Inetetamab is a neotype HER2-targeted monoclonal antibody with amino acids modified Fc segment which optimizes the antibody-dependent cellular cytotoxicity effect. However, robust evidence evaluating the combination of inetetamab combined with pertuzumab, paclitaxel and carboplatin (TCbIP) for neoadjuvant therapy is still lacking. This study aimed to evaluate the efficacy and safety of TCbIP as a neoadjuvant therapy for patients with locally advanced (LA) HER2-positive breast cancer. This phase II trial included female patients with histologically confirmed stage IIA to IIIC HER2-positive primary invasive breast cancer. Eligible patients received TCbIP treatment every three weeks for a maximum of six cycles followed by surgery. The primary endpoint was pathologic complete response (pCR, ypT0/is ypN0) rate. Key secondary endpoints included near pCR (npCR, residual breast disease <1cm) rate, objective response rate (ORR) and safety. From November 2021 to May 2023, 28 patients were enrolled in the trial. One patient received one cycle of the study treatment and was lost to follow-up without surgery, and four patients received one cycle of the study treatment and were still in treatment, leaving 23 patients in the ITT population. Among these 23 patients (82.6% in stage III), 16 patients completed the study treatment and surgery (PP population) and six patients were still undergoing neoadjuvant treatment. The ORR was 91.3% (21/23) in the ITT population and 93.8% (15/16) in the PP population. Among the 16 patients in the PP population, 10 patients (62.5%) achieved pCR. A total of 14 patients (87.5%) achieved npCR. For patients with hormone receptor (HR) negative and positive tumors, the pCR rates were 88.9% (8/9) and 28.6% (2/7), respectively. The most common grade 3 adverse event was neutropenia (25.0%). No significant reduction in the left ventricular ejection fraction was observed in any patient. Neoadjuvant therapy with TCbIP has shown promising efficacy and manageable toxicity in patients with HER2-positive LA breast cancer.

A triphenylamine-based “turn-on” fluorescent chemosensor, (E)-3-(benzyloxy)-N′-[4′-(diphenyl­amino)-4-hydroxy[1,1′-biphenyl]-3-yl]methylidenebenzohydrazide (BDHBMB), containing a 3-benzyloxy­benzo­hydrazide moiety was successfully synthesized. It showed high selectivity, excellent anti-interference performance, and remarkable sensitivity for Al3+ ions in methanol solution. After the addition of Al3+, BDHBMB exhibited strong fluorescence emission (18 times enhancement) at λ 573 nm due to the formation of a rigid conjugate structure based on chelation-enhanced fluorescence (CHEF) mechanism. A great linearity with a correlation coefficient R2 of 0.99 was observed in the concentration range 0–60 μM. The binding constant and the limit of detection (LOD) for Al3+ were calculated to be 1.48×103 M–1 and 8.94×10–8 M, respectively. The “turn-on” fluorescent probe was successfully applied to visual detection of Al3+ in test paper.

Background: Despite the prolonged median disease-free survival (DFS) by adjuvant targeted therapy in non-small-cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations, the relationship between the treatment duration and the survival benefits in patients remains unknown.Patients and methods: In this multicenter, randomized, open-label, phase II trial, eligible patients aged 18-75 years with EGFR-mutant, stage II-IIIA lung adenocarcinoma and who had not received adjuvant chemotherapy after complete tumor resection were enrolled from eight centers in China. Patients were randomly assigned (1 : 1) to receive either 1-year or 2-year icotinib (125 mg thrice daily). The primary endpoint was DFS assessed by investigator. The secondary endpoints were overall survival (OS) and safety. This study was registered at ClinicalTrials.gov (NCT01929200).Results: Between September 2013 and October 2018, 109 patients were enrolled (1-year group, n = 55; 2-year group, n = 54). Median DFS was 48.9 months [95% confidence interval (CI) 33.1-70.1 months] in the 2-year group and 32.9 months (95% CI 26.6-44.8 months) in the 1-year group [hazard ratio (HR) 0.51; 95% CI 0.28-0.94; P = 0.0290]. Median OS for patients was 75.8 months [95% CI 64.4 months-not evaluable (NE)] in the 2-year group and NE (95% CI 66.3 months-NE) in the 1-year group (HR 0.34; 95% CI 0.13-0.95; P = 0.0317). Treatment-related adverse events (TRAEs) were observed in 41 of 55 (75%) patients in the 1-year group and in 36 of 54 (67%) patients in the 2-year group. Grade 3-4 TRAEs occurred in 4 of 55 (7%) patients in the 1-year group and in 3 of 54 (6%) patients in the 2-year group. No treatment-related deaths or interstitial lung disease was reported. Conclusions: Two-year adjuvant icotinib was shown to significantly improve DFS and provide an OS benefit in EGFR- mutant, stage II-IIIA lung adenocarcinoma patients compared with 1-year treatment in this exploratory phase II study.

ObjectivesThis study aimed to analyze the role of estrogen in noise-induced hearing loss (NIHL) and uncover underlying mechanisms.MethodsAn ovariectomized Sprague-Dawley rat model (OVX) was constructed to investigate the hearing threshold and auditory latency before and after noise exposure using the auditory brainstem response (ABR) test. The morphological changes were assessed using immunofluorescence, scanning electron microscopy and transmission electron microscopy. Proteomics and bioinformatics were used to analyze the mechanism. The findings were further verified through western blot and Luminex liquid suspension chip technology.ResultsAfter noise exposure, OVX rats exhibited substantially elevated hearing thresholds. A conspicuous delay in ABR wave I latency was observed, alongside increased loss of outer hair cells, severe collapse of stereocilia and pronounced deformation of the epidermal plate. Accordingly, OVX rats with estrogen supplementation exhibited tolerance to NIHL. Additionally, a remarkable upregulation of the thrombospondin 1 (Tsp1)-CD47 axis in OVX rats was discovered and verified.ConclusionsOVX rats were more susceptible to NIHL, and the protective effect of estrogen was achieved through regulation of the Tsp1-CD47 axis. This study presents a novel mechanism through which estrogen regulates NIHL and offers a potential intervention strategy for the clinical treatment of NIHL.

As a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), aumolertinib has been demonstrated to be effective in EGFR mutant non-small cell lung cancer (NSCLC). The HRQoL data is important for the evaluation of overall clinical benefits of therapeutics, however, the real-world impact of aumolertinib on patients' HRQoL still remains unclear. Hereby, this study aimed to assess the HRQoL of NSCLC patients treated with aumolertinib in real-world setting.

Objective Rheumatoid arthritis (RA) is a chronic inflammatory disorder. Pyridostigmine (PYR), an acetylcholinesterase (AChE) inhibitor, has been shown to reduce inflammation and oxidative stress in several animal models for inflammation-associated conditions. The present study aimed to investigate the effects of PYR on pristane-induced (PIA) in Dark Agouti (DA) rats. Method DA rats were intradermally infused with pristane to establish the PIA model, which was treated with PYR (10 mg/kg/day) for 27 days. The effects of PYR on synovial inflammation, oxidative stress, and gut microbiota were evaluated by determining arthritis scores, H&E staining, quantitative polymerase chain reaction, and biochemical assays, as well as 16S rDNA sequencing. Results Pristane induced arthritis, with swollen paws and body weight loss, increased arthritis scores, synovium hyperplasia, and bone or cartilage erosion. The expression of pro-inflammatory cytokines in synovium was higher in the PIA group than in the control group. PIA rats also displayed elevated levels of malondialdehyde, nitric oxide, superoxide dismutase, and catalase in plasma. Moreover, sequencing results showed that the richness, diversity, and composition of the gut microbiota dramatically changed in PIA rats. PYR abolished pristane-induced inflammation and oxidative stress, and corrected the gut microbiota dysbiosis. Conclusion The results of this study support the protective role of PYR in PIA in DA rats, associated with the attenuation of inflammation and correction of gut microbiota dysbiosis. These findings open new perspectives for pharmacological interventions in animal models of RA.

OBJECTIVE: The clinical value of increased levels of neutrophil gelatinase-associated lipocalin (NGAL) in patients with septic acute kidney injury (AKI) is still unclear. This study aimed to assess the link between illness severity and NGAL in patients with septic AKI. PATIENTS AND METHODS: This is a retrospective observational study that took place at the Fourth Hospital of Hebei Medical University, Shijiazhuang, China. The cohort included 365 patients who were admitted to the ICU during the 21-month period. Of them, 18 patients were diagnosed with sepsis (septic group). The average age of patients in the septic group was over 65, and 60.00% of them eventually progressed to septic AKI. Plasma NGAL (pNGAL) and urine NGAL (uNGAL) levels at defined time points were measured. AKI staging was done based on the Kidney Disease Improving Global Outcomes (KDIGO) classification. The Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation (APACHE) II scores were determined. Patterns and associations between NGAL levels with SOFA scores and different stages of septic AKI were investigated. RESULTS: Both pNGAL and uNGAL showed a positive correlation with SOFA and proved to be reliable predictors of the same. Furthermore, the accuracy of severe sepsis (SOFA ≥ 8) was 0.67 for pNGAL and 0.66 for uNGAL. Real-time detection of pNGAL and uNGAL indicated that they were good biomarkers of severe septic AKI. Area under the receiver operating characteristic (AUROC) for pNGAL and uNGAL were 0.72 (0.69-0.85), and 0.83 (0.71-0.95), respectively. However, only patients with KDIGO 3 AKI presented significantly elevated levels of pNGAL (p < 0.05). Furthermore, the uNGAL level at each stage of septic AKI was higher than that of the non-AKI period (p < 0.01). CONCLUSIONS: In patients with septic AKI, levels of NGAL correlated with SOFA. Levels of pNGAL were good predictors of severe kidney injury and uNGAL levels could detect mild stages of AKI.

Abstract Study question Whether letrozole-stimulated protocol has advantages over hormone replacement therapy (HRT) in frozen embryo transfer in patients with polycystic ovary syndrome (PCOS)? Summary answer Letrozole-stimulated protocol is more suitable for endometrial preparation than HRT in patients with PCOS, which can increase the live birth rate and reduce pregnancy complications. What is known already The current routine endometrial preparation protocol for women with PCOS is HRT. However, HRT is expensive, and recent studies have found HRT may increase the risk of adverse maternal and neonatal complications such as hypertensive disorders of pregnancy. Letrozole induces mono-ovulatory and has no antiestrogenic effect, and has been found to increase live birth rate compared with clomiphene in fresh embryo cycles. However, Letrozole is rarely used in frozen embryo cycles. Whether letrozole-stimulated protocol is suitable for frozen embryo transfer in patients with PCOS and for whom is suitable is still lack of evidence. Study design, size, duration This is a retrospective cohort study involving all frozen embryo transfer cycles with letrozole-stimulated and HRT for PCOS during the period from August 2018 to December 2020 at a tertiary care center. Participants/materials, setting, methods A total of 2011 letrozole-stimulated cycles and 2211 HRT cycles were included in the analysis. Multivariate Logistic regression was used to analyze the differences in clinical pregnancy rate, live birth rate, miscarriage rate, the incidence of other pregnancy and obstetric outcomes between letrozole-stimulated protocol and HRT after adjusting for possible confounding factors. Subgroup analysis was used to explore the population for which letrozole-stimulated protocol was suitable. Main results and the role of chance After adjusting for confounding, letrozole-stimulated protocol increased the clinical pregnancy rate (OR,1.44; 95%CI,1.21-1.70), live birth rate (OR,1.49; 95%CI,1.27-1.74) and reduced the incidence of miscarriage (OR, 0.71; 95%CI,0.55-0.92), hypertensive disorders of pregnancy (OR, 0.66; 95%CI,0.45,0.98), gestational diabetes mellitus (OR,0.75; 95%CI,0.57,0.98) and cesarean section (OR,0.78; 95%CI,0.61,0.99) than HRT. There were no significant differences in other outcomes such as preterm birth, small for gestational age, and large for gestational age between the two endometrial preparation protocols. Subgroup analysis according to maternal age, BMI, insulin resistance and PCOS classification showed that the live birth rate of letrozole-stimulated protocol was significantly higher than that of HRT in all subgroups. Limitations, reasons for caution This study is a retrospective study, the population characteristics of the two endometrial preparation protocols existed differences. Although multivariate logistic regression was used to adjust some factors, the interference of known and unknown factors on the outcomes cannot be completely avoided. Wider implications of the findings This retrospective study found letrozole-stimulated protocol has more advantages than HRT, which can improve the live birth rate and reduce the incidence of hypertensive disorders of pregnancy, gestational diabetes mellitus in patients with PCOS. High-quality well-powered randomised clinical trials and possible mechanistic studies are needed to further validate this conclusion. Trial registration number NA

Tight junctions are involved in skin barrier functions. Bioinformatics analysis revealed expression of decreased claudin 1 (CLDN1), claudin 4 (CLDN4), and occludin (OCLN) in lesions of patients with atopic dermatitis. Similarly, CLDN4 and OCLN were significantly downregulated by interleukin 4 and interleukin 13 in HaCaT cells and human primary keratinocytes. This effect, which was mediated through the Janus kinase–signal transducer and activator of transcription 6(STAT6) signaling pathway, increased paracellular flux of 4-kDa dextran. Benvitimod, an effective treatment for atopic dermatitis, upregulated CLDN4 and OCLN, and decreased paracellular flux of 4-kDa dextran. These functions of benvitimod are mediated through the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator pathway and inhibition of STAT6 phosphorylation. Treatment of keratinocytes with benvitimod induced nuclear translocation of nuclear factor erythroid 2-related factor 2 and reduced production of reactive oxygen species. Our findings indicate that Th2 cytokines are involved in tight junction impairment and benvitimod can inhibit these effects.