Novel molecular typing reveals the risk of recurrence in patients with early-stage papillary thyroid cancer.

BACKGROUND: Papillary thyroid cancer (PTC) is an indolent disease with a favorable prognosis but characterized by a high recurrence rate. We aimed to improve precise stratification of recurrence risk in PTC patients with early stage using multi-gene signatures. PATIENTS AND METHODS: The present study was performed using data from The Cancer Genome Atlas (TCGA) and multi-center datasets. Unsupervised consensus clustering was used to obtain the optimal molecular subtypes and least absolute shrinkage and selection operator (LASSO) analysis was performed to identify potential genes for the construction of recurrence signature. Kaplan-Meier survival analysis and the log-rank test was used to detect survival differences. Harrells concordance index (C-index) was used to assess the performance of the DNA damage repair (DDR) recurrence signature. RESULTS: Through screening 8 candidate gene sets, the entire cohort was successfully stratified into two recurrence-related molecular subtypes based on DDR genes: DDR-high subtype and DDR-low subtype. The recurrence rate of DDR-high subtype was significantly lower than DDR-low subtype [HR = 0.288 (95%CI, 0.084-0.986), P = 0.047]. Further, a two-gene DDR recurrence signature was constructed, including PER1 and EME2. The high-risk group showed a significantly worse recurrence-free survival (RFS) than the low-risk group [HR = 10.647 (95%CI, 1.363-83.197), P = 0.024]. The multi-center data demonstrated that proportion of patients with low expression of PER1 and EME2 was higher in the recurrence group than those in the non-recurrence group. CONCLUSIONS: These findings could help accurately and reliably identify PTC patients with high risk of recurrence so that they could receive more radical and aggressive treatment strategies and more rigorous surveillance practices.

CircTMEM165 facilitates endothelial repair by modulating mitochondrial fission via miR-192/SCP2 in vitro and in vivo.

Constitutive explorations indicate a correlation between circular RNAs (circRNAs) and cardiovascular diseases. However, the involvement of circRNAs in endothelial recuperation and in-stent restenosis (ISR) remains underexplored. CircTMEM165 has first been reported to be highly expressed in hypoxic human umbilical vein endothelial cells (HUVECs). Here, we identified that circTMEM165 was downregulated in ISR patients, inversely correlating with ISR severity. Functionally, circTMEM165 was found to be abundant in endothelial cells, inhibiting inflammation, and adhesion. Particularly, we first observed that circTMEM165 could alleviate HUVECs apoptosis and mitochondrial fission induced by lipopolysaccharide (LPS). Mechanistically, circTMEM165, as a miR-192-3p sponge, enhancing SCP2 expression, which serves as a critical regulator of HUVECs biological functions. Moreover, in vivo, circTMEM165 attenuated intimal hyperplasia and facilitated repair following classic rat carotid artery balloon injury model. These findings investigated the circTMEM165-miR-192-3p-SCP2 axis as a critical determinant of endothelial health and a potential biomarker and therapeutic target for vascular disorders.

A Wolfram-like syndrome family: Case report.

BACKGROUND: Wolfram-like syndrome (WFLS) is an autosomal dominant inherited disease characterized by a single heterozygous pathogenic variant in the WFS1 gene. Its clinical presentation is similar to autosomal recessive Wolfram syndrome. CASE PRESENTATION: We reported a case of a 10-year-old boy and his family members who initially experienced hearing impairment (HI), followed by optic atrophy. Genetic testing revealed the presence of a WFS1 variant (chr4-6302385 exon8 NM_006005.3: c.2590G > A, p. Glu864Lys). CONCLUSION: Wolfram-like syndrome, a rare neurodegenerative genetic disorder, manifested as deafness, optic atrophy, and diabetes mellitus. There hasn't been a definite treatment yet. Early identification of the variant in the WFS1 gene is beneficial for genetic counseling.

Photocatalytic aerobic oxidation of C(sp3)-H bonds.

In modern industries, the aerobic oxidation of C(sp3)-H bonds to achieve the value-added conversion of hydrocarbons requires high temperatures and pressures, which significantly increases energy consumption and capital investment. The development of a light-driven strategy, even under natural sunlight and ambient air, is therefore of great significance. Here we develop a series of hetero-motif molecular junction photocatalysts containing two bifunctional motifs. With these materials, the reduction of O2 and oxidation of C(sp3)-H bonds can be effectively accomplished, thus realizing efficient aerobic oxidation of C(sp3)-H bonds in e.g., toluene and ethylbenzene. Especially for ethylbenzene oxidation reactions, excellent catalytic capacity (861 mmol g cat-1) is observed. In addition to the direct oxidation of C(sp3)-H bonds, CeBTTD-A can also be applied to other types of aerobic oxidation reactions highlighting their potential for industrial applications.

Using Deep Learning to Segment Retinal Vascular Leakage and Occlusion in Retinal Vasculitis.

PURPOSE: Retinal vasculitis (RV) is characterised by retinal vascular leakage, occlusion or both on fluorescein angiography (FA). There is no standard scheme available to segment RV features. We aimed to develop a deep learning model to segment both vascular leakage and occlusion in RV. METHODS: Four hundred and sixty-three FA images from 82 patients with retinal vasculitis were used to develop a deep learning model, in 60:20:20 ratio for training:validation:testing. Parameters, including deep learning architectures (DeeplabV3+, UNet++ and UNet), were altered to find the best binary segmentation model separately for retinal vascular leakage and occlusion, using a Dice score to determine the reliability of each model. RESULTS: Our best model for vascular leakage had a Dice score of 0.6279 (95% confidence interval (CI) 0.5584-0.6974). For occlusion, the best model achieved a Dice score of 0.6992 (95% CI 0.6109-0.7874). CONCLUSION: Our RV segmentation models could perform reliable segmentation for retinal vascular leakage and occlusion in FAs of RV patients.

Homochiral Nanopropeller via Chiral Active Surface Growth.

Under the control of chiral ligand glutathione and in the presence of hexadecyltrimethylammonium bromide, Au deposition on Au seeds is known to give chiral nanostructures. We have previously shown that the protruding chiral patterns, as opposed to flat facets, are likely caused by active surface growth, where nonuniform ligand coverage could be responsible for the focused growth at a few active sites. By pushing the limit of such a growth mode, here, we use decahedral seeds to prepare homochiral nanopropellers with intricate patterns of deep valleys and protruding ridges. Control experiments show that the focused growth depends on the rates of Au deposition by changing either the seed concentration or the reductant concentration, consistent with the proposed mechanism. The dynamic growth competition between the ligand-deficient active sites and the ligand-rich surfaces gradually focuses the growth onto a few active sites, causing the expansion of grooves, squeezing of steep ridges, and a surprising 36° rotation of the pentagonal outline. The imbalanced deposition on the prochiral slopes is responsible for the tilted grooves, the twisted walls, and thus the well-separated and distorted blades, which become the origin of the chiroptical responses.

Cornuside inhibits glucose-induced proliferation and inflammatory response of mesangial cells.

Cornuside is a secoiridoid glucoside compound extracted from the fruits of Cornus officinalis. Cornuside has immunomodulatory and anti-inflammatory properties; however, its potential therapeutic effects on diabetic nephropathy (DN) have not been completely explored. In this study, we established an in vitro model of DN through treating mesangial cells (MMCs) with glucose. MMCs were then treated with different concentrations of cornuside (0, 5, 10, and 30 µM). Cell viability was determined using cell counting kit-8 and 5-ethynyl-2'-deoxyuridine assays. Levels of proinflammatory cytokines, including interleukin (IL)-6, tumor necrosis factor-α, and IL-1ß were examined using enzyme-linked immunosorbent assay. Reverse transcription quantitative real-time polymerase chain reaction and Western blotting were performed to detect the expression of AKT and nuclear factor-kappa B (NF-κB)-associated genes. We found that cornuside treatment significantly reduced glucose-induced increase in MMC viability and expression of pro-inflammatory cytokines. Moreover, cornuside inhibited glucose-induced phosphorylation of AKT and NF-κB inhibitor alpha, decreased the expression of proliferating cell nuclear antigen and cyclin D1, and increased the expression of p21. Our study indicates that the anti-inflammatory properties of cornuside in DN are due to AKT and NF-κB inactivation in MMCs.

Conditional loss of Ube3d in the retinal pigment epithelium accelerates age-associated alterations in the retina of mice.

Several studies have suggested a correlation between the ubiquitin-proteasome system (UPS) and age-related macular degeneration (AMD), with its phenotypic severity ranging from mild visual impairment to blindness, but the mechanism for UPS dysfunction contributing to disease progression is unclear. In this study, we investigated the role of ubiquitin protein ligase E3D (UBE3D) in aging and degeneration in mouse retina. Conditional knockout of Ube3d in the retinal pigment epithelium (RPE) of mice led to progressive and irregular fundus lesions, attenuation of the retinal vascular system, and age-associated deterioration of rod and cone responses. Simultaneously, RPE-specific Ube3d knockout mice also presented morphological changes similar to the histopathological characteristics of human AMD, in which a defective UPS led to RPE abnormalities such as phagocytosis or degradation of metabolites, the interaction with photoreceptor outer segment, and the transport of nutrients or waste products with choroidal capillaries via Bruch's membrane. Moreover, conditional loss of Ube3d resulted in aberrant molecular characterizations associated with the autophagy-lysosomal pathway, oxidative stress damage, and cell-cycle regulation, which are implicated in AMD pathology. Thus, our findings strengthen and expand the impact of UPS dysfunction on retinal pathophysiology during aging, indicating that genetic Ube3d deficiency in the RPE could lead to the abnormal formation of pigment deposits and secondary fundus alterations. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Mean-square consensus of a semi-Markov jump multi-agent system based on event-triggered stochastic sampling.

This paper focuses on achieving leader-follower mean square consensus in semi-Markov jump multi-agent systems. To effectively reduce communication costs and control updates, we propose an event-triggered protocol based on stochastic sampling. The stochastic sampling interval randomly switches between finite given values, while the event-triggered function depends on the stochastic sampled data from neighboring agents. Using the event-triggered strategy, we present sufficient conditions to ensure mean square consensus. Finally, we provide a numerical example demonstrating the effectiveness of the theoretical results.

Secondary succession of shrub-herb communities in the hilly area of Taihang Mountain.

Introduction: To document the successional processes of shrub-herb communities after large-scale human disturbance, and understand how changing environmental conditions affect species replacement in semi-humid hilly areas. Methods: Utilizing the established permanent plots in the hilly area of Taihang Mountain, we evaluated temporal patterns of vegetation and soil following grass-to-shrub succession. Results and Discussion: Along secondary succession, Vitex negundo var. heterophylla gradually dominated in dry sunny slope and shared the dominance with Leptodermis oblonga in shaded slope. Herbaceous dominant species in shrub-herb communities switched from Themeda japonica, Bothriochloa ischaemum, Artemisia sacrorum, and Cleistogenes chinensis in 1986 census to B. ischaemum and A. sacrorum in 2008 census, but herb was no longer dominant in 2020 census. As succession progresses, species dominance increased while richness decreased generally, and herb cover and aboveground biomass decreased, whereas shrub height, cover, and aboveground biomass increased significantly. Soil organic matter (SOM), total nitrogen (TN), total phosphorus (TP), and total potassium (TK) in topsoil increased significantly while pH declined by 1.04 units over the past three decades. Plant communities transitioned from perennial herbs to shrub-herb and then shrub communities, and V. negundo var. heterophylla dominated in the succession of shrub-herb communities. Climate and soil properties, combined with plant attributes, together drive post-disturbance secondary succession. From a management perspective, the tight coupling between vegetation and soil under local climatic conditions should be considered to improve the fragile ecosystem in the hilly area of Taihang Mountain.

Intraoperative slow-release dexamethasone intravitreal implant (Ozurdex) in epiretinal membrane peeling surgery: a prospective randomized controlled trial.

Purpose: This study aimed to determine the efficacy of the dexamethasone (DEX) intravitreal implant for the regression of macular edema and the improvement of best-corrected visual acuity (BCVA) after the removal of idiopathic epiretinal membrane (ERM). Methods: This prospective randomized controlled trial recruited 81 patients with idiopathic ERM. These patients all underwent 25-gauge pars plana vitrectomy combined with ERM and internal limiting membrane peeling surgery. Among them, 41 eyes in the DEX group received additional DEX implants and 40 in the non-DEX group did not. Outcomes including central retinal thickness (CRT), BCVA, and intraocular pressure were measured 1 and 3 months after surgery. Results: The DEX group had thinner CRTs compared to the non-DEX group at 1 month postoperatively (p <0.05), but did not differ significantly at the 1-week and 3-month follow-up visits (p = 0.109 and p = 0.417, respectively). There were no statistical differences with respect to BCVA (p = 0.499, 0.309, 0.246, and 0.517, respectively) and intraocular pressure (p = 0.556, 0.639, 0.741, and 0.517, respectively) between the two groups at each point of follow-up visits. Conclusion: DEX accelerated the reduction of CRT at 1 month after surgery. However, no evidence of further anatomical (CRT) or functional (BCVA) benefits using DEX was observed at 3 months. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT05416827.

Sulfur dioxide-releasing polymeric micelles based on modified hyaluronic acid for combined cancer therapy.

In this study, an amphiphilic polymer mPEG-HA(SA)-DNs was designed and synthesized to fabricate a multifunctional micellar system to enhance the therapeutic efficacy and reduce the toxic effect of paclitaxel (PTX). The polymer was prepared by introducing mPEG, stearic acid (SA) and 2,4-dinitrobenzenesulfonic acid (DNs) to the backbone of hyaluronic acid (HA). With above modifications, the fabricated micelles could encapsulate PTX in the core with high drug loading. The optimized PTX-loaded micelles had a mean size of 158.3 nm. Upon the effect of mPEG, the mPEG-HA(SA)-DNs micelles reduced the non-specific protein adsorption. In vitro drug release study revealed the excellent glutathione (GSH)-triggered PTX release behavior of the micelles. Moreover, GSH could trigger the detachment of DNs segment from mPEG-HA(SA)-DNs, and result in the release of SO2. In vitro and in vivo antitumor efficacy studies demonstrated that the PTX-loaded mPEG-HA(SA)-DNs micelles exhibited outstanding tumor suppression effect. The micelles would be potential carriers for combination cancer therapy by SO2 and PTX.

Functions and mechanisms of protein lysine butyrylation (Kbu): Therapeutic implications in human diseases.

Post-translational modifications (PTM) are covalent modifications of proteins or peptides caused by proteolytic cleavage or the attachment of moieties to one or more amino acids. PTMs play essential roles in biological function and regulation and have been linked with several diseases. Modifications of protein acylation (Kac), a type of PTM, are known to induce epigenetic regulatory processes that promote various diseases. Thus, an increasing number of studies focusing on acylation modifications are being undertaken. Butyrylation (Kbu) is a new acylation process found in animals and plants. Kbu has been recently linked to the onset and progression of several diseases, such as cancer, cardiovascular diseases, diabetes, and vascular dementia. Moreover, the mode of action of certain drugs used in the treatment of lymphoma and colon cancer is based on the regulation of butyrylation levels, suggesting that butyrylation may play a therapeutic role in these diseases. In addition, butyrylation is also commonly involved in rice gene expression and thus plays an important role in the growth, development, and metabolism of rice. The tools and analytical methods that could be utilized for the prediction and detection of lysine butyrylation have also been investigated. This study reviews the potential role of histone Kbu, as well as the mechanisms underlying this process. It also summarizes various enzymes and analytical methods associated with Kbu, with the goal of providing new insights into the role of Kbu in gene regulation and diseases.

Variants in the SOX9 transactivation middle domain induce axial skeleton dysplasia and scoliosis.

SOX9 is an essential transcriptional regulator of cartilage development and homeostasis. In humans, dysregulation of SOX9 is associated with a wide spectrum of skeletal disorders, including campomelic and acampomelic dysplasia, and scoliosis. The mechanism of how SOX9 variants contribute to the spectrum of axial skeletal disorders is not well understood. Here, we report four novel pathogenic variants of SOX9 identified in a large cohort of patients with congenital vertebral malformations. Three of these heterozygous variants are in the HMG and DIM domains, and for the first time, we report a pathogenic variant within the transactivation middle (TAM) domain of SOX9 . Probands with these variants exhibit variable skeletal dysplasia, ranging from isolated vertebral malformation to acampomelic dysplasia. We also generated a Sox9 hypomorphic mutant mouse model bearing a microdeletion within the TAM domain ( Sox9 Asp272del ). We demonstrated that disturbance of the TAM domain with missense mutation or microdeletion results in reduced protein stability but does not affect the transcriptional activity of SOX9. Homozygous Sox9 Asp272del mice exhibited axial skeletal dysplasia including kinked tails, ribcage anomalies, and scoliosis, recapitulating phenotypes observed in human, while heterozygous mutants display a milder phenotype. Analysis of primary chondrocytes and the intervertebral discs in Sox9 Asp272del mutant mice revealed dysregulation of a panel of genes with major contributions of the extracellular matrix, angiogenesis, and ossification-related processes. In summary, our work identified the first pathologic variant of SOX9 within the TAM domain and demonstrated that this variant is associated with reduced SOX9 protein stability. Our finding suggests that reduced SOX9 stability caused by variants in the TAM domain may be responsible for the milder forms of axial skeleton dysplasia in humans.

Quadristerols A-G: Seven undescribed ergosterols from Aspergillus quadrilineata.

Quadristerols A-G, seven undescribed ergosterols, were obtained from Aspergillus quadrilineata. Their structures and absolute configurations were determined based on HRESIMS, NMR, quantum-chemical calculations, and single-crystal X-ray diffraction analyses. Quadristerols A-G featured ergosterol skeletons with different attachments; quadristerols A-C were three diastereoisomers possessing a 2-hydroxy-propionyloxy group at C-6, and quadristerols D-G were two pairs of epimers with a 2,3-butanediol group at C-6. All of these compounds were evaluated for their immunosuppressive activities in vitro. Quadristerols B and C showed excellent inhibitory effects against concanavalin A-induced T lymphocyte proliferation with IC50 values of 7.43 and 3.95 µM, respectively, and quadristerols D and E strongly inhibited lipopolysaccharide-induced B lymphocyte proliferation with IC50 values of 10.96 and 7.47 µM, respectively.

The impact of artificial intelligence on retinal disease management: Vision Academy retinal expert consensus.

PURPOSE OF REVIEW: The aim of this review is to define the "state-of-the-art" in artificial intelligence (AI)-enabled devices that support the management of retinal conditions and to provide Vision Academy recommendations on the topic. RECENT FINDINGS: Most of the AI models described in the literature have not been approved for disease management purposes by regulatory authorities. These new technologies are promising as they may be able to provide personalized treatments as well as a personalized risk score for various retinal diseases. However, several issues still need to be addressed, such as the lack of a common regulatory pathway and a lack of clarity regarding the applicability of AI-enabled medical devices in different populations. SUMMARY: It is likely that current clinical practice will need to change following the application of AI-enabled medical devices. These devices are likely to have an impact on the management of retinal disease. However, a consensus needs to be reached to ensure they are safe and effective for the overall population.

Current status and practical considerations of artificial intelligence use in screening and diagnosing retinal diseases: Vision Academy retinal expert consensus.

PURPOSE OF REVIEW: The application of artificial intelligence (AI) technologies in screening and diagnosing retinal diseases may play an important role in telemedicine and has potential to shape modern healthcare ecosystems, including within ophthalmology. RECENT FINDINGS: In this article, we examine the latest publications relevant to AI in retinal disease and discuss the currently available algorithms. We summarize four key requirements underlining the successful application of AI algorithms in real-world practice: processing massive data; practicability of an AI model in ophthalmology; policy compliance and the regulatory environment; and balancing profit and cost when developing and maintaining AI models. SUMMARY: The Vision Academy recognizes the advantages and disadvantages of AI-based technologies and gives insightful recommendations for future directions.

UVEAL EFFUSION ASSOCIATED WITH LOCALIZED SCLERODERMA BECAUSE OF SCLERAL FIBROSIS.

BACKGROUND/PURPOSE: To report a case of uveal effusion associated with localized scleroderma because of scleral collagen fibrosis. Partial-thickness sclerectomy treatment was successful in acquiring the resolution of the uveal effusion. METHODS: Case report. RESULTS: A 44-year-old Chinese woman with known localized scleroderma visited the retinal clinic complaining of insidious onset blurring of vision in both eyes for 8 months. The best-corrected visual acuity was 20/200. Ophthalmoscopy revealed apparent inferior bullous serous retinal detachments in the right eye. Optical coherence tomography showed subretinal fluid and folds of the retinal pigment epithelium layer in both eyes. B-scan ultrasonographic image of the right eye confirmed a 360-degree serous retinal detachment in the right eye accompanied with increased thickness of the ocular wall. Ultrasound biomicroscopy of the anterior segment detected a shallow ciliary body detachment in the right eye. Fluorescein angiography and indocyanine green angiography demonstrated the leopard-spot pattern in all phases. Partial-thickness sclerectomy treatment was successful in acquiring the resolution of the uveal effusion. Histopathologic examinations of the sclera flaps revealed scleral collagen fibrosis. CONCLUSION: This clinicopathologic report first describes a patient with localized scleroderma and scleral collagen fibrosis, resulting in uveal effusion that responded to partial-thickness sclerectomy.

Chinese Guideline on the Management of Polypoidal Choroidal Vasculopathy (2022).

Background In mainland China, patients with neovascular age-related macular degeneration (nAMD) have approximately an 40% prevalence of polypoidal choroidal vasculopathy (PCV). This disease leads to recurrent retinal pigment epithelium detachment (PED), extensive subretinal or vitreous hemorrhages, and severe vision loss. China has introduced various treatment modalities in the past years and gained comprehensive experience in treating PCV.Methods A total of 14 retinal specialists nationwide with expertise in PCV were empaneled to prioritize six questions and address their corresponding outcomes, regarding opinions on inactive PCV, choices of anti-vascular endothelial growth factor (anti-VEGF) monotherapy, photodynamic therapy (PDT) monotherapy or combined therapy, patients with persistent subretinal fluid (SRF) or intraretinal fluid (IRF) after loading dose anti-VEGF, and patients with massive subretinal hemorrhage. An evidence synthesis team conducted systematic reviews, which informed the recommendations that address these questions. This guideline used the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach to assess the certainty of evidence and grade the strengths of recommendations. Results The panel proposed the following six conditional recommendations regarding treatment choices. (1) For patients with inactive PCV, we suggest observation over treatment. (2) For treatment-na?ve PCV patients, we suggest either anti-VEGF monotherapy or combined anti-VEGF and PDT rather than PDT monotherapy. (3) For patients with PCV who plan to initiate combined anti-VEGF and PDT treatment, we suggest later/rescue PDT over initiate PDT. (4) For PCV patients who plan to initiate anti-VEGF monotherapy, we suggest the treat and extend (T&E) regimen rather than the pro re nata (PRN) regimen following three monthly loading doses. (5) For patients with persistent SRF or IRF on optical coherence tomography (OCT) after three monthly anti-VEGF treatments, we suggest proceeding with anti-VEGF treatment rather than observation. (6) For PCV patients with massive subretinal hemorrhage (equal to or more than four optic disc areas) involving the central macula, we suggest surgery (vitrectomy in combination with tissue-plasminogen activator (tPA) intraocular injection and gas tamponade) rather than anti-VEGF monotherapy. Conclusions Six evidence-based recommendations support optimal care for PCV patients' management.

Synthesis and Antineoplastic Activity of a Dimer, Spiroindolinone Pyrrolidinecarboxamide.

The mutation or function loss of tumour suppressor p53 plays an important role in abnormal cell proliferation and cancer generation. Murine Double Minute 2 (MDM2) is one of the key negative regulators of p53. p53 reactivation by inhibiting MDM2-p53 interaction represents a promising therapeutic option in cancer treatment. Here, to develop more effective MDM2 inhibitors with lower off-target toxicities, we synthesized a dimer, spiroindolinone pyrrolidinecarboxamide XR-4, with potent MDM2-p53 inhibition activity. Western blotting and qRT-PCR were performed to detect the impact of XR-4 on MDM2 and p53 protein levels and p53 downstream target gene levels in different cancers. Cancer cell proliferation inhibition and clonogenic activity were also investigated via the CCK8 assay and colony formation assay. A subcutaneous 22Rv1-derived xenografts mice model was used to investigate the in vivo anti-tumour activity of XR-4. The results reveal that XR-4 can induce wild-type p53 accumulation in cancer cells, upregulate the levels of the p53 target genes p21 and PUMA levels, and then inhibit cancer cell proliferation and induce cell apoptosis. XR-4 can also act as a homo-PROTAC that induces MDM2 protein degradation. Meanwhile, the in vivo study results show that XR-4 possesses potent antitumour efficacy and a favourable safety property. In summary, XR-4 is an interesting spiroindolinone pyrrolidinecarboxamide-derivative dimer with effective p53 activation activity and a cancer inhibition ability.