Biomedical Journal最新文献

Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor that plays a critical role in cancer progression, particularly in skin cancers. PAI-1 is widely recognized for its role in inhibiting fibrinolysis; however, emerging evidence suggests that it also contributes to tumor progression through multiple mechanisms, including tumor angiogenesis, immunomodulation, and stromal cell regulation. In the tumor microenvironment (TME), PAI-1 influences tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), promoting an immunosuppressive environment that supports cancer growth and therapy resistance. Furthermore, PAI-1 has been implicated in the regulation of programmed death-ligand 1 (PD-L1) expression via the JAK/STAT signaling pathway, thereby influencing immune evasion in various skin cancers. The significance of PAI-1 as a therapeutic target has been demonstrated in melanoma and other cutaneous malignancies, where inhibition of PAI-1 has shown promise in overcoming resistance to immune checkpoint inhibitors. Additionally, clinical trials evaluating PAI-1 inhibitors, such as TM5614, highlight its potential as an adjunctive therapy for melanoma and cutaneous angiosarcoma. This review comprehensively explores PAI-1's role in skin cancer progression, its influence on tumor-stromal interactions, and its potential as a therapeutic target.

Background: A consensus regarding the optimal time to administer anti-hypertensive medications has not been reached. Possible differential effects of different anti-hypertensive drugs on the circadian pattern of blood pressure (BP) and differential responses of individual patients receiving the same treatment at different times of the day may partly account for the controversy.

Methods: Ambulatory blood pressure monitoring (ABPM) data available at 30-minute intervals for 7 days from previous studies are reanalyzed to compare the effect of five drugs (amlodipine, atenolol, captopril retard, long-acting carteolol, and nilvadipine) taken 1.5 hours after awakening or twice a day on the 24-hour profile of BP from 7 to 13 conventionally diagnosed patients per treatment group. Similar data from 30 patients receiving losartan/hydrochlorothiazide for at least one month at each of six different times in relation to their time of awakening serve to compare the effect of treatment time in different patients.

Results: Some but not all drugs affected the 24-hour amplitude and/or phase of BP or the contribution of the 12-hour harmonic term to modify the circadian waveform of BP. While evening dosing increased the 24-hour amplitude of BP in some patients, other patients achieved such a desired effect with morning dosing.

Conclusion: Personalized optimization of treatment timing to best match a healthy circadian BP pattern is recommended, guided by chronobiological analyses of ABPM data collected over several days in view of the large day-to-day variability in all features of the 24-hour BP rhythm.

Background: Anaplastic lymphoma kinase (ALK) inhibitors have been effective in treating non-small cell lung cancers (NSCLC) with ALK translocation. However, high background autofluorescence in lung tissues interferes with fluorescence in situ hybridization (FISH) assays, masking molecular probe signals and hindering data interpretation.

Materials and methods: To reduce autofluorescence, NSCLC tissue sections were treated with various proteases, including collagenase types I, II, IV, and elastase, to determine the most effective enzyme. We then conducted ALK break-apart FISH assays on 120 NSCLC samples comparing standard and novel pretreatment protocols.

Results: Elastase was identified as the most effective enzyme for reducing autofluorescence while preserving nuclear integrity. The elastase-based pretreatment enabled clear FISH signal detection in all cases, reducing the retest rate from 86.7% to 0%. Furthermore, two additional ALK translocated cases were detected with elastase pretreatment, which were indeterminable with pepsin treatment alone.

Conclusions: This novel elastase pretreatment protocol addresses autofluorescence interference in lung tissues and can significantly improve the reliability of FISH assays for targeted therapy decisions.

The increased prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and its profound implications for global health have sparked extensive research endeavors aimed at developing potential diagnostic methods for this condition. Despite the achievements in defining various environmental factors and genetic predispositions linked to MASLD, diagnosis and clinical staging of the disease remain challenging. Recently, extracellular vesicles (EVs) have garnered considerable attention owing to their roles in metabolic dysfunctions and their potential as biomarkers for various conditions. This study aimed to investigate whether microRNAs (miRNAs) in serum EVs could be utilized for diagnosing and staging MASLD. We applied an innovative and efficient approach that involves capturing and analyzing extracellular vesicles using wheat germ agglutinin (WGA)-coupled magnetic beads, subsequently employing reverse transcription quantitative polymerase chain reaction (RT-qPCR) for analysis. MiR-574-3p, miR-542-3p, and miR-200a-3p in serum extracellular vesicles were significantly elevated in patients with MASLD, indicating their potential as diagnostic markers. This study has established a straightforward assay platform for isolating extracellular vesicles without the need for purification and for quantitatively detecting miR-574-3p, miR-542-3p, and miR-200a-3p in serum extracellular vesicles.

Background: Autologous bone remains the gold standard for surgical bone reconstruction but presents clinical challenges like donor site complications and operational difficulties.

Method: We investigate the osteogenic effects of a newly designed, ceramic and collagen-based, submicron-processed Flexible Hydrated-Hardening Bone Graft (FHBG), using both murine and human mesenchymal stem cells. We also compare the efficacy and safety of FHBG with a commercially available (CA) graft in New Zealand white rabbits with cranial bone defects. Rabbits were divided into three groups: no graft, CA, and FHBG, and evaluated using Micro-CT and histological analysis at three and six weeks post-surgery. Safety was assessed through blood samples.

Results: In vitro, FHBG promoted osteogenesis and upregulated osteogenic-associated genes in mesenchymal stem cells. In vivo, FHBG significantly enhanced bone regeneration, showing approximately 25% and 30% more improvement than the control at three and six weeks post-surgery. FHBG also had about half the residual content compared to the CA group. Blood analysis showed no hepatotoxicity or nephrotoxicity associated with the graft.

Conclusion: FHBG significantly promotes bone regeneration both in vitro and in vivo. Additionally, FHBG has been demonstrated to be safe, with fewer residuals remaining in the body compared to currently in-use clinical bone grafts. This study validates the ability of the newly designed FHBG to facilitate osteogenesis in vitro and demonstrates its efficacy and safety in new bone formation in vivo. The lower residual material further suggests a reduced long-term impact and associated risk with the graft.

Background: Hidradenitis suppurativa (HS) and alopecia areata (AA) share similar inflammatory pathway and pro-inflammatory cytokines. However, the association between HS and AA was unclear. We aimed to evaluate the risk of incident AA among patients with HS.

Material and methods: We performed a multicenter cohort study by using the US Collaborative Network in the TriNetX Research Network. Patients with HS diagnosis were recruited and 1:1 propensity score matching was performed to identify the non-HS control group. Hazard ratio (HR) of AA in different sensitivity models were calculated within the follow-up periods.

Results: Comparing with non-HS controls, the risk of incident AA in HS patients was 1.79-fold higher (95% confidence interval (CI) 1.31-2.44) within 15-year follow up. Similar trends were observed in 3-year and 8-year follow up. For female HS patients, the risk of incident AA was 1.75-fold higher than non-HS female (95% CI 1.23-2.48). However, the trend was not observed in male HS patients (HR 1.52; 95% CI 0.79-2.94).

Conclusions: Patients with HS were associated with increased risk of incident AA. Clinicians should be aware of the observed association and the actual immunological interplay between the two diseases should be clarified in future lab-based studies.

Background: Limited research has explored the immunological effects of a second COVID-19 vaccine booster in older adults within Western Pacific countries.

Methods: This study involved healthcare workers aged ≥65 years who received two doses of ChAdOx1 nCoV-19 (A), mRNA-1273 (M), or MVC-COV1901 (Mc), followed by a booster dose of mRNA-1273. Younger adults served as controls. Humoral and cellular immune responses were measured before and after the vaccination.

Results: Younger adults exhibited the highest fold-rise in anti-spike IgG levels (13.20, p < 0.001), followed by the AAMM (9.93, p < 0.001), McMcMM (6.97), and MMMM (4.9, p < 0.05) groups. Cellular response increased most in the McMcMM group (3.77), followed by AAMM (3.04, p < 0.001), MMMM (2.24), and the younger group (1.08). Neutralizing activity against the D614G variant was highest in younger adults (7.77, p < 0.001), followed by AAMM (4.07, p < 0.001), MMMM (2.89, p < 0.05), and McMcMM (2.76). Against the XBB.1.16 variant, titers were significantly lower (17.33-29.08 times less than wild type). The highest fold-rise was observed in the McMcMM group (8.59), followed by AAMM (7.66, p < 0.001), MMMM (4.16), and younger adults (2.26).

Conclusions: A second mRNA COVID-19 booster increased neutralizing antibodies and enhanced T cell responses against SARS-CoV-2 variants. Adapted vaccines targeting new subvariants are critical to strengthen immunity, particularly for older adults facing vaccine-resistant strains.

Background: Cerebral Palsy (CP) poses a substantial challenge to pediatric motor function, necessitating effective rehabilitative interventions. This review focuses on the potential of Repetitive Transcranial Magnetic Stimulation (rTMS) as a therapeutic approach for pediatric CP. The context and purpose are framed within the need for novel strategies to enhance motor function in affected children.

Material and methods: The study scrutinizes existing literature to assess the efficacy of rTMS in pediatric CP. Methodological details, including stimulation protocols, are explored. Statistical tests employed in the reviewed studies are outlined, providing insight into the scientific rigor applied in evaluating rTMS outcomes.

Results: The main findings from the literature review highlight the positive impact of rTMS on motor function and spasticity reduction in children with CP. The synergistic effects observed when combining rTMS with conventional therapies such as physical or occupational therapy and constraint-induced movement therapy are emphasized.

Conclusions: Evidences from literature review affirm that rTMS yields constructive outcomes, encompassing enhanced motor function and diminished spasticity, especially when combined with therapies like physical or occupational therapy, and constraint-induced movement therapy. Nevertheless, optimizing rTMS necessitates further fine-tuning of stimulation parameters. Ethical considerations and adherence to safety guidelines are crucial in pediatric settings, despite rare and typically benign side effects. Future research should focus on larger samples, stringent research designs, and long-term follow-ups to rTMS as an effective therapy for managing motor impediments in children with CP.

Rationale & objective: The data on tenofovir alafenamide (TAF) in kidney transplant recipients (KTRs) with chronic hepatitis B virus (HBV) infection is limited.

Study design: Retrospective cohort study SETTING & STUDY POPULATIONS: HBsAg-positive KTRs who received TAF between 2019 and 2022 were included in the analysis, categorized into treatment-naïve and treatment-experienced groups. Additionally, a subgroup of patients receiving ETV was analyzed for comparison.

Results: Four treatment-naïve (Group I) and 35 treatment-experienced (Group II) patients received TAF for 26.4±11.3 and 43.7±19.0 months, respectively. Both groups showed significant HBV DNA reduction, but Group I achieved higher rates of undetectable HBV DNA (50%, 75%, 75%, 100% at 6, 12, 24, 30 months, compared with 16.7%, 25.3%, 31.4%, 34.7% in Group II, p=0.018). Renal allograft function remained stable during follow-up, and bone toxicity was minimal. For ETV, 10 patients demonstrated excellent viral suppression (HBV DNA undetectable in 70% at 48 weeks and 100% at 96 weeks) with stable renal function over a median of 5.2 years.

Limitations: Retrospective study with a lack of prospective comparison of TAF and ETV.

Conclusions: Our results suggest that TAF provides favorable efficacy, renal safety, and tolerability in KTRs. ETV also provided effective and sustainable viral suppression. TAF may offer additional advantages such as no concern of viral resistance and dose adjustment by eGFR levels for long-term management of HBsAg-positive KTRs.