Sirtuin 1-mediated autophagy regulates testosterone synthesis in Leydig cells of piglets.

Testosterone is secreted by Leydig cells (LCs), which play an important physiological role in preserving male secondary sex characteristics, protecting male reproductive function, and establishing the blood-testis barrier. Studies have shown that autophagy is particularly active in LCs; however, its involvement in testosterone synthesis in porcine LCs has not been fully explored. Therefore, this experiment aimed to investigate the influence of autophagy on testosterone secretion in porcine LCs and its potential regulatory mechanism. Our results demonstrated that both testicular autophagy and serum testosterone levels increased in piglets during postnatal development from 4 to 18 weeks. In addition, autophagy was found to degrade the Na+/H+ exchange regulatory factor 2 (NHERF2), leading to the up-regulation of scavenger receptor class B type 1 (SRB1). This process resulted in increased cholesterol intake and enhanced testosterone production. The observable level of sirtuin 1 (SIRT1) was directly proportional to the level of autophagy. In vitro investigations have shown that SIRT1 can affect the level of autophagy, cholesterol uptake as well as testosterone release. In conclusion, testosterone synthesis during pig development is regulated by SIRT1. SIRT1 mediates the degradation of NHERF2 through autophagy, thereby weakening its negative regulatory effect on the high-density lipoprotein receptor SRB1 in Leydig cells. This process increases cholesterol uptake and enhances testosterone synthesis.

A patient with primary intracranial granuloma with difficulty in differential diagnosis: A case report and literature review.

There are few reports about primary intracranial granulomas without an identifiable infectious history. A 25-year-old male with intracranial granuloma. The patient presented with a history of tinnitus with intermittent headache for 1 week. Consequently, MRI showed pronounced and extensive enhancement lesions in the left frontal lobe involved in the cerebral longitudinal fissure cistern and the inside of the right frontal lobe, accompanied by a moderate degree of oedema; The lesion was a pilomyxoid astrocytoma preoperatively. Following a systemic examination, gross total resection of the lesion was performed, and postoperative pathological examination revealed the presence of inflammatory lesions. The patient exhibited notable symptom amelioration post-surgery, leading to discharge after the treatment. Subsequently, a sequential treatment involving steroid therapy was administered, resulting in successful patient recovery.

Systematic analysis of constitutive models of brain tissue materials based on compression tests.

It's crucial to understand the biomechanical properties of brain tissue to comprehend the potential mechanisms of traumatic brain injury. This study, distinct from homogeneous models, integrates axonal coupling in both axial and transverse compressive experiments within a continuum mechanics framework to capture its intricate mechanical behaviors. Fresh porcine brains underwent unconfined compression at strain rates of 0.001/s and 0.1/s to 0.3 strain, allowing for a comprehensive statistical analysis of the directional, regional, and strain-rate-dependent mechanical properties of brain tissue. The established constitutive model, fitted to experimental data, delineates material parameters providing intuitive insights into the stiffness of gray/white matter isotropic matrices and neural fibers. Additionally, it predicts the mechanical performance of white matter matrix and axonal fibers under compressive loading. Results reveal that gray matter is insensitive to loading direction, exhibiting insignificant stiffness variations within regions. White matter, however, displays no significant differences in mechanical properties under axial and transverse loading, with an overall higher average stress than gray matter and a more pronounced strain-rate effect. Stress-strain curves indicate that, under axial compression, white matter axons primarily resist the load before transitioning to a matrix-dominated response. Under transverse loading, axonal fibers exhibit weaker resistance to lateral pressure. The mechanical behavior of brain tissue is highly dependent on loading rate, region, direction, and peak strain. This study, by combining experimentation with phenomenological modeling, elucidates certain phenomena, contributing valuable insights for the development of precise computational models.

Inetetamab combined with sirolimus and chemotherapy for the treatment of HER2-positive metastatic breast cancer patients with abnormal activation of the PI3K/Akt/mTOR pathway after trastuzumab treatment.

Background: We explored the efficacy and safety of inetetamab combined with sirolimus and chemotherapy for the treatment of human epidermal factor receptor 2 (HER2)-positive metastatic breast cancer patients with abnormal activation of the PI3K/Akt/mTOR (PAM) pathway after trastuzumab treatment. Methods: For this prospective multicenter clinical study, HER2-positive metastatic breast cancer patients with PAM pathway mutations confirmed by histology or peripheral blood genetic testing were enrolled from July 2021 to September 2022. Patients were randomly assigned to a trial or control group. The patients in the trial group received inetetamab combined with sirolimus and chemotherapy, while the control group patients received pyrotinib and chemotherapy. The RECIST v1.1 standard was used to evaluate efficacy. Descriptive statistics were used to summarize the clinicopathological features, and the Kaplan-Meier method was used to generate survival curves. The log-rank test was used to compare progression-free survival (PFS) between the two groups. Results: A total of 59 HER2-positive metastatic breast cancer patients with abnormal activation of the PAM pathway were included, of which 37 received inetetamab combined with sirolimus and chemotherapy treatment and 22 received pyrotinib and chemotherapy treatment. The median PFS was 4.64 months in the inetetamab group and 5.69 months in the pyrotinib group, with no statistically significant difference (p = 0.507). The objective response rates were 27.3% for the inetetamab group and 29.4% for the pyrotinib group. The safety assessment indicated that the adverse event (AE) incidences were 86.1% (31/36) in the inetetamab group and 78.9 (15/19) in the pyrotinib group, with 9 (25%) and four (21.1%) Grade 3/4 AEs in the inetetamab and pyrotinib groups, respectively. Conclusions: For metastatic HER2-positive breast cancer patients with abnormal PAM pathway activation and previous trastuzumab treatment, the combination of inetetamab with sirolimus and chemotherapy is equivalent to the combination of pyrotinib and chemotherapy. Therefore, this regimen could be a treatment option for PAM pathway-activated metastatic HER2-positive breast cancer patients.

Major pathologic response and long-term clinical benefit in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer after neoadjuvant chemotherapy.

BACKGROUND: The majority of HR+/HER2-breast cancer patients can also achieve long-term survival despite not attaining pCR, indicating limited prognostic value of pCR in this population. This study aimed to identify novel pathologic end points for predicting long-term outcomes in HR+/HER2-breast cancer after neoadjuvant chemotherapy. METHODS: We analyzed HR+/HER2-breast cancer patients with stage II-III tumors who underwent curative surgery after neoadjuvant chemotherapy from three hospitals. Major pathologic response (MPR), defined as the presence of Miller-Payne grades 3-5 and positive lymph node ratio of ≤10 %, was used as a pathological evaluation indicator. We assessed the association between MPR and event-free survival (EFS) and performed Multivariable Cox regression to identify independent factors associated with EFS. RESULTS: From January 2010 to December 2020, 386 patients were included in the final analysis. 28 patients (7.3 %) achieved pCR and 118 patients (30.6 %) achieved MPR. The median duration of follow-up was 54.4 months,5-year EFS was 87 % in the MPR group vs. 68 % in the non-MPR group. Multivariate analysis showed that low PR expression, high clinical stage, lower Miller-Payne grades and Positive lymph node ratio were independent poor prognostic factors for EFS (all P values < 0.05). The prognostic effect of MPR remained in multivariable models (hazard ratio (HR), 0.45; 95 % confidence interval (CI), 0.26-0.76; P = 0.008), In non-pCR patients, those who achieved MPR exhibited a similar EFS compared with pCR patients (HR, 2.25; 95 % CI, 0.51-9.84; P = 0.28). CONCLUSION: MPR may be a novel pathologic end point in HR+/HER2-breast cancer after neoadjuvant chemotherapy, holding greater applicability in the prognosis evaluation than pCR.

A Crowdsourced AI Framework for Atrial Fibrillation Detection in Apple Watch and Kardia Mobile ECGs.

Background: Atrial fibrillation (AFib) detection via mobile ECG devices is promising, but algorithms often struggle to generalize across diverse datasets and platforms, limiting their real-world applicability. Objective: This study aims to develop a robust, generalizable AFib detection approach for mobile ECG devices using crowdsourced algorithms. Methods: We developed a voting algorithm using random forest, integrating six open-source AFib detection algorithms from the PhysioNet Challenge. The algorithm was trained on an AliveCor dataset and tested on two disjoint AliveCor datasets and one Apple Watch dataset. Results: The voting algorithm outperformed the base algorithms across all metrics: the average of sensitivity (0.884), specificity (0.988), PPV (0.917), NPV (0.985), and F1-score (0.943) on all datasets. It also demonstrated the least variability among datasets, signifying its highest robustness and effectiveness in diverse data environments. Moreover, it surpassed Apple's algorithm on all metrics and showed higher specificity but lower sensitivity than AliveCor's Kardia algorithm. Conclusions: This study demonstrates the potential of crowdsourced, multi-algorithmic strategies in enhancing AFib detection. Our approach shows robust cross-platform performance, addressing key generalization challenges in AI-enabled cardiac monitoring and underlining the potential for collaborative algorithms in wearable monitoring devices.

Clinical benefit and safety profile of cross-line therapy with CDK4/6 inhibitors: a retrospective study of HR+/HER2- advanced breast cancer.

OBJECTIVE: CDK4/6 inhibitors (CDK4/6is) in combination with endocrine therapy have secured a central role in the treatment of hormone receptor (HR)-positive advanced breast cancer (ABC) and have transformed the therapeutic landscape. Cross-line CDK4/6i therapy in which another CDK4/6i is continued after progression on a prior CDK4/6i may still offer advantageous therapeutic effects. Cross-line CDK4/6i therapy is an area of active investigation in the ongoing pursuit to improve outcomes for patients with HR+/human epidermal growth factor receptor 2 (HER2)- ABC. METHODS: This retrospective study enrolled 82 patients with HR+/HER2- ABC who were treated with cross-line CDK4/6is (abemaciclib, palbociclib, ribociclib, and dalpiciclib) after progression with another CDK4/6i. The primary endpoint was progression-free survival (PFS) according to version 1.1 of the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included toxicity, objective response rate, disease control rate, and overall survival. Adverse events (AEs) were graded according to version 5.0 of the Common Terminology Criteria for Adverse Events, as promulgated by the U.S. Department of Health and Human Services. RESULTS: Eighty-two HR+/HER2- ABC patients who received cross-line CDK4/6i therapy from January 2022 to February 2024 were enrolled. The median age of the patients was 60 years. The median PFS of all patients was 7.6 months (95% CI, 5.9-9.2). Cox regression analysis identified lung metastasis and a switch to endocrine therapy following prior CDK4/6i therapy as independent predictive factors for PFS. Notably, patients who previously received abemaciclib and switched to palbociclib upon disease progression had a median PFS of 10.7 months. The strategy of transitioning to chemotherapy after progression on a prior CDK4/6i, then to a subsequent CDK4/6i merits further investigation. Hematologic toxicity was the most common grade ≥ 3 AEs. No instances of fatal safety events were observed. CONCLUSIONS: Cross-line CDK4/6i therapy is associated with significant clinical benefits and manageable safety profiles in patients with HR+/HER2- ABC, which underscores cross-line CDK4/6i therapy potential as an effective treatment strategy.

Sulindac (K-80003) with nab-paclitaxel and gemcitabine overcomes drug-resistant pancreatic cancer.

The Nab-paclitaxel combined with gemcitabine (AG) regimen is the main chemotherapy regimen for pancreatic cancer, but drug resistance often occurs. Currently, the ability to promote sensitization in drug-resistant cases is an important clinical issue, and the strategy of repurposing conventional drugs is a promising strategy. This study aimed to identify a classic drug that targets chemotherapy resistance's core signaling pathways and combine it with the AG regimen to enhance chemosensitivity. We also aimed to find reliable predictive biomarkers of drug combination sensitivity. Using RNA sequencing, we found that abnormal PI3K/Akt pathway activation plays a central role in mediating resistance to the AG regimen. Subsequently, through internal and external verification of randomly selected AG-resistant patient-derived organoid (PDO) and PDO xenograft models, we discovered for the first time that the classic anti-inflammatory drug sulindac K-80003, an inhibitor of the PI3K/Akt pathway that we focused on, promoted sensitization in half (14/28) of AG-resistant pancreatic ductal adenocarcinoma cases. Through RNA-sequencing, multiplex immunofluorescent staining, and immunohistochemistry experiments, we identified cFAM124A as a novel biomarker through which sulindac K-80003 promotes AG sensitization. Its role as a sensitization marker is explained via the following mechanism: cFAM124A enhances both the mRNA expression of cathepsin L and the activity of the cathepsin L enzyme. This dual effect stimulates the cleavage of RXRα, leading to large amounts of truncated RXRα, which serves as a direct target of K-80003. Consequently, this process results in the pathological activation of the PI3K/Akt pathway. In summary, our study provides a new treatment strategy and novel biological target for patients with drug-resistant pancreatic cancer.

Foliar application of silicon and selenium reduce the toxicity of cadmium to soybeans.

Silicon (Si) and selenium (Se), two environmental protection materials, which are beneficial to plant growth and stress resistance, can also alleviate crop stress induced by heavy metals. However, the effects of Si, Se and their interactions in reducing cadmium (Cd) toxicity and the related mechanisms require further elucidation. Hence, this study implemented a foliar application of Si and Se on soybean (Glycine max L.) that subjected to Cd-induced stress with four treatments (sole/combined application of Si, Se, no fertilizer treatment). The results demonstrated that Si and Se showed effective mitigation of Cd toxicity on soybeans mainly by promoting growth, enhancing photosynthesis, maintaining root vigor, improving antioxidant capacity, alleviating oxidative damage, altering the storage form, subcellular distribution of Cd in soybeans, and was more noticeable when combined overall (Si + Se＞Se＞Si). Si + Se increased root activity by 28% and CAT activity in leaves by 130.65%. Overall, the combined application of Si and Se exhibited a pronounced synergistic effect in enhancing the healthy growth of soybean plants under Cd pollution, with a more prominent impact observed following the second fertilization.

A mannose-rich exopolysaccharide-1 isolated from Bifidobacterium breve mitigates ovalbumin-induced intestinal damage in mice by modulation CD4 + T cell differentiation and inhibiting NF-κB signaling pathway.

Ovalbumin (OVA)-induced intestinal injury is a recurrent and potentially fatal condition. Previous studies have highlighted the roles of exopolysaccharides, particularly a mannose-rich (89.59 %) exopolysaccharide-1 (EPS-1) with a molecular weight of 39.9 kDa, isolated from Bifidobacterium breve H4-2, in repairing intestinal barriers and regulating immune responses. In this study, a mouse model of OVA-induced intestinal injury was used to investigate the effects of EPS-1 on intestinal barrier restoration. The results demonstrated that EPS-1 treatment (400 mg/kg. d) significantly reduced the allergic index (3.25 ± 0.43) in OVA-challenged mice (p < 0.05), improved the physical integrity of the intestinal barrier by increasing mucin content and goblet cell number in the ileum (p < 0.05). EPS-1 treatment (400 mg/kg. d) also maintained immune barrier integrity by restoring imbalanced CD4 + T/CD8 + T ratios from 0.86 ± 0.02 to 1.04 ± 0.06, regulating Th1/Th2 and Th17/Treg cells balance, as well as inhibited the NF-κB signaling pathway. Furthermore, EPS-1 maintained microbiota homeostasis by increasing the abundances of Ruminococcus, Butyricicoccus, and Muribaculaceae, while reducing Streptococcus and Candidatus arthromitus. This microbiota modulation enhanced the levels of metabolites such as tyrosine, methionine, tryptophan, triglycerides, and salidroside. In conclusion, EPS-1 shows promise as a functional polysaccharide for therapeutic use.

Polystyrene nanoplastic exposure actives ferroptosis by oxidative stress-induced lipid peroxidation in porcine oocytes during maturation.

BACKGROUND: Polystyrene nanoplastics (PS-NPs) are becoming increasingly prevalent in the environment with great advancements in plastic products, and their potential health hazard to animals has received much attention. Several studies have reported the toxicity of PS-NPs to various tissues and cells; however, there is a paucity of information about whether PS-NPs exposure can have toxic effects on mammalian oocytes, especially livestock. Herein, porcine oocytes were used as the model to investigate the potential effects of PS-NPs on mammalian oocytes. RESULTS: The findings showed that different concentrations of PS-NPs (0, 25, 50 and 100 µg/mL) entering into porcine oocytes could induce mitochondrial stress, including a significant decrease in mitochondrial membrane potential (MMP), and the destruction of the balance of mitochondrial dynamic and micromorphology. Furthermore, there was a marked increase in reactive oxygen species (ROS), which led to oocyte lipid peroxidation (LPO). PS-NPs exposure induced abnormal intracellular iron overload, and subsequently increased the expression of transferrin receptor (TfRC), solute carrier family 7 member 11 (SLC7a11), and acyl-CoA synthetase long-chain family member 4 (ACSL4), which resulted in ferroptosis in oocytes. PS-NPs also induced oocyte maturation failure, cytoskeletal dysfunction and DNA damage. Cotreatment with 5 µmol/L ferrostatin-1 (Fer-1, an inhibitor of ferroptosis) alleviated the cellular toxicity associated with PS-NPs exposure during porcine oocyte maturation. CONCLUSIONS: In conclusion, PS-NPs caused ferroptosis in porcine oocytes by increasing oxidative stress and altering lipid metabolism, leading to the failure of oocyte maturation.

Berberine sensitizes immune checkpoint blockade therapy in melanoma by NQO1 inhibition and ROS activation.

Unprecedented progress in immune checkpoint blockade (ICB) therapy has been made in cancer treatment. However, the response to ICB therapy is limited to a small subset of patients. The development of ICB sensitizers to improve cancer immunotherapy outcomes is urgently needed. Berberine (BBR), a well-known phytochemical compound isolated from many kinds of medicinal plants such as Berberis aristata, Coptis chinensis, and Phellondendron chinense Schneid, has shown the ability to inhibit the proliferation, invasion and metastasis of cancer cells. In this study, we investigated whether BBR can enhance the therapeutic benefit of ICB for melanoma, and explored the underlying mechanisms involved. The results showed that BBR could sensitize ICB to inhibit tumor growth and increased the survival rate of mice. Moreover, BBR stimulated intracellular ROS production partially by inhibiting NQO1 activity, which induced immunogenic cell death (ICD) in melanoma, elevated the levels of damage-associated molecular patterns (DAMPs), and subsequently activated DC cells and CD8 + T cells in vitro and in vivo. In conclusion, BBR is a novel ICD inducer. BBR could enhance the therapeutic benefit of ICB for melanoma. These effects were partially mediated through the inhibition of NQO1 and ROS activation.

Evolution and prognostic significance of HER-2 conversion from primary to residual disease in HER-2 negative patients with breast cancer after neoadjuvant chemotherapy.

This study aimed to analyze HER-2 zero or HER-2 low conversion in HER-2 negative patients after neoadjuvant chemotherapy (NAC) and evaluate its prognostic significance. HER-2 negative patients with breast cancer with residual disease after NAC and paired pre- and post-therapeutic HER-2 testing results were analyzed retrospectively. HER-2 low, defined as immunohistochemistry (IHC) scores of 1+ or 2+/in situ hybridization (ISH), were not amplified. HER-2 zero is defined as an IHC score of 0. A total of 571 patients were enrolled, including primary HER-2 zero (n=201, 35.2%) and HER-2 low (n=370, 64.8%). The overall HER-2 change rate was 32.4%. Multivariable logistic regression showed that patients with hormone receptor-positive status before NAC was significantly associated with the conversion of HER-2 zero to low (OR=3.436, P < 0.0001). The median follow-up time was 50.0 months. In patients who are primary HER-2 zero, HER-2 zero to low was significantly associated with better disease-free survival (DFS) than constant HER-2 zero (HR=0.49, P=0.01) after adjustment (4-year DFS 80.1% vs 55.7%, Log-rank P=0.033). Subgroup analysis revealed that among patients who are primary HER-2 zero with hormone receptor-positive, HER-2 zero to low had a significantly better DFS than constant HER-2 zero (Log-rank P=0.037). In contrast, patients with hormone receptor-negative status did not. In conclusion, almost one-third of patients who are HER-2 negative underwent HER-2 zero or HER-2 low conversion after NAC. HER-2 zero to low conversion was associated with better DFS in patients who are HER-2 zero. These results provide a valuable reference for the potential application of anti-HER-2 ADC in an adjuvant setting for patients with residual disease after NAC.

Subdivision of M1 category and prognostic stage for de novo metastatic breast cancer to enhance prognostic prediction and guide the selection of locoregional therapy.

BACKGROUND: Although de novo metastatic breast cancer (dnMBC) is acknowledged as a heterogeneous disease, the current staging systems do not distinguish between patients within the M1 or stage IV category. This study aimed to refine the M1 category and prognostic staging for dnMBC to enhance prognosis prediction and guide the choice of locoregional treatment. METHODS: We selected patients with dnMBC from the SEER database (2010-2019), grouping them into training (N = 8048) and internal validation (N = 3450) cohorts randomly at a 7:3 ratio. An independent external validation cohort (N = 660) was enrolled from dnMBC patients (2010-2023) treated in three hospitals. Nomogram-based risk stratification was employed to refine the M1 category and prognostic stage, incorporating T/N stage, histologic grade, subtypes, and the location and number of metastatic sites. Both internal and external validation sets were used for validation analyses. RESULTS: Brain, liver, or lung involvement and multiple metastases were independent prognostic factors for overall survival (OS). The nomogram-based stratification effectively divided M1 stage into three groups: M1a (bone-only involvement), M1b (liver or lung involvement only, with or without bone metastases), and M1c (brain metastasis or involvement of both liver and lung, regardless of other metastatic sites). Only subtype and M1 stage were included to define the final prognostic stage. Significant differences in OS were observed across M1 and prognostic subgroups. Patients with the M1c stage benefited less from primary tumor surgery in comparison with M1a stage. CONCLUSION: Subdivision of the M1 and prognostic stage could serve as a supplement to the current staging guidelines for dnMBC and guide locoregional treatment.

Zearalenone Triggers Programmed Cell Death and Impairs Milk Fat Synthesis via the AKT-mTOR-PPARγ-ACSL4 Pathway in Bovine Mammary Epithelial Cells.

Zearalenone (ZEN), a mycotoxin from Fusarium fungi, impairs fertility and milk production in female animals, however, the mechanisms remain poorly understood. Using the bovine mammary epithelial cells (MAC-T) as the model, this study investigated the impacts of ZEN on programmed cell death (PCD) and milk fat synthesis, and explored the underlying mechanism. We found that 10 ng/mL prolactin (PRL) notably enhanced the differentiation of MAC-T cells, promoting the expression of genes related to the synthesis of milk fat, protein, and lactose. Next, the toxic effects of different doses of ZEN on the differentiated MAC-T with PRL treatment were determined. 10 µM and 20 µM ZEN significantly reduced cell viability, induced oxidative stress, and triggered PCD (e.g. apoptosis and necrosis). Notably, ZEN exposure downregulated the mRNA/protein levels of critical factors involving in milk fat synthesis by disrupting the AKT-mTOR-PPARγ-ACSL4 pathway. Interestingly, melatonin (MT), known for its antioxidant properties, protected against the above ZEN-induced effects by enhancing the binding of PPARγ to the promoter regions of ACSL4, which led to the upregulated expression of ACSL4 gene. These results underscored the potential of MT to mitigate the adverse effects of ZEN on mammary cells, highlighting a way for potential therapeutic intervention.

Long-term outcomes of left bundle branch area pacing compared to right ventricular pacing in TAVI patients.

BACKGROUND: New-onset permanent pacemaker implantation (PPMI) is still a common complication after transcatheter aortic valve implantation (TAVI) with adverse clinical outcomes. OBJECTIVE: To investigate whether left bundle branch area pacing (LBBAP) improves long-term clinical results compared to traditional right ventricular pacing (RVP) in patients requiring PPMI following TAVI. METHODS: A total of 237 consecutive patients undergoing RVP (N=117) or LBBAP (N=120) following TAVI were retrospectively included. Long-term outcomes including all-cause death, heart failure rehospitalization (HFH) and left ventricular ejection fraction (LVEF) change compared to baseline were obtained until 5 years post-TAVI. RESULTS: The mean age of the overall population was 74 years with a mean surgical risk score as 4.4%. The paced QRS duration was significantly longer in RVP group compared to LBBAP group (151 ± 18 vs. 122 ± 12 ms, P<0.001). There was no difference between two groups in all-cause death (13.7% vs. 13.3%, adjusted HR: 0.76; 95% CI: 0.37 to 1.58; P=0.466) or the composite endpoint of death and HFH (29.9% vs. 19.2%, adjusted HR: 1.22; 95% CI: 0.70 to 2.13; P=0.476), however, the risk of HFH was significantly higher in RVP group at 5 years after TAVI (21.4% vs. 7.5%, adjusted HR: 2.26; 95% CI: 1.01 to 5.08; P=0.048). There was a greater improvement of LVEF over time in LBBAP group (P=0.046 for LVEF changes over time between groups). CONCLUSIONS: LBBAP improved long-term clinical outcomes compared to RVP in patients undergoing PPMI after TAVI in terms of less HFH and better LVEF improvement.

Family history and genetic risk score combined to guide cancer risk stratification: A prospective cohort study.

Family history (FH) of cancer and polygenic risk scores (PRS) are pivotal for cancer risk assessment, yet their combined impact remains unclear. Participants in the UK Biobank (UKB) were recruited between 2006 and 2010, with complete follow-up data updated until February 2020 for Scotland and January 2021 for England and Wales. Using UKB data (N = 442,399), we constructed PRS and incidence-weighted overall cancer PRS (CPRS). FH was assessed through self-reported standardized questions. Among 202,801 men (34.6% with FH) and 239,598 women (42.0% with FH), Cox regression was used to examine the associations between FH, PRS, and cancer risk. We found a significant dose-response relationship between FH of cancer and corresponding cancer risk (Ptrend < .05), with over 10 significant pairs of cross-cancer effects of FH. FH and PRS are positively correlated and independent. Joint effects of FH of cancer (multiple cancers) and PRS (CPRS) on corresponding cancer risk were observed: for instance, compared with participants with no FH of cancer and low PRS, men with FH of cancer and high PRS had the highest risk of colorectal cancer (hazard ratio [HR]: 3.69, 95% confidence interval [CI]: 3.01-4.52). Additive interactions were observed in prostate and overall cancer risk for men and breast cancer for women, with the most significant result being a relative excess risk of interaction (RERI) of 2.98, accounting for ~34% of the prostate cancer risk. In conclusion, FH and PRS collectively contribute to cancer risk, supporting their combined application in personalized risk assessment and early intervention strategies.

Clearance and transport of amyloid ß by peripheral monocytes correlate with Alzheimer's disease progression.

Impaired clearance of amyloid ß (Aß) in late-onset Alzheimer's disease (AD) affects disease progression. The role of peripheral monocytes in Aß clearance from the central nervous system (CNS) is unclear. We use a flow cytometry assay to identify Aß-binding monocytes in blood, validated by confocal microscopy, Western blotting, and mass spectrometry. Flow cytometry immunophenotyping and correlation with AD biomarkers are studied in 150 participants from the AIBL study. We also examine monocytes in human cerebrospinal fluid (CSF) and their migration in an APP/PS1 mouse model. The assay reveals macrophage-like Aß-binding monocytes with high phagocytic potential in both the periphery and CNS. We find lower surface Aß levels in mild cognitive impairment (MCI) and AD-dementia patients compared to cognitively unimpaired individuals. Monocyte infiltration from blood to CSF and migration from CNS to peripheral lymph nodes and blood are observed. Here we show that Aß-binding monocytes may play a role in CNS Aß clearance, suggesting their potential as a biomarker for AD diagnosis and monitoring.

Inetetamab-based therapy in real-world treatment patterns with HER2-positive advanced breast cancer patients: a retrospective single-center study.

Background: Inetetamab is a novel antibody targeting human epidermal growth factor receptor 2 (HER2) developed in China. Due to its optimized antibody-dependent cell-mediated cytotoxicity effect compared with trastuzumab, it has shown good efficacy and safety in the treatment of HER2-positive advanced breast cancer (ABC). Objectives: This study aimed to investigate the efficacy and safety of inetetamab combination therapy in the treatment of HER2-positive ABC in real-world clinical practice. Design: Retrospective study. Methods: A total of 133 patients with HER2-positive ABC who were treated with inetetamab-based regimens between March 2020 and January 2024 were retrospectively included in this study. The main endpoint was median progression-free survival (mPFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Results: The study included 133 HER2-positive ABC patients, and the median age was 55 years. The mPFS was 8.0 (6.7-9.3) months. The ORR was 50.4%, while the DCR was 88.7%. The mPFS for patients receiving inetetamab-based therapy as first to second, third to fourth, and later lines of metastatic treatment were 14.0, 7.0, and 6.0 months, respectively. Patients treated with inetetamab plus pyrotinib plus chemotherapy, especially with capecitabine, had the best outcomes (mPFS = 14.0 months). Multivariate analysis revealed that prior HER2-TKI treatment was significantly associated with worse PFS (hazard ratios 2.829, 95% confidence interval 1.265-6.328, p = 0.011). Subgroup analysis indicated that patients without visceral metastases had significantly better PFS (14.0 months vs 8.0 months, p = 0.003). The overall incidence of any grade adverse events (AEs) was 100%, with most being grades 1-2. Severe complications included neutropenia (37.6%) and leukopenia (33.1%). Conclusions: Inetetamab-based combination therapy shows promising efficacy and good safety in patients with HER2-positive ABC. It is one of the late-line treatment options for Chinese patients with HER2-positive ABC.

An insight into structure-activity relationships in subclass IIb bacteriocins: Plantaricin EvF.

This study reports the structure-activity relationships of a unique subclass IIb bacteriocin, plantaricin EvF, which consists of two peptide chains and possesses potent antimicrobial activity. Because the plantaricin Ev peptide chain lacks an α-helix structure, plantaricin EvF is unable to exert its antimicrobial activity through helix-helix interactions like typical subclass IIb bacteriocins. We have shown by various structural evaluation methods that plantaricin Ev can be stabilized by hydrogen bonding at amino acid residues R3, V12, and R13 to the N-terminal region of plantaricin F. This binding gives plantaricin EvF a special spade-shaped structure that exerts antimicrobial activity. In addition, the root-mean-square deviations (RMSDs) of the amino acid residues Y6, F8, and R13 of plantaricin Ev pre- and post-binding were 1.512, 1.723, and 1.369, respectively, indicating that they underwent large structural changes. The alanine scanning experiments demonstrated the important role of the above key amino acids in maintaining the structural integrity of plantaricin EvF. This study not only reveals the unique structural features of plantaricin EvF, but also provides an insight into the structure-activity relationships of subclass IIb bacteriocins.