Efficient electro-Fenton degradation of organic pollutants via the synergistic effect of 1O2 and •OH generated on single FeN4 sites.

The electro-Fenton with in situ generated 1O2 and •OH is a promising method for the degradation of micropollutants. However, its application is hindered by the lack of catalysts that can efficiently generate 1O2 and •OH from electrochemical oxygen reduction. Herein, N-doped stacked carbon nanosheets supported Fe single atoms (Fe-NSC) with FeN4 sites were designed for simultaneous generation of 1O2 and •OH to enhance electro-Fenton degradation. Due to the synergistic effect of 1O2 and •OH, a variety of contaminants (phenol, 2,4-dichlorophenol, sulfamethoxazole, atrazine and bisphenol A) were efficiently degraded with high kinetic constants of 0.037-0.071 min-1 by the electro-Fenton with Fe-NSC as cathode (-0.6 V vs Ag/AgCl, pH 6). Moreover, the superior performance for electro-Fenton degradation was well maintained in a wide pH range from 3 to 10 even with interference of various inorganic salt ions. It was found that FeN4 sites with pyridinic N coordination were responsible for its good performance for electro-Fenton degradation. Its 1O2 yield was higher than •OH yield, and the contribution of 1O2 was more significant than •OH for pollutant degradation.

Remodeling ceramide homeostasis promotes functional maturation of human pluripotent stem cell-derived ß cells.

Human pluripotent stem cell-derived ß cells (hPSC-ß cells) show the potential to restore euglycemia. However, the immature functionality of hPSC-ß cells has limited their efficacy in application. Here, by deciphering the continuous maturation process of hPSC-ß cells post transplantation via single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq), we show that functional maturation of hPSC-ß cells is an orderly multistep process during which cells sequentially undergo metabolic adaption, removal of negative regulators of cell function, and establishment of a more specialized transcriptome and epigenome. Importantly, remodeling lipid metabolism, especially downregulating the metabolic activity of ceramides, the central hub of sphingolipid metabolism, is critical for ß cell maturation. Limiting intracellular accumulation of ceramides in hPSC-ß cells remarkably enhanced their function, as indicated by improvements in insulin processing and glucose-stimulated insulin secretion. In summary, our findings provide insights into the maturation of human pancreatic ß cells and highlight the importance of ceramide homeostasis in function acquisition.

Interferon-Alpha Induces Psoriatic Inflammation in Mice by Phosphorylating FOXO3.

Psoriasis is a chronic, immune-mediated inflammatory skin disease characterized by epidermal thickening and inflammatory cell infiltration. Excessive proliferation of keratinocytes and resistance to apoptosis lead to thickening of the epidermis. Plasmacytoid dendritic cells are involved in the occurrence of psoriasis mainly by secreting interferon-alpha (IFN-α). IFN-α is a glycoprotein with antiviral, antitumor, and immunomodulatory effects, but its role in psoriasis remains unclear. In this investigation, a mild psoriatic phenotype was observed in mice upon topical application of IFN-α cream, and the inflammation was exacerbated when combined with imiquimod (IMQ). Immunohistochemical analyses demonstrated that IFN-α induces psoriatic inflammation in mice by stimulating phosphorylation of forkhead box O3, consistent with the involvement of this protein in cell proliferation, apoptosis, and inflammation. Our results suggested that topical IFN-α caused psoriatic inflammation and that the psoriatic inflammation was exacerbated by the combination of IFN-α and IMQ, possibly due to the dysfunction of forkhead box O3.

Patient-derived tumor-like cell clusters for personalized chemo- and immunotherapies in non-small cell lung cancer.

Many patient-derived tumor models have emerged recently. However, their potential to guide personalized drug selection remains unclear. Here, we report patient-derived tumor-like cell clusters (PTCs) for non-small cell lung cancer (NSCLC), capable of conducting 100-5,000 drug tests within 10 days. We have established 283 PTC models with an 81% success rate. PTCs contain primary tumor epithelium self-assembled with endogenous stromal and immune cells and show a high degree of similarity to the original tumors in phenotypic and genotypic features. Utilizing standardized culture and drug-response assessment protocols, PTC drug-testing assays reveal 89% overall consistency in prospectively predicting clinical outcomes, with 98.1% accuracy distinguishing complete/partial response from progressive disease. Notably, PTCs enable accurate prediction of clinical outcomes for patients undergoing anti-PD1 therapy by combining cell viability and IFN-γ value assessments. These findings suggest that PTCs could serve as a valuable preclinical model for personalized medicine and basic research in NSCLC.

Rh family C glycoprotein contributes to psoriatic inflammation through regulating the dysdifferentiation and cytokine secretion of keratinocytes.

BACKGROUND: Keratinocyte dysdifferentiation and proinflammatory cytokine production play a central role in psoriatic inflammation. According to recent studies, the Rh family C glycoprotein (RHCG) enhances cell proliferation and disrupts cell differentiation. However, the specific role of RHCG psoriasis development remains unclear. OBJECTIVE: We here explored the effect of RHCG on keratinocytes under psoriatic inflammation. METHODS: The cell counting kit­8 assay was conducted to assess proliferation. RHCG protein expression was assessed through western blotting and enzyme-linked immunosorbent assays. The expression of proinflammatory cytokines and differentiation markers was analyzed through a quantitative reverse-transcription polymerase chain reaction. RESULTS: Both RHCG mRNA and protein levels increased in psoriatic skin. Notably, cultured keratinocytes treated with an M5 cocktail, which mimics psoriatic inflammation, exhibited higher RHCG expression. Furthermore, RHCG overexpression promoted keratinocyte proliferation, accompanied by an increase in the production of interleukin (IL)-1ß, IL-6, and IL-8, and tumor necrosis factor-α. RHCG overexpression also resulted in higher expression of keratin 17, a differentiation marker. Conversely, RHCG gene knockdown reduced keratinocyte proliferation and cytokine secretion. RHCG inhibition in cells recovered both keratin 1 and loricrin expression. Additionally, RHCG overexpression facilitated the phosphorylation of nuclear factor-kappa B and extracellular signal-regulated protein kinase signaling pathways. Importantly, when these signaling pathways were inhibited, the effect of RHCG on keratinocytes was attenuated. CONCLUSION: These findings support the substantial role of RHCG in psoriatic inflammation development and suggest that RHCG serves as a potential target for psoriasis treatment.

Beneficial implications of adjuvant chemotherapy for stage IB lung adenocarcinoma exhibiting elevated SUVmax in FDG-PET/CT: a retrospective study from a single center.

Background: Controversy surrounds the efficacy of adjuvant chemotherapy (ACT) in the treatment of stage I lung adenocarcinoma (LUAD). The objective of this study was to examine the impact of the maximum standardized uptake value (SUVmax) as measured by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) on the efficacy of ACT in patients diagnosed with stage I LUAD. Methods: We scrutinized the medical records of 928 consecutive patients who underwent complete surgical resection for pathological stage I LUAD at our institution. The ideal cut-off value for primary tumor SUVmax in terms of disease-free survival (DFS) and overall survival (OS) was determined using the X-tile software. The Kaplan-Meier method and Cox regression analysis were used for survival analysis. Results: Based on the SUVmax algorithm, the ideal cutoff values were determined to be 4.9 for DFS and 5.0 for OS. We selected 5.0 as the threshold because OS is the more widely accepted predictive endpoint. In a multivariate Cox regression analysis, SUVmax ≥ 5.0, problematic IB stage, and sublobectomy were identified as independent risk factors for poor DFS and OS. It is noteworthy that patients who were administered ACT had significantly longer DFS and OS than what was observed in the subgroup of patients with pathological stage IB LUAD and SUVmax ≥ 5.0 (p < 0.035 and p ≤ 0.046, respectively). However, there was no observed survival advantage for patients in stages IA or IB who had an SUVmax < 5.0. Conclusion: The preoperative SUVmax of tumors served as an indicator of the impact of ACT in the context of completely resected pathological stage I LUAD. Notably, patients within the Stage IB category exhibiting elevated SUVmax levels emerged as a subgroup experiencing substantial benefits from postoperative ACT.

Anti-DNA antibody-targeted D-peptide nanoparticles ameliorate lupus nephritis in MRL/lpr mice.

Peptide ALW (ALWPPNLHAWVP) targeting anti-dsDNA antibodies has shown promising therapeutic effects in alleviating lupus nephritis, but is potentially limited by poor stability and non-kidney targeting. We recently developed a D-form modified ALW, called D-ALW, which has the capacity to widely inhibit pathogenic polyclonal anti-dsDNA antibody reactions. Further modification of D-ALW using PEG-PLGA nanoparticles to enhance good kidney-targeting ability and extend half-life. Here, we demonstrate that the D-form modified ALW maintains higher binding and inhibition efficiencies and achieves higher stability. Most importantly, D-ALW nanoparticles exhibit excellent kidney-targeting ability and prolong the half-life of the peptides in BALB/c mice. Additionally, compared to D-ALW, D-ALW nanoparticles significantly reduce the glomerular deposition of IgG and C3, improve renal histopathologies, such as glomerular proliferation and inflammatory cells infiltration, and markedly prolong lifespan in MRL/lpr lupus-prone mice. Overall, these results establish that the D-ALW nanoparticles offer synergistic benefits in both safety and efficacy, providing long-term renal preservation and treatment advantages in lupus nephritis.

Diannexin alleviates myocardial ischemia-reperfusion injury by orchestrating cardiomyocyte oxidative damage, macrophage polarization and fibrotic process by TLR4-NF-kB-mediated inactivation of NLRP3 inflammasome.

Myocardial ischemia-reperfusion (I/R) injury is a pathogenic mechanism of myocardial infarction and heart failure, constituting a major health concern globally. Diannexin is a homodimer of recombinant human annexin V and elicits important roles in several I/R injuries. Nevertheless, its function in MI/R remains elusive. Here, Diannexin alleviated simulated I/R (SI/R)-induced cardiomyocyte death and oxidative injury by increasing cell viability and inhibiting cell apoptosis, ROS, lactate dehydrogenase, malondialdehyde production and anti-oxidative SOD activity. Diannexin inhibited SI/R-induced expression of fibrotic protein collagen I and collagen III. Furthermore, Diannexin suppressed LPS-induced macrophage polarization towards pro-inflammatory M1-like phenotype and enhanced IL-4-evoked anti-inflammatory M2 polarization. Concomitantly, Diannexin inhibited SI/R exposure-induced macrophage polarization to M1 subtypes. Importantly, conditioned medium (CM) from SI/R-stimulated macrophages evoked cardiomyocyte apoptosis, which was reversed when cells were co-cultured with CM from Diannexin-treated macrophages under SI/R conditions. Mechanically, the activation of TLR4/NF-κB/NLRP3 inflammasome signaling in SI/R-treated cells was mitigated by Diannexin. Reactivating this pathway antagonized the protective effects of Diannexin on SI/R-induced cardiomyocyte oxidative injury, fibrotic protein expression and macrophage polarization and M1 macrophage-induced apoptosis of cardiomyocytes. In vivo, Diannexin alleviated abnormal cardiac structure, dysfunction and collagen position in MI/R mice. Additionally, Diannexin reduced M1-polarized and elevated M2-polarized macrophages in heart tissues at five days post-MI/R. The activation of TLR4/NF-κB/NLRP3 inflammasome pathway in MI/R mice was attenuated after Diannexin administration. Together, Diannexin may alleviate the development of MI/R injury by directly regulating cardiomyocyte oxidative injury, fibrotic potential and indirectly affecting macrophage polarization-mediated cardiomyocyte apoptosis, indicating a promising therapeutic strategy for MI/R.

BCSwinReg: A cross-modal attention network for CBCT-to-CT multimodal image registration.

Computed tomography (CT) and cone beam computed tomography (CBCT) registration plays an important role in radiotherapy. However, the poor quality of CBCT makes CBCT-CT multimodal registration challenging. Effective feature fusion and mapping often lead to better registration results for multimodal registration. Therefore, we proposed a new backbone network BCSwinReg and a cross-modal attention module CrossSwin. Specifically, a cross-modal attention CrossSwin is designed to promote multi-modal feature fusion, map the multi-modal domain to the common domain, and thus helping the network learn the correspondence between images better. Furthermore, a new network, BCSwinReg, is proposed to discover correspondence through cross-attention exchange information, obtain multi-level semantic information through a multi-resolution strategy, and finally integrate the deformation of multi-resolutions by the divide-conquer cascade method. We performed experiments on the publicly available 4D-Lung dataset to demonstrate the effectiveness of CrossSwin and BCSwinReg. Compared with VoxelMorph, the BCSwinReg has obtained performance improvements of 3.3% in Dice Similarity Coefficient (DSC) and 0.19 in the average 95% Hausdorff distance (HD95).

Radiotherapy may exacerbated anti-programmed cell death 1 treatment induced vitiligo: A case report.

Immunotherapy with programmed cell death 1 (PD-1) checkpoint inhibitors combined with chemoradiotherapy shows great potential for cancer treatment and is getting extensively researched. However, a plethora of immune-related adverse events (irAEs) has been observed during anti-PD-1 treatment, including cutaneous adverse events, such as vitiligo and pruritus. These adverse events may lead to treatment discontinuation. When anti-PD-1 treatment is combined with radiotherapy (RT), irAEs may be exacerbated. Here we present a case report of an elderly patient with stage IIIb rectal cancer, who developed PD-1 inhibitor-associated vitiligo. After a session of RT, vitiligo lesions enlarged shortly thereafter. After discontinuation of anti-PD-1 treatment, vitiligo lesions and pruritus quickly improved with appropriate treatment. The rectal cancer achieved clinical complete response with no sign of recurrence or metastasis during follow-up. Considering the similar mechanism of anti-PD-1 treatment in targeting cancer and in inducing irAEs, cutaneous adverse events may be associated with favourable clinical response. Additionally, cutaneous irAEs aggravated by RT in this patient may suggested significant immune activation, which may occasionally contribute to tumour regression and favourable clinical outcome.

A Collaborative Self-supervised Domain Adaptation for Low-Quality Medical Image Enhancement.

Medical image analysis techniques have been employed in diagnosing and screening clinical diseases. However, both poor medical image quality and illumination style inconsistency increase uncertainty in clinical decision-making, potentially resulting in clinician misdiagnosis. The majority of current image enhancement methods primarily concentrate on enhancing medical image quality by leveraging high-quality reference images, which are challenging to collect in clinical applications. In this study, we address image quality enhancement within a fully self-supervised learning setting, wherein neither high-quality images nor paired images are required. To achieve this goal, we investigate the potential of self-supervised learning combined with domain adaptation to enhance the quality of medical images without the guidance of high-quality medical images. We design a Domain Adaptation Self-supervised Quality Enhancement framework, called DASQE. More specifically, we establish multiple domains at the patch level through a designed rule-based quality assessment scheme and style clustering. To achieve image quality enhancement and maintain style consistency, we formulate the image quality enhancement as a collaborative self-supervised domain adaptation task for disentangling the low-quality factors, medical image content, and illumination style characteristics by exploring intrinsic supervision in the low-quality medical images. Finally, we perform extensive experiments on six benchmark datasets of medical images, and the experimental results demonstrate that DASQE attains state-of-the-art performance. Furthermore, we explore the impact of the proposed method on various clinical tasks, such as retinal fundus vessel/lesion segmentation, nerve fiber segmentation, polyp segmentation, skin lesion segmentation, and disease classification. The results demonstrate that DASQE is advantageous for diverse downstream image analysis tasks.

Study protocol of short-course radiotherapy combined with CAPOX and PD-1 inhibitor for locally advanced colon cancer: a randomised, prospective, multicentre, phase II trial (TORCH-C).

INTRODUCTION: The preliminary result of the TORCH trial has shown a promising complete response (CR) for managing locally advanced rectal cancer with neoadjuvant short-course radiotherapy (SCRT) combined with chemotherapy and PD-1 inhibitor. For locally advanced colon cancer (LACC) with bulky nodal disease and/or clinically T4, neoadjuvant chemotherapy followed by colectomy with en bloc removal of regional lymph nodes is the suggested treatment. However, the CR rate is less than 5%. TORCH-C will aim to investigate neoadjuvant SCRT combined with chemotherapy and PD-1 inhibitor in LACC. METHODS AND ANALYSIS: TORCH-C is a randomised, prospective, multicentre, double-arm, open, phase II trial of SCRT combined with chemotherapy and immunotherapy in LACC with microsatellite stable (MSS) patients and cT4 or bulky nodes. Eligible patients will be identified by the multidisciplinary team. 120 patients will be randomised 1:1 to the intervention or control arm. The patients in the control arm will receive four cycles of capecitabine plus oxaliplatin (CAPOX). The patients in the intervention arm will receive SCRT, followed by four cycles of CAPOX and PD-1 inhibitor (serplulimab). Both arms will receive curative surgery, followed by four cycles of CAPOX. The primary endpoint is pathological complete regression.TORCH-C (TORCH-colon) trial aims to investigate whether the combination of immunotherapy and chemoradiotherapy improves the treatment effect in LACC with MSS. TORCH-C will establish the TORCH platform, a key part of our long-term strategy to develop neoadjuvant treatment for colorectal cancer. ETHICS AND DISSEMINATION: This study was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (approval number: 2211265-12). TRIAL REGISTRATION NUMBER: NCT05732493.

Advances in Thyroid Organoids Research and Applications.

INTRODUCTION: Organoids are three-dimensional cellular aggregates derived from stem cells or primary tissues that can self-organize into organotypic structures and showcase the physiological functions of that organ. Organoids typically comprise multiple organ-specific cell types that are responsible for organ function in vivo. They may also incorporate various cellular and molecular stromal components to recapitulate the in vivo microenvironment of the target organ. METHODS: All articles related to thyroid-like organs were synthesized. Articles published between 1959 and 2023 were assessed, categorized, and analyzed using relevant keywords. RESULTS: As such, organoids provide a model of greater physiological relevance than 2D cell culture for basic and translational research. Murine and human organoids of the thyroid have been established from embryonic stem cells (ESCs), pluripotent stem cells (PSCs) and from various healthy or diseased thyroid tissues. These thyroid organoids have been used in basic and translation research on thyroid-related diseases including hyperthyroidism, Graves' disease, and Hashimoto's thyroiditis. In addition, organoids derived from patients with thyroid cancer retain histopathological features and mutational profile of the original tumor. These patient-derived organoids have been successfully used in in vitro evaluation of drug response of individual patients, demonstrating their potential application in personalized treatment of thyroid cancer. CONCLUSION: In this review article, we have discussed various techniques for establishing thyroid organoids and their applications in thyroid-related diseases as disease models, regenerative medicines, or a tool for drug testing.

Sketch-Supervised Histopathology Tumour Segmentation: Dual CNN-Transformer With Global Normalised CAM.

Deep learning methods are frequently used in segmenting histopathology images with high-quality annotations nowadays. Compared with well-annotated data, coarse, scribbling-like labelling is more cost-effective and easier to obtain in clinical practice. The coarse annotations provide limited supervision, so employing them directly for segmentation network training remains challenging. We present a sketch-supervised method, called DCTGN-CAM, based on a dual CNN-Transformer network and a modified global normalised class activation map. By modelling global and local tumour features simultaneously, the dual CNN-Transformer network produces accurate patch-based tumour classification probabilities by training only on lightly annotated data. With the global normalised class activation map, more descriptive gradient-based representations of the histopathology images can be obtained, and inference of tumour segmentation can be performed with high accuracy. Additionally, we collect a private skin cancer dataset named BSS, which contains fine and coarse annotations for three types of cancer. To facilitate reproducible performance comparison, experts are also invited to label coarse annotations on the public liver cancer dataset PAIP2019. On the BSS dataset, our DCTGN-CAM segmentation outperforms the state-of-the-art methods and achieves 76.68 % IOU and 86.69 % Dice scores on the sketch-based tumour segmentation task. On the PAIP2019 dataset, our method achieves a Dice gain of 8.37 % compared with U-Net as the baseline network.

Covalent PROTAC design method based on a sulfonyl pyridone probe.

Covalent proteolysis-targeting chimeras (PROTACs) offer enhanced selectivity, prolonged action, and increased efficacy against challenging target proteins. The conventional approach relies on covalent ligands, but our study presents an innovative method employing an N-sulfonyl pyridone warhead to selectively target tyrosine (Tyr) residues. The von Hippel-Lindau (VHL) moiety is transferred from the warhead to the exposed Tyr, allowing us to design a STING degrader (DC50 0.53 µM, Dmax 56.65%). This approach showcases the potential of nucleophilic amino acid labeling probes, particularly for proteins lacking easily accessible cysteine residues, opening new possibilities for covalent PROTAC design and targeted protein degradation therapies.

Low H3K27me3 deposition at CYP82E4 determines the nicotinic conversion rate in Nicotiana tabacum.

Nicotine conversion is the process by which nornicotine is synthesized from nicotine. The capacity of a plant to carry out this process is represented by the nicotine conversion rate (NCR), which is defined as the percentage of nornicotine content out of the total nicotine + nornicotine content. Nicotine conversion in tobacco is mediated by CYP82E4. Although there are cultivar-specific differences in NCR, these do not correspond to differences in the CYP82E4 promoter or gene body sequences, and little is known about the underlying regulatory mechanism. Here, we found that histone H3 Lysine 27 trimethylation (H3K27me3) was involved in CYP82E4 expression, functioning as a transcriptional repressor. Compared to a high-NCR near-isogenic line, a low-NCR cultivar showed increased levels of the repressive histone modification markers H3K27me3 and H3K9me3 at CYP82E4. Comparison of histone markers between several cultivars with varying NCRs showed that H3K27me3 and H3K9me3 levels were significantly associated with cultivar-specific differences in NCR. Treatment with the H3K27me3 demethylase inhibitor GSK-J4 increased total H3K27me3 levels and enriched H3K27me3 at the CYP82E4 locus; the increased levels of H3K27me3 further inhibited CYP82E4 expression. Knocking out E(z), an indispensable gene for H3K27me3 formation, decreased H3K27me3 levels at CYP82E4, leading to a more than three-fold increase in CYP82E4 expression. Changes in CYP82E4 expression during leaf senescence and chilling stress were also strongly correlated with H3K27me3 levels. These findings reveal a strong correlation between CYP82E4 expression and histone modifications, and demonstrate an instance of histone-mediated alkaloid regulation for the first time.

The advance of the third­generation EGFR­TKI in the treatment of non­small cell lung cancer (Review).

Lung cancer is currently the second most common type of cancer with the second incidence rate and the first mortality rate worldwide. Non­small cell lung cancer (NSCLC) accounts for ~85% of the total number of cases of lung cancers. Concerning the treatment of NSCLC, targeted therapy has become a research hotspot in recent years because of its favorable efficacy, high selectivity and minimal adverse reactions. Among the drugs used in targeted therapy, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the most common and are categorized into four generations. The use of first and second­generation drugs leads to drug resistance within 8­14 months. This resistance is primarily caused by the T790M mutation, which is the most observed mechanism. A third­generation drug has been developed to address this issue and a fourth­generation drug is expected to overcome multiple resistance mechanisms, including third­generation drug resistance. However, the fourth­generation drug has not been launched yet. At present, multiple third­generation targeted drugs have been launched globally, with three being launched in China and several being at research and clinical trial stages. The present article provides a review of the development process, mechanism of action and clinical trials of the third­generation EGFR­TKIs, aiming to provide some reference and suggestions for the clinical treatment of NSCLC and scientific research on third­generation targeted drugs.

TORCH-R trial protocol: hypofractionated radiotherapy combined with chemotherapy and toripalimab for locally recurrent rectal cancer: a prospective, single-arm, two-cohort, phase II trial.

For patients with locally recurrent rectal cancer (LRRC), the response rate to chemoradiotherapy is 40%-50%. Additionally, only approximately 40%-50% of patients with recurrent rectal cancer are able to undergo R0 resection. Recent studies in locally advanced rectal cancer (LARC) have shown promising synergistic effects when combining immunotherapy (PD-1/PD-L1 antibodies) with neoadjuvant chemoradiotherapy (nCRT). Therefore, incorporating immunotherapy into the treatment regimen for LRRC patients has the potential to further improve response rates and prognosis. To investigate this, the TORCH-R trial was conducted. This prospective, single-arm, two-cohort, phase II trial focuses on the use of hypofractionated radiotherapy, chemotherapy, and immunotherapy in LRRC patients without or with oligometastases. The trial will include two cohorts: cohort A consists of rectal cancer patients who are treatment-naive for local recurrence, and cohort B includes patients with progressive disease after first-line chemotherapy. Cohort A and cohort B patients will receive 25-40 Gy/5 Fx irradiation or 15-30 Gy/5 Fx reirradiation for pelvic recurrence, respectively. Subsequently, they will undergo 18 weeks of chemotherapy, toripalimab, and stereotactic ablative radiotherapy (SABR) for all metastatic lesions between chemoimmunotherapy cycles. Decisions regarding follow-up of complete response (CR), radical surgery, sustained treatment of non-resection, or exiting the trial are made by a multidisciplinary team (MDT). The primary endpoint of this study is the local objective response rate (ORR). The secondary endpoints include the extrapelvic response rate, duration of response, local recurrence R0 resection rate, progression-free survival (PFS), overall survival (OS), and safety and tolerability. Notably, this trial represents the first clinical exploration of inducing hypofractionated radiotherapy, chemotherapy, and immunotherapy in LRRC patients. Clinical trial registration: https://clinicaltrials.gov/study/NCT05628038, identifier NCT05628038.

IL-17A promotes the progression of Alzheimer's disease in APP/PS1 mice.

BACKGROUND: Alzheimer's disease (AD), which is the most common cause of dementia in elderly individuals, is a progressive neurodegenerative disorder. Neuroinflammation, which is an immune response that is activated by glial cells in the central nervous system, plays an important role in neurodegenerative diseases. Many studies have shown that interleukin-17A (IL-17A) plays an important role in AD, but research on the pathological effects of IL-17A on AD is limited. METHODS: We report the effect of IL-17A on AD progression in APPswe/PS1dE9 (APP/PS1) mice, which are the most widely used AD model mice. The BV2 cell line, which is a microglial cell line derived from C57/BL6 mice, was used to establish a cell model to verify the role of IL-17A in neuroinflammation at the cellular level. The HT22 hippocampal neuronal cell line was used to investigate the relationship between IL-17A and Aß deposition. RESULTS: In this research, we found that IL-17A promotes the progression of AD in the APP/PS1 mouse model. The role of IL-17A in neuroinflammation is related to tumour necrosis factor (TNF)-α. Circulating IL-17A stimulates the secretion of TNF-α by microglia through the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signalling pathway, thus exacerbating neuroinflammation. In addition, intraperitoneal injection of IL-17A antibody (IL17Ab) significantly improved the cognitive function of APP/PS1 mice. CONCLUSIONS: IL-17A increased TNF-α levels in the brain and exacerbated neuroinflammation through the TLR4/NF-κB signalling pathway and microglial activation in APP/PS1 mice. Moreover, IL-17A promoted the progression of AD by enhancing neuroinflammation, inhibiting microglial phagocytosis, and promoting the deposition of ß-amyloid 42 in AD model mice.

Covalent Peptide LSD1 Inhibitor Specifically Recognizes Cys360 in the Enzyme-Active Region.

Lysine-specific demethylase 1 (LSD1) is a promising therapeutic target, especially in cancer treatment. Despite several LSD1 inhibitors being discovered for the cofactor pocket, none are FDA-approved. We aimed to develop stabilized peptides for irreversible LSD1 binding, focusing on unique cysteine residue Cys360 in LSD1 and SNAIL1. We created LSD1 C360-targeting peptides, like cyclic peptide S9-CMC1, using our Cysteine-Methionine cyclization strategy. S9-CMC1 effectively inhibited LSD1 at the protein level, as confirmed by MS analysis showing covalent bonding to Cys360. In cells, S9-CMC1 inhibited LSD1 activity, increasing H3K4me1 and H3K4me2 levels, leading to G1 cell cycle arrest and apoptosis and inhibiting cell proliferation. Remarkably, S9-CMC1 showed therapeutic potential in A549 xenograft animal models, regulating LSD1 activity and significantly inhibiting tumor growth with minimal organ damage. These findings suggest LSD1 C360 as a promising site for covalent LSD1 inhibitors' development.