroacupuncture and methotrexate cooperate to ameliorate psoriasiform skin inflammation by regulating the immune balance of Th17/Treg.

Psoriasis is an autoinflammatory dermatosis, while methotrexate (MTX) is an immunosuppressant used to treat psoriasis. However, conventional immunosuppressants may cause various side effects. Acupuncture has potential benefits in treating psoriasis based on its anti-inflammatory effects. However, the immune mechanisms underlying its effects remain unclear. In this study, imiquimod-induced psoriatic mice were used to investigate the effects and mechanisms of electroacupuncture (EA) and, in particular, its joint treatment with MTX. We found that treatment with either EA or MTX ameliorated psoriasiform skin lesions, improved skin pathology and reduced proinflammatory cytokines in the skin, while joint treatment with both EA and MTX further alleviated the skin lesions and inflammation compared to either one alone. Moreover, percentages of CD4+ IL-17A+ Th17 cells in the skin and lymph nodes were decreased by EA or MTX and further lowered by combined EA+MTX treatment. Similarly, EA or MTX also reduced their RORγt expression. On the contrary, CD4+ FoxP3+ Treg frequency in psoriatic mice was augmented by EA or MTX and further increased by the joint treatment. However, depleting Tregs mostly reversed the therapeutic effects of EA or EA plus MTX. Additionally, the phosphorylated NF-κB (p65) expression was suppressed by treatment with EA, MTX or better with EA+MTX. Meanwhile, the anti-inflammatory effects of EA plus MTX were offset by an NF-κB agonist. Thus, this study has revealed that EA cooperates with MTX to balance Th17/Treg responses and to ameliorate psoriasiform skin inflammation through suppressing NF-κB activation. Our findings may be implicated for treating human psoriasis.

Electrostimulation suppresses allograft rejection via promoting lymphatic regulatory T cell migration mediated by lymphotoxin - lymphotoxin receptor ß signaling.

Conventional immunosuppressants that suppress allograft rejection cause various side effects. Although regulatory T cells (Tregs) are essential for allograft survival, the limited efficacy of Treg therapy demands improvement. Thus, it is imperative to seek new approaches to enhancing Treg suppression. Low-intensity electrostimulation (ES) has been shown to exert antiinflammatory effects without causing major adverse reactions. However, it remains unknown whether and how ES regulates alloimmunity. Here, we found that regional ES delayed murine skin allograft rejection and promoted long-term allograft survival induced by an mTOR inhibitor, rapamycin. ES also extended islet allograft survival. Mechanistically, ES enhanced the expression of lymphotoxin α (LTα) on Tregs after transplantation. Blockade of lymphotoxin ß receptor-mediated nonclassical NFκB signaling suppressed lymphatic Treg migration and largely reversed the effects of ES on allograft survival. Moreover, ES failed to extend allograft survival when recipients lacked LTα/lymph nodes or if transferred Tregs lacked LTα. Therefore, ES promoted the lymphatic migration of CD4+Foxp3+ Tregs by upregulating their surface expression of LTα. Finally, ES augmented expression of LTα on murine or human Tregs, but not conventional T cells, while promoting their calcium influx in vitro. This ES-mediated upregulation of LTα relied on calcium influx. Thus, our findings have unveiled novel mechanisms underlying ES-mediated immunoregulation.

Effects of the combination of various pharmacological treatments and exercise on knee osteoarthritis: a systematic review and network meta-analysis.

Purpose: The combination of pharmacological and non-pharmacological interventions is strongly recommended by current guidelines for knee osteoarthritis. However, few systematic reviews have validated their combined efficacy. In this study, we investigated the effects of the combination of pharmacological agents and exercise on knee osteoarthritis. Methods: Randomized controlled trials that investigated the efficacy of pharmacological agents combined with exercise for knee osteoarthritis were searched in PubMed, Embase, and Cochrane Library up to February 2024. The network meta-analysis was performed within the frequentist framework. Standardized mean difference (SMD) with 95% CI was estimated for pain and function. Grading of recommendations, assessment, development, and evaluations were used to evaluate the certainty of evidence. Results: In total, 71 studies were included. The combination therapy outperformed pharmacological or exercise therapy alone. Among the various pharmacological agents combined with exercise, mesenchymal stem cell injection was ranked the best for short-term pain reduction (SMD: -1.53, 95% CI: -1.92 to -1.13, high certainty), followed by botulinum toxin A, dextrose, and platelet-rich plasma. For long-term pain relief, dextrose prolotherapy was the optimal (SMD: -1.76, 95% CI: -2.65 to -0.88, moderate certainty), followed by mesenchymal stem cells, platelet rich in growth factor, and platelet-rich plasma. Conclusion: Exercise programs should be incorporated into clinical practice and trial design. For patients undergoing exercise therapies, mesenchymal stem cell, dextrose, platelet-rich plasma, platelet rich in growth factor, and botulinum toxin A may be the optimal agents.

Identification of an osteopontin-derived peptide that binds neuropilin-1 and activates vascular repair responses and angiogenesis.

The osteopontin-derived peptide FOL-005 stimulates hair growth. Using ligand-receptor glyco-capture technology we identified neuropilin-1 (NRP-1), a known co-receptor for vascular endothelial growth factor (VEGF) receptors, as the most probable receptor for FOL-005 and the more stable analogue FOL-026. X-ray diffraction and microscale thermophoresis analysis revealed that FOL-026 shares binding site with VEGF in the NRP-1 b1-subdomain. Stimulation of human umbilical vein endothelial cells with FOL-026 resulted in phosphorylation of VEGFR-2, ERK1/2 and AKT, increased cell growth and migration, stimulation of endothelial tube formation and inhibition of apoptosis in vitro. FOL-026 also promoted angiogenesis in vivo as assessed by subcutaneous Matrigel plug and hind limb ischemia models. NRP-1 knock-down or treatment of NRP-1 antagonist EG00229 blocked the stimulatory effects of FOL-026 on endothelial cells. Exposure of human coronary artery smooth muscle cells to FOL-026 stimulated cell growth, migration, inhibited apoptosis, and induced VEGF gene expression and VEGFR-2/AKT phosphorylation by an NRP-1-dependent mechanism. RNA sequencing showed that FOL-026 activated pathways involved in tissue repair. These findings identify NRP-1 as the receptor for FOL-026 and show that its biological effects mimic that of growth factors binding to the VEGF receptor family. They also suggest that FOL-026 may have therapeutical potential in conditions that require vascular repair and/or enhanced angiogenesis.

Association of Matrix Metalloproteinase-9 Genotypes With Nasopharyngeal Carcinoma Risk.

BACKGROUND/AIM: The up-regulation of matrix metalloproteinase-9 (MMP-9) expression is a characteristic feature observed across various malignancies, including nasopharyngeal carcinoma (NPC). Nevertheless, the influence of MMP-9 genotype in the context of NPC remains underexplored. This study examined the implications of MMP-9 promoter rs3918242 genotypes on the susceptibility to NPC in Taiwan. MATERIALS AND METHODS: In a cohort comprising 208 NPC cases and 416 healthy controls, genotyping of MMP-9 rs3918242 was conducted utilizing polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: Individuals harbouring the variant CT or TT genotype of MMP-9 rs3918242 did not demonstrate a discernible alteration in NPC risk when compared to wild-type CC carriers [odds ratio (OR)=0.83 and 0.79, with 95% confidence intervals (95%CI)=0.56-1.24 and 0.27-2.29; p=0.4205 and 0.8675, respectively]. Moreover, the presence of the variant T allele did not confer a modified risk of NPC (OR=0.84, 95%CI=0.60-1.19, p=0.3761). Intriguingly, a protective effect associated with the MMP-9 rs3918242 CT genotype against NPC risk was discerned among individuals abstaining from betel quid chewing behaviour (OR=0.51, 95%CI=0.30-0.87, p=0.0166). Notably, no significant association was established between the MMP-9 rs3918242 CT or TT genotype and NPC risk among individuals with or without smoking or alcohol consumption habits. CONCLUSION: Presence of the variant CT or TT genotype at MMP-9 rs3918242 did not appear to substantially contribute to an elevated risk of NPC. Notably, a protective effect against NPC risk was observed in individuals carrying the CT genotype, particularly in those abstaining from betel quid chewing.

Nailfold capillary measurements correlated to NOTCH3 R544C mutation in preclinical CADASIL patients.

BACKGROUND: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary disease caused by NOTCH3 mutation. Nailfold capillaroscopy is a non-invasive technique typically used for rheumatic diseases. It has potential in other conditions linked to vascular pathology. However, capillaroscopy in CADASIL has not been explored. This study aims to investigate whether capillaroscopy measurements can correlate with brain vascular changes in preclinical CADASIL patients, specifically those with NOTCH3 mutation. METHODS: This study included 69 participants from the Taiwan Precision Medicine Initiative (TPMI) dataset who visited Taichung Veterans General Hospital from January to December 2022. All individuals underwent genetic studies, brain imaging and nailfold capillaroscopy. The Mann-Whitney U test was used to compare results of brain imaging between carriers and controls. It was also used to compare measurements in nailfold capillaroscopy within each group. Spearman Rank Correlation Analysis was used to explore the relationship between capillary measurements and brain MRI results. RESULTS: White matter hyperintensities (WMH) expression was positively correlated with capillary dimension and negatively correlated with density. Our results presented that R544C carriers exhibited a diffuse increase in WMH (p < 0.001) and a global reduction in gray matter volume but preserved in specific areas. The white matter lesion scores in all brain regions were higher in the mutation carriers than the controls. (p < 0.001). CONCLUSION: This research highlights the association of nailfold capillaroscopy findings with white matter lesions in preclinical CADASIL patients. Capillaroscopy guides an effective screening strategy in individuals with NOTCH3 mutations.

Revealing the Singlet Fission Mechanism for a Silane-Bridged Thienotetracene Dimer.

Tetraceno[2,3-b]thiophene is regarded as a strong candidate for singlet fission-based solar cell applications due to its mixed characteristics of tetracene and pentacene that balance exothermicity and triplet energy. An electronically weakly coupled tetraceno[2,3-b]thiophene dimer (Et2Si(TIPSTT)2) with a single silicon atom bridge has been synthesized, providing a new platform to investigate the singlet fission mechanism involving the two acene chromophores. We study the excited state dynamics of Et2Si(TIPSTT)2 by monitoring the evolution of multiexciton coupled triplet states, 1TT to 5TT to 3TT to T1 + S0, upon photoexcitation with transient absorption, temperature-dependent transient absorption, and transient/pulsed electron paramagnetic resonance spectroscopies. We find that the photoexcited singlet lifetime is 107 ps, with 90% evolving to form the TT state, and the complicated evolution between the multiexciton states is unraveled, which can be an important reference for future efforts toward tetraceno[2,3-b]thiophene-based singlet fission solar cells.

The Evaluation of Teleost-Derived Antimicrobial Peptides Against Neisseria gonorrhoeae.

Introduction Gonorrhea has become an emerging sexually transmitted infection worldwide. The multi-antibiotic resistance facilitates the transmission; thus, new antibiotics or alternatives are needed. Antimicrobial peptides (AMP) are antimicrobials naturally secreted by the host as a defense material. Teleost-derived AMP have gained attention over the past two decades due to their potent efficacy toward microorganisms. This study examines teleost-derived AMP against Neisseria gonorrhoeae (GC), the responsible bacteria for gonorrhea, to evaluate the antibiotic potential as a future alternative for preventing gonorrhea. Methods Minimal inhibitory concentration (MIC) and time-killed assay were conducted to evaluate the inhibition concentration of each AMP. Transmission electron microscopy was used to confirm the potential mode of action. The inhibition of microcolony formation and adherence to epithelial cells were examined to assess the infection inhibition. Results Pardaxin-based (flatfish pardaxin {PB2}) and piscidin-based (striped bass piscidin 1 {PIS} and tilapia piscidin {TP} 4) AMP were effective toward GC under or equal to 7.5 µg/mL as of minimal inhibitory concentration. Transmission electron microscopy images revealed that these AMP attack bacterial membranes as membrane blebbing and breakage were observed. These AMP also effectively reduced the GC biofilm formation, as well as their adherence to human endocervical epithelial cells. Conclusion Pardaxin-based (PB2) and piscidin-based (PIS and TP4) teleost-derived AMP can inhibit GC and potentially serve as the new antibiotic alternative for preventing GC colonization and infection. This study will shed some light on the future development of teleost-derived AMP in treating gonorrhea and maintaining reproductive health.

Clinical Outcomes of Severe Rhinosinusitis Complicated with Cavernous Sinus Syndrome.

Background: Various diseases involving the cavernous sinus can cause a condition called cavernous sinus syndrome (CSS), which is characterized by ophthalmoplegia or sensory deficits over the face resulting from the compression effect of internal structure. While tumor compression is the most reported cause of CSS, statistical data on CSS caused by infections are limited. Its risk factors, treatment methods, and clinical outcomes are not well-documented. Methods: In this retrospective study, we reviewed the data of patients admitted to a tertiary medical center from 2015 to 2022 with a diagnosis of acute and chronic sinusitis and at least one diagnostic code for CSS symptoms. We manually reviewed whether patients were involved in two or more of the following cranial nerves (CN): CN III, CN IV, CN V, or CN VI, or at least one of these nerves with a neuroimaging-confirmed lesion in the cavernous sinus. Results: Nine patients were diagnosed with rhinosinusitis-related CSS. The most common comorbidity was type 2 diabetes, and the most common clinical manifestations were diplopia and blurred vision. The sphenoid sinus was the most affected sinus. One patient expired due to a severe brain abscess infection without surgery. The remaining patients underwent functional endoscopic sinus surgery, and 50% of the pathology reports indicated fungal infections. Staphylococcus spp. was the most cultured bacteria, and Amoxycillin/Clavulanate was the most used antibiotic. Only four patients had total recovery during the follow-up one year later. Conclusions: CSS is a rare but serious complication of rhinosinusitis. Patients with diabetes and the elderly may be at a higher risk for this complication. Even after treatment, some patients may still have neurological symptoms.

Integrative analyses of genetic characteristics associated with skeletal endothelial cells.

The osseous vascular endothelium encompasses a vast intricate framework that regulates bone remodeling. Osteoporosis, an age-associated systemic bone disease, is characterized by the degeneration of the vascular architecture. Nevertheless, the precise mechanisms underpinning the metamorphosis of endothelial cells (ECs) with advancing age remain predominantly enigmatic. In this study, we conducted a systematic analysis of differentially expressed genes (DEGs) and the associated pathways in juvenile and mature femoral ECs, utilizing data sourced from the Gene Expression Omnibus (GEO) repositories (GSE148804) and employing bioinformatics tools. Through this approach, we successfully discerned six pivotal genes, namely Adamts1, Adamts2, Adamts4, Adamts14, Col5a1, and Col5a2. Subsequently, we constructed a miRNA-mRNA network based on miRNAs displaying differential expression between CD31hiEMCNhi and CD31lowEMCNlow ECs, utilizing online repositories for prediction. The expression of miR-466i-3p and miR-466i-5p in bone marrow ECs exhibited an inverse correlation with age. Our in vivo experiments additionally unveiled miR-466i-5p as a pivotal regulator in osseous ECs and a promising therapeutic target for age-related osteoporosis.

Gender associations between phthalate exposure and biomarkers of oxidative stress: A prospective cohort study.

Previous epidemiologic research has shown that phthalate exposure in pregnant women is related to adverse birth outcomes in a sex-specific manner. However, the biological mechanism of phthalate exposure that causes these birth outcomes remains poorly defined. In this research, we investigated the association between phthalate exposure and placental oxidative stress in a large population-based cohort study, aiming to initially explore the relationship between phthalate exposure and gene expression in placental oxidative stress in a sex-specific manner. Quantitative PCR was performed to measure the expression of placental inflammatory mRNAs (HO-1, HIF1α, and GRP78) in 2469 placentae. The multiple linear regression models were used to investigate the associations between mRNA and urinary phthalate monoesters. Phthalate metabolites monomethyl phthalate (MMP) and mono-n-butyl phthalate (MBP) were positively correlated with higher HIF1α expression in placentae of male fetuses (p < .05). Mono-benzyl phthalate (MBzP) increased the expression of HO-1, HIF1α, and GRP78 in placentae of male fetuses, and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) up-regulated the expression of HIF1α and GRP78. Additionally, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) was negatively correlated with HO-1, HIF1α, and GRP78 in placentae of female fetuses. Maternal phthalate exposure was associated with oxidative stress variations in placental tissues. The associations were closer in the placentas of male fetuses than in that of female ones. The placenta oxidative stress is worth further investigation as a potential mediator of maternal exposure-induced disease risk in children.

Zhen-Wu-Tang ameliorates lupus nephritis by diminishing renal tissue-resident memory CD8+ T cells via suppressing IL-15/STAT3 pathway.

Zhen-Wu-Tang (ZWT), a conventional herbal mixture, has been recommended for treating lupus nephritis (LN) in clinic. However, its mechanisms of action remain unknown. Here we aimed to define the immunological mechanisms underlying the effects of ZWT on LN and to determine whether it affects renal tissue-resident memory T (TRM) cells. Murine LN was induced by a single injection of pristane, while in vitro TRM cells differentiated with IL-15/TGF-ß. We found that ZWT or mycophenolate mofetil treatment significantly ameliorated kidney injury in LN mice by decreasing 24-h urine protein, Scr and anti-dsDNA Ab. ZWT also improved renal pathology and decreased IgG and C3 depositions. In addition, ZWT down-regulated renal Desmin expression. Moreover, it lowered the numbers of CD8+ TRM cells in kidney of mice with LN while decreasing their expression of TNF-α and IFN-γ. Consistent with in vivo results, ZWT-containing serum inhibited TRM cell differentiation induced by IL-15/TGF-ß in vitro. Mechanistically, it suppressed phosphorylation of STAT3 and CD122 （IL2/IL-15Rß）expression in CD8+ TRM cells. Importantly, ZWT reduced the number of total F4/80+CD11b+ and CD86+, but not CD206+, macrophages in the kidney of LN mice. Interestingly, ZWT suppressed IL-15 protein expression in macrophages in vivo and in vitro. Thus, we have provided the first evidence that ZWT decoction can be used to improve the outcome of LN by reducing CD8+ TRM cells via inhibition of IL-15/IL-15R /STAT3 signaling.

miR-26 Deficiency Causes Alterations in Lens Transcriptome and Results in Adult-Onset Cataract.

Purpose: Despite strong evidence demonstrating that normal lens development requires regulation governed by microRNAs (miRNAs), the functional role of specific miRNAs in mammalian lens development remains largely unexplored. Methods: A comprehensive analysis of miRNA transcripts in the newborn mouse lens, exploring both differential expression between lens epithelial cells and lens fiber cells and overall miRNA abundance, was conducted by miRNA sequencing. Mouse lenses lacking each of three abundantly expressed lens miRNAs (miR-184, miR-26, and miR-1) were analyzed to explore the role of these miRNAs in lens development. Results: Mice lacking all three copies of miR-26 (miR-26TKO) developed postnatal cataracts as early as 4 to 6 weeks of age. RNA sequencing analysis of neonatal lenses from miR-26TKO mice exhibited abnormal reduced expression of a cohort of genes found to be lens enriched and linked to cataract (e.g., Foxe3, Hsf4, Mip, Tdrd7, and numerous crystallin genes) and abnormal elevated expression of genes related to neural development (Lhx3, Neurod4, Shisa7, Elavl3), inflammation (Ccr1, Tnfrsf12a, Csf2ra), the complement pathway, and epithelial to mesenchymal transition (Tnfrsf1a, Ccl7, Stat3, Cntfr). Conclusions: miR-1, miR-184, and miR-26 are each dispensable for normal embryonic lens development. However, loss of miR-26 causes lens transcriptome changes and drives cataract formation.

Effects of Helicobacter pylori and Moluodan on the Wnt/ß-catenin signaling pathway in mice with precancerous gastric cancer lesions.

BACKGROUND: Helicobacter pylori (H. pylori) is the primary risk factor for gastric cancer (GC), the Wnt/ß-Catenin signaling pathway is closely linked to tumourigenesis. GC has a high mortality rate and treatment cost, and there are no drugs to prevent the progression of gastric precancerous lesions to GC. Therefore, it is necessary to find a novel drug that is inexpensive and preventive to against GC. AIM: To explore the effects of H. pylori and Moluodan on the Wnt/ß-Catenin signaling pathway and precancerous lesions of GC (PLGC). METHODS: Mice were divided into the control, N-methyl-N-nitrosourea (MNU), H. pylori + MNU, and Moluodan groups. We first created an H. pylori infection model in the H. pylori + MNU and Moluodan groups. A PLGC model was created in the remaining three groups except for the control group. Moluodan was fed to mice in the Moloudan group ad libitum. The general condition of mice were observed during the whole experiment period. Gastric tissues of mice were grossly and microscopically examined. Through quantitative real-time PCR (qRT-PCR) and Western blotting analysis, the expression of relevant genes were detected. RESULTS: Mice in the H. pylori + MNU group showed the worst performance in general condition, gastric tissue visual and microscopic observation, followed by the MNU group, Moluodan group and the control group. QRT-PCR and Western blotting analysis were used to detect the expression of relevant genes, the results showed that the H. pylori + MNU group had the highest expression, followed by the MNU group, Moluodan group and the control group. CONCLUSION: H. pylori can activate the Wnt/ß-catenin signaling pathway, thereby facilitating the development and progression of PLGC. Moluodan suppressed the activation of the Wnt/ß-catenin signaling pathway, thereby decreasing the progression of PLGC.

Extend the benchmarking indel set by manual review using the individual cell line sequencing data from the Sequencing Quality Control 2 (SEQC2) project.

Accurate indel calling plays an important role in precision medicine. A benchmarking indel set is essential for thoroughly evaluating the indel calling performance of bioinformatics pipelines. A reference sample with a set of known-positive variants was developed in the FDA-led Sequencing Quality Control Phase 2 (SEQC2) project, but the known indels in the known-positive set were limited. This project sought to provide an enriched set of known indels that would be more translationally relevant by focusing on additional cancer related regions. A thorough manual review process completed by 42 reviewers, two advisors, and a judging panel of three researchers significantly enriched the known indel set by an additional 516 indels. The extended benchmarking indel set has a large range of variant allele frequencies (VAFs), with 87% of them having a VAF below 20% in reference Sample A. The reference Sample A and the indel set can be used for comprehensive benchmarking of indel calling across a wider range of VAF values in the lower range. Indel length was also variable, but the majority were under 10 base pairs (bps). Most of the indels were within coding regions, with the remainder in the gene regulatory regions. Although high confidence can be derived from the robust study design and meticulous human review, this extensive indel set has not undergone orthogonal validation. The extended benchmarking indel set, along with the indels in the previously published known-positive set, was the truth set used to benchmark indel calling pipelines in a community challenge hosted on the precisionFDA platform. This benchmarking indel set and reference samples can be utilized for a comprehensive evaluation of indel calling pipelines. Additionally, the insights and solutions obtained during the manual review process can aid in improving the performance of these pipelines.

miR-26 deficiency causes alterations in lens transcriptome and results in adult-onset cataract.

Purpose: Despite strong evidence demonstrating that normal lens development requires regulation governed by miRNAs, the functional role of specific miRNAs in mammalian lens development remains largely unexplored. Methods: A comprehensive analysis of miRNA transcripts in the newborn mouse lens, exploring both differential expression between lens epithelial cells and lens fiber cells and overall miRNA abundance was conducted by miRNA-seq. Mouse lenses lacking each of three abundantly expressed lens miRNAs: miR-184, miR-26 and miR-1 were analyzed to explore the role of these miRNAs in lens development. Results: Mice lacking all three copies of miR-26 (miR-26TKO) developed postnatal cataracts as early as 4-6 weeks of age. RNA-seq analysis of neonatal lenses from miR-26TKO mice exhibited abnormal reduced expression of a cohort of genes found to be lens-enriched and linked to cataract (e.g. Foxe3, Hsf4, Mip, Tdrd7, and numerous crystallin genes), and abnormal elevated expression of genes related to neural development (Lhx3, Neurod4, Shisa7, Elavl3 ), inflammation (Ccr1, Tnfrsf12a, Csf2ra), the complement pathway, and epithelial to mesenchymal transition (Tnfrsf1a, Ccl7, Stat3, Cntfr). Conclusion: miR-1, miR-184 and miR-26 are each dispensable for normal embryonic lens development. However, loss of miR-26 causes lens transcriptome changes and drives cataract formation.

The TOPK Inhibitor HI-TOPK-032 Enhances CAR T-cell Therapy of Hepatocellular Carcinoma by Upregulating Memory T Cells.

Chimeric antigen receptor (CAR) T cells are emerging as an effective antitumoral therapy. However, their therapeutic effects on solid tumors are limited because of their short survival time and the immunosuppressive tumor microenvironment. Memory T cells respond more vigorously and persist longer than their naïve/effector counterparts. Therefore, promoting CAR T-cell development into memory T cells could further enhance their antitumoral effects. HI-TOPK-032 is a T-LAK cell-originated protein kinase (TOPK)-specific inhibitor that moderately represses some types of tumors. However, it is unknown whether HI-TOPK-032 works on hepatocellular carcinoma (HCC) and whether it impacts antitumoral immunity. Using both subcutaneous and orthotopic xenograft tumor models of two human HCC cell lines, Huh-7 and HepG2, we found that HI-TOPK-032 significantly improved proliferation/persistence of CD8+ CAR T cells, as evidenced by an increase in CAR T-cell counts or frequency of Ki-67+CD8+ cells and a decrease in PD-1+LAG-3+TIM-3+CD8+ CAR T cells in vivo. Although HI-TOPK-032 did not significantly suppress HCC growth, it enhanced the capacity of CAR T cells to inhibit tumor growth. Moreover, HI-TOPK-032 augmented central memory CD8+ T cell (TCM) frequency while increasing eomesodermin expression in CD8+ CAR T cells in tumor-bearing mice. Moreover, it augmented CD8+ CAR TCM cells in vitro and reduced their expression of immune checkpoint molecules. Finally, HI-TOPK-032 inhibited mTOR activation in CAR T cells in vitro and in tumors, whereas overactivation of mTOR reversed the effects of HI-TOPK-032 on CD8+ TCM cells and tumor growth. Thus, our studies have revealed mechanisms underlying the antitumoral effects of HI-TOPK-032 while advancing CAR T-cell immunotherapy.

Efficacy of Adjuvant Sublingual Immunotherapy After Septomeatoplasty.

BACKGROUND: The efficacy of adjuvant sublingual immunotherapy (SLIT) in correcting structural problems in patients with allergic rhinitis (AR) caused by mite who have undergone septomeatoplasty (SMP) has not been studied. METHODS: This non-randomized controlled study recruited patients with AR (caused by mite) and concurrent septal deviation and inferior turbinate hypertrophy, at a tertiary hospital in Taiwan. SMP was performed on all patients as a surgical intervention. The patients were then divided into two groups: the control group, which underwent surgery only, and the experimental group, which received SLIT as an adjuvant treatment. Demographic data and rhinitis control assessment test (RCAT) results were analyzed. RESULTS: A total of 96 patients were enrolled in the study (SMP + SLIT group, n = 52; SMP only group, n = 44). No significant differences were observed in any of the variables between the two groups before and one month after surgery. However, during evaluations at the third and sixth month, the SMP + SLIT group showed significant improvement in the total RCAT scores compared to the SMP only group (28.6 ± 1.56 vs. 24.5 ± 3.66, p < 0.001; 27.1 ± 2.87 vs. 19.9 ± 5.56, p < 0.001). In addition, significantly better control of all RCAT sub-categories was observed in the SMP + SLIT group at the third and sixth month evaluations. CONCLUSIONS: SLIT may serve as an ideal adjuvant therapy after SMP in patients with AR. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:3073-3079, 2024.

Intervention to reduce loneliness among older adults in the community: Making friends with volunteers.

AIM: This study aimed to examine the effects of providing a program that introduced volunteers to make friends with older adults to reduce loneliness and increase loneliness literacy. METHODS: Eight community development associations in Taiwan participated in the study. In the first stage, older people living alone or with only a spouse, or those with a family, but without substantial interactions, were screened for loneliness. Older adults with a higher risk of loneliness were given priority to be invited to participate in this intervention. This 3-month intervention program was designed by each community development association and delivered at the older adults' homes. A total of 87 older persons completed both waves of the interviews. RESULTS: Loneliness was reduced (UCLA-6 Loneliness Scale scores decreased from 13.5 to 11.6), and loneliness literacy improved (loneliness literacy scores increased from 38.9 to 42.0) compared with what it was before the program. In a generalized linear model, when controlling for covariates, loneliness was reduced, but not significantly (B = -0.934, P > 0.05), whereas loneliness literacy improved significantly for older participants (B = 2.088, P < 0.05). CONCLUSIONS: Making friends with older adults who are lonely might improve their loneliness literacy. Geriatr Gerontol Int 2024; 24: 240-245.

Effect of acidosis on adipose-derived stem cell impairment and gene expression.

Based on disappointing results of stem cell-based application in clinical trials for patients with critical limb ischemia, we hypothesized that the acidic environment might be the key factor limiting cell survival and function. In the present study, we used microdialysis to determine presence of acidosis and metabolic imbalance in critical ischemia. Moreover, we explored the effect of extracellular acidosis on adipose-derived stem cells (ADSCs) at molecular and transcriptional level. Our data demonstrate that low pH negatively regulates cell proliferation and survival, also, it results in cell cycle arrest, mitochondrial dynamics disorder, DNA damage as well as the impairment of proangiogenic function in a pH-dependent manner. Further transcriptome profiling identified the pivotal signaling pathways and hub genes in response to acidosis. Collectively, these findings provide strong evidences for a critical role of acidosis in ADSCs impairment with ischemic condition and suggest treatments focus on tissue pH balance and acidosis-mediated hub genes may have therapeutic potential in stem cell-based application.