Citations

Abstract Semaglutide (Smg), a GLP‐1 receptor agonist (GLP‐1RA), shows renal protective effects in patients with diabetic kidney disease (DKD). However, the exact underlying mechanism remains elusive. This study employs transcriptome sequencing and identifies β ‐Klotho (KLB) as the critical target responsible for the role of Smg in kidney protection. Smg treatment alleviates diabetic kidney injury by inhibiting ferroptosis in patients, animal models, and HK‐2 cells. Notably, Smg treatment significantly increases the mRNA expression of KLB through the activation of the cyclic adenosine monophosphate (cAMP) signaling pathway, specifically through the phosphorylation of protein kinase A (PKA) and cAMP‐response element‐binding protein (CREB). Subsequently, the adenosine monophosphate‐activated protein kinase (AMPK) signaling pathway is activated, reprograming the key metabolic processes of ferroptosis such as iron metabolism, fatty acid synthesis, and the antioxidant response against lipid peroxidation. Suppression of ferroptosis by Smg further attenuates renal inflammation and fibrosis. This work highlights the potential of GLP‐1RAs and KLB targeting as promising therapeutic approaches for DKD management.

Abstract Background Nicotinamide adenosine dinucleotide phosphate oxidases (NOX) play important roles in mediating stress-induced depression. Three NOX isotypes are expressed mainly in the brain: NOX2, NOX3 and NOX4. In this study, the expression and cellular sources of these NOX isoforms was investigated in the context of stress-induced depression. Methods Chronic restraint stress (CRS)-induced depressive-like behaviour and cognitive deficits were evaluated by tail suspension tests, forced swimming tests and the Morris water maze test. Hippocampal NOX expression was determined by immunofluorescence staining and western blotting. The hippocampal levels of the brain-derived neurotrophic factor (BDNF) mRNA were determined via quantitative real-time –polymerase chain reaction. Glucocorticoid levels in the hippocampus were measured using ELISA kits. Results In the mouse CRS model, a significant increase in NOX2 expression was observed in the hippocampus, whereas no significant changes in NOX3 and NOX4 expression were detected. Next, NOX2 expression was primarily localised to neurons (NeuN+) but not microglia (Iba-1+) or astrocytes (GFAP+). Treatment with gp91ds-tat, a specific NOX2 inhibitor, effectively mitigated the behavioural deficits induced by CRS. The decreased expression of the BDNF mRNA in the hippocampus of CRS mice was restored upon gp91ds-tat treatment. A positive correlation was identified between neuronal NOX2 expression and serum glucocorticoid levels. Conclusions Our study indicated that neuronal NOX2 may be a critical mediator of depression-like behaviours and spatial cognitive deficits in mice subjected to CRS. Blockade of NOX2 signalling may be a promising therapeutic strategy for depression.

BackgroundMultiparametric MRI may cause overdiagnosis of clinically significant prostate cancer (csPCa) with the Prostate Imaging Reporting and Data System version 2.1 (PI‐RADS v2.1).ObjectivesTo investigate the diagnostic performance of stiffness as a standalone and complementary marker to PI‐RADS v2.1 for diagnosing csPCa.Study TypeProspective.SubjectsOne hundred forty‐seven participants with pathologically confirmed prostate lesions (≥1 cm), including 71 with csPCa.Field Strength/SequenceT1‐weighted fast spin‐echo, T2‐weighted fast spin‐echo, single‐shot echo‐planar diffusion‐weighted imaging, fast 3D gradient‐echo T1‐weighted dynamic contrast‐enhanced imaging, and 3D single‐shot spin‐echo based echo‐planar MR elastography at 3.0 T.AssessmentThe PI‐RADS v2.1 score was assessed by three radiologists independently. Lesion shear stiffness (SS) values at 60 Hz and 90 Hz were measured. A modified PI‐RADS integrating stiffness with PI‐RADS v2.1 was developed. Diagnostic performance for csPCa was compared between stiffness, PI‐RADS v2.1 and the modified PI‐RADS.Statistical TestSpearman's correlation, Fleiss κ and intraclass correlation, Pearson correlation, one‐way analysis of variance, area under the receiver operating characteristic curve (AUC), and the Delong test. Significance level was P < 0.05.ResultsIn the peripheral zone, csPCa (N = 35) had significantly higher SS than non‐csPCa at 60 Hz (3.22 ± 0.66 kPa vs. 2.56 ± 0.56 kPa) and at 90 Hz (5.64 ± 1.30 kPa vs. 4.48 ± 0.84 kPa). PI‐RADS v2.1 showed 100% sensitivity, 58% specificity, and 0.79 AUC for detecting csPCa. SS achieved 97% sensitivity, 52% specificity, and 0.80 AUC at 60 Hz, while SS had 63% sensitivity, 87% specificity, and 0.78 AUC at 90 Hz. The modified PI‐RADS, combing SS at 60 Hz with PI‐RADS v2.1, resulted in a significantly increased AUC (0.86) compared to that of PI‐RADS v2.1, with a sensitivity of 97% and specificity of 75%.Data ConclusionStiffness can help identifying csPCa in the peripheral zone. Combining stiffness with the PI‐RADS v2.1 improved the diagnostic accuracy and specificity for csPCa.Evidence Level1Technical EfficacyStage 2

Abstract Purpose: To determine the relationship between germline pathogenic variants (PV) in cancer predisposition genes and the risk of ductal carcinoma in situ (DCIS). Experimental Design: Germline PV frequencies in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, PALB2, RAD51C, and RAD51D) were compared between DCIS cases and unaffected controls and between DCIS and invasive ductal breast cancer (IDC) cases from a clinical testing cohort (n = 9,887), a population-based cohort (n = 3,876), and the UK Biobank (n = 2,421). The risk of contralateral breast cancer (CBC) for DCIS cases with PV was estimated in the population-based cohort. Results: Germline PV were observed in 6.5% and 4.6% of women with DCIS in the clinical testing and population-based cohorts, respectively. BRCA1, BRCA2, and PALB2 PV frequencies were significantly lower among women with DCIS than those with IDC (clinical cohort: 2.8% vs. 5.7%; population-based cohort: 1.7% vs. 3.7%), whereas the PV frequencies for ATM and CHEK2 were similar. ATM, BRCA1, BRCA2, CHEK2, and PALB2 PV were significantly associated with an increased risk of DCIS (OR &gt; 2.0), but only BRCA2 PV were associated with high risk (OR &gt; 4) in both cohorts. The cumulative incidence of CBC among carriers of PV in high-penetrance genes with DCIS was 23% over 15 years. Conclusions: The enrichment of PV in ATM, BRCA1, BRCA2, CHEK2, and PALB2 among women with DCIS suggests that multigene panel testing may be appropriate for women with DCIS. Elevated risks of CBC in carriers of PV in high-penetrance genes with DCIS confirmed the utility of testing for surgical decision-making.

Abstract Background The incidence of respiratory syncytial virus (RSV)–acute respiratory infection (ARI) in community-dwelling adults after the Omicron variant of the COVID-19 pandemic is unknown. Our aim was to assess the incidence of RSV-ARI in adults aged 18 to 64 years over 2 consecutive RSV seasons (October–April 2022–2024) in 4 US states. Methods This community-based prospective cohort study comprised 7501 participants in Minnesota, Wisconsin, Florida, and Arizona. We calculated RSV-ARI and RSV–lower respiratory tract disease (LRTD) incidence and attack rates. We reported unadjusted incidence by age group, gender, race and ethnicity, Charlson Comorbidity Index, socioeconomic status, residential state, and rural/urban setting. Results Seasons 1 and 2 had 2250 and 2377 ARI episodes, respectively, with an RSV-ARI positivity rate of 5.5% for season 1 and 5.8% for season 2 among those tested. In season 1, the overall incidence of RSV-ARI was 27.71 (95% CI, 22.82–33.34) per 1000 person-years (1.49% attack rate). Almost half (49.0%) had RSV-LRTD, with an incidence of 13.53 (95% CI, 10.19–17.61) per 1000 person-years (0.73% attack rate). In season 2, the RSV-ARI and RSV-LRTD incidence rates were 26.39 (95% CI, 21.73–31.75) per 1000 person-years (1.51% attack rate) and 12.43 (95% CI, 9.31–16.26) per 1000 person-years (0.72% attack rate). RSV-ARI incidence peaked in November 2022 and December 2023. Conclusions Our observations suggest that RSV-ARI incidence and seasonal pattern are shifting to prepandemic RSV epidemiology.

Abstract Mounting evidence indicates the involvement of peripheral immunity in the regulation of brain function, influencing aspects such as neuronal development, emotion, and cognitive abilities. Previous studies from our laboratory have revealed that neonatal hepatitis B vaccination can downregulate hippocampal neurogenesis, synaptic plasticity and spatial learning memory. In the current post-epidemic era characterized by universal vaccination, understanding the impact of acquired immunity on neuronal function and neuropsychiatric disorders, along with exploring potential underlying mechanisms, becomes imperative. We employed hepatitis B vaccine-induced CD3 positive T cells in immunodeficient mice to investigate the key mechanisms through which T cell subsets modulate hippocampal neurogenesis and anxiety-like behaviours. Our data revealed that mice receiving hepatitis B vaccine-induced T cells exhibited heightened anxiety and decreased hippocampal cell proliferation compared to those receiving phosphate-buffered saline-T cells or wild-type mice. Importantly, these changes were predominantly mediated by infiltrated CD8+ T cells into the brain, rather than CD4+ T cells. Transcriptome profiling of CD8+ T cells unveiled that C-X-C motif chemokine receptor 6 positive (CXCR6+) CD8+ T cells were recruited into the brain through microglial and astrocyte-derived C-X-C motif chemokine ligand 16 (CXCL16). This recruitment process impaired neurogenesis and induced anxiety-like behaviour via tumour necrosis factor-α-dependent mechanisms. Our findings highlight the role of glial cell derived CXCL16 in mediating the recruitment of CXCR6+CD8+ T cell subsets into the brain. This mechanism represents a potential avenue for modulating hippocampal neurogenesis and emotion-related behaviours after hepatitis B vaccination.

Abstract Objective To provide a comprehensive assessment of various fractionation schemes in radiation therapy for breast cancer, with a focus on side effects, cosmesis, quality of life, risks of recurrence, and survival outcomes. Design Systematic review and meta-analysis. Data sources Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (from inception to 23 October 2023). Study selection Included studies were randomised controlled trials focusing on conventional fractionation (CF; daily fractions of 1.8-2 Gy, reaching a total dose of 50-50.4 Gy over 5-6 weeks), moderate hypofractionation (MHF; fraction sizes of 2.65-3.3 Gy for 13-16 fractions over 3-5 weeks), and/or ultra-hypofractionation (UHF; schedule of only 5 fractions). Data extraction Two independent investigators screened studies and extracted data. Risk of bias and quality of evidence were assessed using the Cochrane Collaboration’s tool and the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach, respectively. Data synthesis Pooled risk ratios (RRs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random effects model. Heterogeneity was analysed using Cochran’s Q test and I 2 statistic. Network meta-analysis was used to integrate all available evidence. Main outcome measures The pre-specified primary outcome was grade ≥2 acute radiation dermatitis and late radiation therapy related side effects; secondary outcomes included cosmesis, quality of life, recurrence, and survival metrics. Results From 1754 studies, 59 articles representing 35 trials (20 237 patients) were assessed; 21.6% of outcomes showed low risk of bias, whereas 78.4% had some concerns or high risk, particularly in outcome measurement (47.4%). The RR for grade ≥2 acute radiation dermatitis for MHF compared with CF was 0.54 (95% CI 0.49 to 0.61; P<0.001) and 0.68 (0.49 to 0.93; P=0.02) following breast conserving therapy and mastectomy, respectively. Hyperpigmentation and grade ≥2 breast shrinkage were less frequent after MHF than after CF, with RRs of 0.77 (0.62 to 0.95; P=0.02) and 0.92 (0.85 to 0.99; P=0.03), respectively, in the combined breast conserving therapy and mastectomy population. However, in the breast conserving therapy only trials, these differences in hyperpigmentation (RR 0.79, 0.60 to 1.03; P=0.08) and breast shrinkage (0.94, 0.83 to 1.07; P=0.35) were not statistically significant. The RR for grade ≥2 acute radiation dermatitis for UHF compared with MHF was 0.85 (0.47 to 1.55; P=0.60) for breast conserving therapy and mastectomy patients combined. MHF was associated with improved cosmesis and quality of life compared with CF, whereas data on UHF were less conclusive. Survival and recurrence outcomes were similar between UHF, MHF, and CF. Conclusions MHF shows improved safety profile, cosmesis, and quality of life compared with CF while maintaining equivalent oncological outcomes. Fewer randomised controlled trials have compared UHF with other fractionation schedules, but its safety and oncological effectiveness seem to be similar with short term follow-up. Given the advantages of reduced treatment time, enhanced convenience for patients, and potential cost effectiveness, MHF and UHF should be considered as preferred options over CF in appropriate clinical settings, with further research needed to solidify these findings. Systematic review registration PROSPERO CRD42023460249.

Abstract Background: Breast cancer has been associated with monogenic, polygenic, and epidemiologic (clinical, reproductive, and lifestyle) risk factors, but studies evaluating the combined effects of these factors have been limited. Methods: We extended previous work in breast cancer risk modeling, incorporating pathogenic variants (PV) in six breast cancer predisposition genes and a 105-SNP polygenic risk score (PRS), to include an epidemiologic risk score (ERS) in a sample of non-Hispanic White women drawn from prospective cohorts and population-based case–control studies, with 23,518 cases and 22,832 controls, from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium. Results: The model predicts 4.4-fold higher risk of breast cancer for postmenopausal women with no predisposition PV and median PRS, but with the highest versus lowest ERS. Overall, women with CHEK2 PVs had &gt;20% lifetime risk of breast cancer. However, 15.6% of women with CHEK2 PVs and a family history of breast cancer, and 45.1% of women with CHEK2 PVs but without a family history of breast cancer, had low (&lt;20%) predicted lifetime risk and thus were below the threshold for MRI screening. CHEK2 PV carriers at the 10th percentile of the joint distribution of ERS and PRS, without a family history of breast cancer, had a predicted lifetime risk similar to the general population. Conclusions: These results illustrate that an ERS, alone and combined with the PRS, can contribute to clinically relevant risk stratification. Impact: Integrating monogenic, polygenic, and epidemiologic risk factors in breast cancer risk prediction models may inform personalized screening and prevention efforts.

The lung is an inherently mechanosensitive organ that can respond to mechanical forces in adaptive or maladaptive ways, including via remodeling resulting in increased fibrosis. We explored the mechanisms that link mechanical forces to remodeling using human lung fibroblasts. We found that mechanosensitive Piezo channels increase with stretch and mediate extracellular matrix formation and the fibroblast-to-myofibroblast transition that occurs with stretch. Our data highlight the importance of Piezo channels in lung mechanotransduction toward remodeling.