Publications by authors named "Renbing Jia"

113 Publications

Eye-preserving therapies for advanced retinoblastoma: a multicenter cohort of 1678 patients in China.

Ophthalmology 2021 Sep 15. Epub 2021 Sep 15.

Department of Ophthalmology, Hainan Eye Hospital and Key laboratory of ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University.

Purpose: Multiple eye-preserving treatments have been widely used in China for the last 15 years, however, controversy remains on using eye-preserving therapies for advanced retinoblastoma (The International Intraocular Retinoblastoma Classification: groups D and E). This study attempts to estimate the impact of eye-preserving therapies for the long-term prognosis of advanced retinoblastoma with regard to overall survival and ocular salvage.

Design: A retrospective cohort study covering all 31 provinces (38 retinoblastoma treating centers) of Chinese mainland.

Participants: A total of 1678 patients diagnosed with groups D or E retinoblastoma from January 2006 to May 2016.

Methods: Medical charts review was performed. The patients were divided into primary enucleation and eye-preserving groups, and they were followed up for survival status. The impact of initial treatment on survival was evaluated by Cox analyses.

Main Outcome Measures: Overall survival and final eye-preservation rate.

Results: After a median follow-up period of 43.9 months, 196 (12%) patients died, and the 5-year overall survival was 86%. In total, the eyeball preservation rate was 48%. In this cohort, 1172 (70%) patients had unilateral retinoblastoma, whereas 506 (30%) were bilateral. For unilateral patients, 570 (49%) eyes had primary enucleation, and 602 (51%) patients had eye-preserving therapies initially. During the follow-up (median: 45.6 months), 59 (10%) patients from primary enucleation group and 56 (9.3%) patients from eye-preserving group died. Multivariate Cox analyses indicated no significant difference in overall survival between the two groups (HR=1.25; 95%CI:0.85-1.84; p=0.250). For bilateral patients, only 95 (19%) eyes had primary enucleation, and 411 (81%) patients had eye-preserving therapies initially. During the follow-up (median: 40.1 months), 12 (13%) patients from primary enucleation group and 69 (17%) patients from eye-preserving group died. For bilateral retinoblastoma with the worse eye of group E, patients had primary enucleation exhibited better overall survival (HR=2.35; 95%CI:1.10-5.01; p=0.027), however, this survival advantage was not evident until passing 22.6 months after initial diagnosis.

Conclusion: Eye-preserving therapies have been widely used for advanced retinoblastoma in China. Bilateral patients with the worse eye of group E initially underwent eye-preserving therapies exhibited a worse overall survival. The choice of primary treatment for advanced retinoblastoma should be carefully weighed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ophtha.2021.09.002DOI Listing
September 2021

Cellular heterogeneity and immune microenvironment revealed by single-cell transcriptome in venous malformation and cavernous venous malformation.

J Mol Cell Cardiol 2021 Sep 15. Epub 2021 Sep 15.

Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address:

Venous malformation (VM) and cavernous venous malformation (CVM) are two types of vascular malformations. Even if the two diseases are similar in appearance and imaging, the distinct cellular components and signaling pathways between them might help distinguish the two from a molecular perspective. Here, we performed single-cell profiling of 35,245 cells from two VM samples and three CVM samples, with a focus on endothelial cells (ECs), smooth muscle cells (SMCs) and immune microenvironment (IME). Clustering analysis based on differential gene expression unveiled 11 specific cell types, and determined CVM had more SMCs. Re-clustering of ECs and SMCs indicated CVM was dominated by arterial components, while VM is dominated by venous components. Gene set variation analysis suggested the activation of inflammation-related pathways in VM ECs, and upregulation of myogenesis pathway in CVM SMCs. In IME analysis, immune cells were identified to accounted for nearly 30% of the total cell number, including macrophages, monocytes, NK cells, T cells and B cells. Notably, more macrophages and monocytes were discovered in VM, indicating innate immune responses might be more closely related to VM pathogenesis. In addition, angiogenesis pathway was highlighted among the significant pathways of macrophages & monocytes between CVM and VM. In VM, VEGFA was highly expressed in macrophages & monocytes, while its receptors were all abundantly present in ECs. The close interaction of VEGFA on macrophages with its receptors on ECs was also predicted by CellPhoneDB analysis. Our results document cellular composition, significant pathways, and critical IME in CVM and VM development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yjmcc.2021.09.004DOI Listing
September 2021

Intralesional diode laser pretreatment facilitates surgery for orbital venous malformations: initial experience with 23 consecutive patients.

Graefes Arch Clin Exp Ophthalmol 2021 Aug 11. Epub 2021 Aug 11.

Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.

Purpose: This study aims to evaluate the efficacy and safety of intralesional diode laser pretreatment for facilitating surgery for orbital venous malformations (OVMs).

Methods: This is a retrospective, non-comparative, interventional cohort involving 23 consecutive OVM patients undergoing intralesional laser pretreatment followed by surgical excision. The main outcome measures included volumetric changes, exophthalmometry, cosmesis, and symptom scores as well as treatment-related adverse events.

Results: Following intralesional diode laser, the mean volume dropped significantly from 2366 ± 1887 to 129 ± 119 mm (t = 5.716; p < 0.001). After a single treatment session, a mean 90 ± 13% volume shrinkage was achieved in all 23 OVM. The mean Hertel exophthalmometry decreased significantly from 14 ± 3 to 13 ± 1 mm (t = 2.515; P < 0.02). The resolution of periocular dyschromasia and swelling were evident in 20 patients (87%). Symptom scores improved significantly from 6.5 ± 1.4 (very intense discomfort or effect on daily living) to 1.2 ± 1.0 (very mild discomfort or effect on daily living; p < 0.001). Short-term bruises and swelling were reported in 20 patients (87%).

Conclusion: Intralesional laser pretreatment is effective to facilitate surgery especially for the deep involving orbital venous malformations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00417-021-05272-3DOI Listing
August 2021

A novel standardized distraction test to evaluate lower eyelid tension using three-dimensional stereophotogrammetry.

Quant Imaging Med Surg 2021 Aug;11(8):3735-3748

Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cologne, Germany.

Background: Standardized pre-operative assessment of the lower eyelid tension is essential to determine the optimal surgical technique. However, quantitative analysis using the conventional distraction test is inaccurate and user-dependent. Our purpose was to introduce a novel, standardized three-dimensional distraction test for measuring lower eyelid tension and to determine its standard values in a Caucasian population.

Methods: In 94 participants (50 men and 44 women; age 21-85 years), a 15.9-g weighted eyelid hook was used to pull down the lower eyelid. Two three-dimensional images were acquired with a VECTRA M3 stereophotogrammetry device-one in the neutral position without a hook and the other in the distracted position with the eyelid hook. The images of all participants in both positions were measured twice by a single observer.

Results: There was no clinical (>1 mm) or statistically significant difference between the two repeated measurements of all the inter-landmark linear distances in both positions (P≥0.05, respectively). The mean distracted displacement between the neutral and distracted position for margin reflex distance was 5.50±1.53 mm, without any age-specific difference (P=0.08); however, a significant gender-specific difference was observed as men had significantly greater displacement than women (P<0.001).

Conclusions: Our proposed standardized three-dimensional distraction test for assessing lower eyelid tension using an eyelid hook and a simple landmark-based system seems to provide high reliability. This novel and simple method might be helpful for the preoperative planning of eyelid surgeries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/qims-20-1016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245927PMC
August 2021

A Novel Stimuli-Responsive Injectable Antibacterial Hydrogel to Achieve Synergetic Photothermal/Gene-Targeted Therapy towards Uveal Melanoma.

Adv Sci (Weinh) 2021 Jul 31:e2004721. Epub 2021 Jul 31.

Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, P. R. China.

Uveal melanoma (UM) is the most prevalent primary intraocular malignant tumor with a high lethal rate. Patients who undergo conventional enucleation treatments consistently suffer permanent blindness, facial defects, and mental disorders, therefore, novel therapeutic modalities are urgently required. Herein, an injectable and stimuli-responsive drug delivery antibacterial hydrogel ([email protected]@DC_AC50) is constructed via a facile grinding method that is inspired by the preparation process of traditional Chinese medicine. The incorporation of gold nanorods can enhance the mechanical strength of the hydrogel and realize photothermal therapy (PTT) and thermosensitive gel-sol transformation to release the gene-targeted drug DC_AC50 on demand in response to low-density near-infrared (NIR) light. The orthotopic model of UM is built successfully and indicates the excellent efficiency of [email protected]@DC_AC50 in killing tumors without damage to normal tissue because of its synergistic mild temperature PTT and gene-targeted therapy. Moreover, the eyeball infection model reveals the remarkable antibacterial properties of the hydrogel which can prevent endophthalmitis in the eyeball. There is negligible difference between the [email protected]@DC_AC50+NIR group and normal group. This NIR light-triggered gene-targeted therapy/PTT/antibacterial treatment pattern provides a promising strategy for building multifunctional therapeutic platform against intraocular tumors and exhibits great potential for the clinical treatment of UM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/advs.202004721DOI Listing
July 2021

Standardized Three-Dimensional Lateral Distraction Test: Its Reliability to Assess Medial Canthal Tendon Laxity.

Aesthetic Plast Surg 2021 Jul 7. Epub 2021 Jul 7.

Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany.

Background: Assessment of MCT laxity is critical to the surgery options. Our study aimed to analyze the reliability of measuring medial canthal tendon (MCT) laxity by using a novel standardized three-dimensional lateral distraction test (3D-LDT).

Methods: Forty-eight Caucasian volunteers (25 males and 23 females, 96 eyes) between 22 and 84 years of age (55.6 ± 18.6 years old) were included in our study. From a neutral position, the lower eyelid was gently pulled laterally along a horizontal line to define the most distracted position of the lower punctum. Both in the neutral and distracted position, standardized 3D images were acquired for each subject by two observers, and each image were measured twice by two raters. Four landmarks and six corresponding linear measurements were evaluated for intra-rater, inter-rater, and inter-method reliability.

Results: Intra-rater, inter-rater and inter-method reliability analyses of 3D-LDT revealed an intraclass correlation of more than 95%, a mean absolute difference of less than 1 mm, and a technical error of measurement of less than 1 mm. Measurements of relative error (2.59-12.04%) and relative technical error (1.83-16.05%) for the inter-landmarks distance from pupil center to the lower punctum were higher than those from limbus nasal center to the lower punctum (6.13-30.39 and 4.34-26.85%, respectively).

Conclusions: This study provided high reliability of the three-dimensional lateral distraction test (3D-LDT) for assessing medial canthal tendon (MCT) laxity, which were never evaluated by digital imaging system.

Level Of Evidence Iv: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00266-021-02440-yDOI Listing
July 2021

Comparison of Intra-Arterial Chemotherapy Efficacy Delivered Through the Ophthalmic Artery or External Carotid Artery in a Cohort of Retinoblastoma Patients.

Front Med (Lausanne) 2021 11;8:658305. Epub 2021 Jun 11.

Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.

To evaluate the efficacy of an external carotid artery (ECA) alternative route in intra-arterial chemotherapy (IAC) for treatment of retinoblastoma. In this retrospective, single-centre, case-control study, 98 retinoblastoma patients who received successful IAC were included. The drug delivery routes were the primary ophthalmic artery (OA) route and the ECA route when OA catheterization was not feasible. A total of 337 successful IAC procedures were performed in our study, of which 32 (9.5%) procedures were performed through the ECA route. Eighteen eyes (18.4%) accepted at least one IAC through branches of the ECA. Statistical analysis showed that there was no significant difference in ocular clinical results (enucleation, death, recurrence and event-free) between the ECA and OA routes. No significant association was found between the route of drug delivery and the ocular survival time ( = 0.69). The use of ECA catheterization in at least one IAC cycle was not a predictor of enucleation (HR: 1.58; 95% CI: 0.56-4.46, = 0.39). The increasing number of procedures through the ECA route did not increase the risk of enucleation (HR: 1.64; 95% CI: 0.42-6.39, = 0.48). The ECA alternative route did not affect the efficacy of IAC in retinoblastoma. When the standard OA approach is not feasible, ECA system catheterization should be considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmed.2021.658305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225945PMC
June 2021

Publication Trends of Research on Retinoblastoma During 2001-2021: A 20-Year Bibliometric Analysis.

Front Med (Lausanne) 2021 21;8:675703. Epub 2021 May 21.

Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.

Retinoblastoma is the most common primary intraocular malignancy of childhood. Despite high survival and eye salvage as the result of various types of therapies, retinoblastoma remains a disease that places a considerable burden on developing countries. Our study attempted to analyse the research trends in retinoblastoma research and compare contributions from different countries, institutions, journals, and authors. We extracted all publications concerning retinoblastoma from 2001 to 2021 from the Web of Science database. Microsoft Excel and VOSviewer were employed to collect publication data, analyse publication trends, and visualize relevant results. A total of 1,675 publications with 30,148 citations were identified. The United States contributed the most publications (643) and citations (16,931 times) with the highest H-index value (67) as of February 4, 2021. China ranked second in the number of publications (259), while ranking fourth in both citations (2,632 times) and the H-index (26) ranked fourth. The was the most productive journal concerning retinoblastoma, and Abramson DH had published the most papers in the field. Keywords were categorized into three clusters; tumor-related research, clinical research, and management-related research. The keywords "intravitreal," "intraarterial," and "intravenous" appeared the most frequently, with the average appearing year being 2018.1, 2017.7, and 2017.1, respectively. Management-related research has been recognized as a heavily researched topic in the field. We conclude that the United States, China, and India made the most exceptional contributions in the field of retinoblastoma research, while China still has a disparity between the quantity and quality of publications. Management-related research, including intravitreal, intraarterial, and intravenous chemotherapy was considered as a potential focus for future research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmed.2021.675703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175655PMC
May 2021

Risk factors for ophthalmic artery stenosis and occlusion in patients with retinoblastoma treated with intra-arterial chemotherapy.

Br J Ophthalmol 2021 May 26. Epub 2021 May 26.

Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P. R. China

Purpose: To explore the risk factors for ophthalmic artery (OA) stenosis and occlusion after intra-arterial chemotherapy (IAC) with selective ophthalmic artery catheterisation (OAC) in the treatment of retinoblastoma.

Design: Retrospective, single centre case-control study.

Methods: The study was conducted including consecutive patients with unilateral or bilateral intraocular retinoblastoma undergoing IAC between June 2016 and June 2019 with a follow-up time of 4 years. Main outcomes are rate of IAC-induced OA occlusion and OA diameter.

Results: 346 attempted OAC infusions were successful. The total incidence of OA occlusion was 15.89%. The occlusion and control groups were similar in patients' age, sex and disease stage. Median OA diameter was 0.49 mm in those with OA occlusion, and 0.66 mm in those without occlusion. In the occlusion group, the OA diameter difference was significantly larger between the first IAC and the final IAC (0.22mm vs 0.12mm, p=0.001). In both groups, the median number of IAC treatments was 3. Multivariate Cox regression models included initial OA diameter (OR: 0.005, p=0.001), ratio of OA orifice diameter differences between first and last IAC to the initial OA orifice diameter (OR: 4.661, p=0.003), and number of IAC (OR: 1.538, p=0.042) as clinical features significantly associated with OA occlusion.

Conclusions: The OA diameter at first IAC treatment, the ratio of OA orifice diameter differences between first and last IAC to the initial OA orifice diameter and total number of IAC treatments may be three main clinical predictors for OA occlusion after IAC for retinoblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bjophthalmol-2021-319118DOI Listing
May 2021

Dose-Dependent Carbon-Dot-Induced ROS Promote Uveal Melanoma Cell Tumorigenicity via Activation of mTOR Signaling and Glutamine Metabolism.

Adv Sci (Weinh) 2021 04 25;8(8):2002404. Epub 2021 Feb 25.

Department of Ophthalmology Shanghai Ninth People's Hospital Shanghai JiaoTong University School of Medicine Shanghai 200011 China.

Uveal melanoma (UM) is the most common intraocular malignant tumor in adults and has a low survival rate following metastasis; it is derived from melanocytes susceptible to reactive oxygen species (ROS). Carbon dot (Cdot) nanoparticles are a promising tool in cancer detection and therapy due to their unique photophysical properties, low cytotoxicity, and efficient ROS productivity. However, the effects of Cdots on tumor metabolism and growth are not well characterized. Here, the effects of Cdots on UM cell metabolomics, growth, invasiveness, and tumorigenicity are investigated in vitro and in vivo zebrafish and nude mouse xenograft model. Cdots dose-dependently increase ROS levels in UM cells. At Cdots concentrations below 100 µg mL, Cdot-induced ROS promote UM cell growth, invasiveness, and tumorigenicity; at 200 µg mL, UM cells undergo apoptosis. The addition of antioxidants reverses the protumorigenic effects of Cdots. Cdots at 25-100 µg mL activate Akt/mammalian target of rapamycin (mTOR) signaling and enhance glutamine metabolism, generating a cascade that promotes UM cell growth. These results demonstrate that moderate, subapoptotic doses of Cdots can promote UM cell tumorigenicity. This study lays the foundation for the rational application of ROS-producing nanoparticles in tumor imaging and therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/advs.202002404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061404PMC
April 2021

Clinical and pathological risk factors for worse stage and mortality of eyelid and periocular squamous cell carcinoma.

Br J Ophthalmol 2021 Apr 20. Epub 2021 Apr 20.

Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China

Background: The clinical and pathological risk factors for worse T stage and prognosis in eyelid and periocular squamous cell carcinomas (SCCs) remain unclear. P63 was reported to predict a worse prognosis in other SCCs; however, this correlation was not validated in eyelid and periocular SCCs.

Methods: We reported on a retrospective case series of 85 consecutive patients with eyelid and periocular SCCs from 1995 to 2019. Cox proportional hazards regression models and logistic regression models were applied for risk factor analysis.

Results: Thirty-nine (45.8%) patients were diagnosed with T4 SCCs. Four (5.1%) patients developed nodal metastasis, and five (6.4%) patients developed distant metastasis during the follow-up. 2-year and 5-year disease-specific survival rates were 95.3% and 86.4%, respectively. Poorly or moderately differentiated eyelid and periocular SCCs were associated with worse T stage (p=0.001; p=0.008). Poor differentiation was associated with a higher risk of recurrence (p=0.024). Disease-specific death was more common in patients with T4 stage SCCs (p=0.038, HR=9.05). P63 expression was more common in patients with T3c or worse stage (p=0.008, OR=3.77). P63 expression alone was associated with worse differentiation (p=0.029), higher risk of perineural invasion (p=0.042, OR=4.61) and metastasis (p=0.009, HR=3.99). P63 expression (p=0.012, HR=7.80), coexpression of P63 and Ki67 (p=0.007, HR=9.21) and distant metastasis (p=0.001, HR=11.23) were associated with disease-specific death.

Conclusion: Patients presented with more aggressive orbital invasion features and a higher rate of distant metastasis in this cohort. P63 and coexpression of Ki67 predicted a worse stage, differentiation and prognosis, including metastasis and death due to disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bjophthalmol-2020-317546DOI Listing
April 2021

Fangchinoline suppresses conjunctival melanoma by directly binding FUBP2 and inhibiting the homologous recombination pathway.

Cell Death Dis 2021 04 7;12(4):380. Epub 2021 Apr 7.

State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China.

Conjunctival melanoma (CM) is a rare and fatal ocular tumour with poor prognosis. There is an urgent need of effective therapeutic drugs against CM. Here, we reported the discovery of a novel potential therapeutic target for CM. Through phenotypic screening of our in-house library, fangchinoline was discovered to significantly inhibit the growth of CM cells including CM-AS16, CRMM1, CRMM2 and CM2005.1. Further mechanistic experiments indicated that fangchinoline suppressed the homologous recombination (HR)-directed DNA repair by binding with far upstream element binding protein 2 (FUBP2) and downregulating the expression of HR factors BRCA1 and RAD51. In vitro and in vivo antitumour experiments revealed that fangchinoline increased the efficacy of cisplatin by blocking HR factors and reduced the drug dose and toxicity. In conclusion, our work provides a promising therapeutic strategy for the treatment of CM that is worthy of extensive preclinical investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-021-03653-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027391PMC
April 2021

Case Report: Favorable Response to the Tyrosine Kinase Inhibitor Apatinib in Recurrent Merkel Cell Carcinoma.

Front Oncol 2021 3;11:625360. Epub 2021 Mar 3.

Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.

Background: As angiogenesis is an essential step in tumor growth and metastasis, the tyrosine kinase inhibitor (TKI) apatinib has become a revolutionary anticancer therapy across various malignancies. However, its efficiency and safety in Merkel cell carcinoma (MCC) are uncertain.

Case Presentation: The current study described the case of a 91-year-old man who presented with a 3.2 × 3.0 × 2.2 cm rapidly growing, solitary tumor of the right lower eyelid. It was diagnosed as MCC pathologically. Twenty-seven days after the surgery, the patient returned to the hospital with recurrent MCC. Apatinib was then administered to this patient. The patient had a complete response (CR) to apatinib after 4.4 months of targeted therapy. Twenty-seven months of progression-free survival (PFS) was achieved with controllable treatment-related adverse events (AEs).

Conclusion: Treatment with apatinib demonstrated clinical benefit in our patient with recurrent MCC, highlighting its potential utility in other MCC patients. Further clinical trials are needed to determine the efficacy and safety of apatinib in MCC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.625360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966513PMC
March 2021

Histone lactylation drives oncogenesis by facilitating mA reader protein YTHDF2 expression in ocular melanoma.

Genome Biol 2021 03 16;22(1):85. Epub 2021 Mar 16.

Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China.

Background: Histone lactylation, a metabolic stress-related histone modification, plays an important role in the regulation of gene expression during M1 macrophage polarization. However, the role of histone lactylation in tumorigenesis remains unclear.

Results: Here, we show histone lactylation is elevated in tumors and is associated with poor prognosis of ocular melanoma. Target correction of aberrant histone lactylation triggers therapeutic efficacy both in vitro and in vivo. Mechanistically, histone lactylation contributes to tumorigenesis by facilitating YTHDF2 expression. Moreover, YTHDF2 recognizes the m6A modified PER1 and TP53 mRNAs and promotes their degradation, which accelerates tumorigenesis of ocular melanoma.

Conclusion: We reveal the oncogenic role of histone lactylation, thereby providing novel therapeutic targets for ocular melanoma therapy. We also bridge histone modifications with RNA modifications, which provides novel understanding of epigenetic regulation in tumorigenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13059-021-02308-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962360PMC
March 2021

LACTB suppresses melanoma progression by attenuating PP1A and YAP interaction.

Cancer Lett 2021 05 4;506:67-82. Epub 2021 Mar 4.

Department of Ophthalmology, Ninth People's Hospital of Shanghai, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address:

Very limited progress has been made in the management of advanced melanoma, especially melanoma of uveal origin. Lactamase β (LACTB) is a novel tumor suppressor; however, its biological function in melanoma remains unknown. Herein we demonstrated markedly lower LACTB expression levels in melanoma tissues and cell lines. Overexpression of LACTB suppressed the proliferation, migration and invasion of melanoma cells in vitro. Mechanistically, LACTB inhibited the activity of yes-associated protein (YAP). We showed that the level of phospho-YAP (Serine 127) was increased upon LACTB overexpression, which prevented the translocation of YAP to the nucleus. Further, LACTB could directly bind to PP1A and attenuate the interaction between PP1A and YAP, resulting in decreased YAP dephosphorylation and inactivation in a LATS1-independent manner. Additionally, transfection of phosphorylation-defective YAP mutants reversed LACTB-induced tumor suppression. Upstream, we demonstrated that SOX10 binds to the LACTB promoter and negatively regulates its transcription. Overexpression of LACTB also suppressed the tumorigenicity and lung metastasis of MUM2B uveal melanoma cells in vivo. Taken together, our findings indicate a novel SOX10/LACTB/PP1A signaling cascade that renders YAP inactive and modulates melanoma progression, offering a new therapeutic target for melanoma treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2021.02.022DOI Listing
May 2021

Benefits of Zebrafish Xenograft Models in Cancer Research.

Front Cell Dev Biol 2021 11;9:616551. Epub 2021 Feb 11.

Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

As a promising tool for cancer research, zebrafish have been widely applied in various tumor studies. The zebrafish xenograft model is a low-cost, high-throughput tool for cancer research that can be established quickly and requires only a small sample size, which makes it favorite among researchers. Zebrafish patient-derived xenograft (zPDX) models provide promising evidence for short-term clinical treatment. In this review, we discuss the characteristics and advantages of zebrafish, such as their transparent and translucent features, the use of vascular fluorescence imaging, the establishment of metastatic and intracranial orthotopic models, individual pharmacokinetics measurements, and tumor microenvironment. Furthermore, we introduce how these characteristics and advantages are applied other in tumor studies. Finally, we discuss the future direction of the use of zebrafish in tumor studies and provide new ideas for the application of it.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2021.616551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905065PMC
February 2021

mA RNA hypermethylation-induced BACE2 boosts intracellular calcium release and accelerates tumorigenesis of ocular melanoma.

Mol Ther 2021 06 15;29(6):2121-2133. Epub 2021 Feb 15.

Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200001, China. Electronic address:

Ocular melanoma, including uveal melanoma (UM) and conjunctival melanoma (CM), is the most common and deadly eye cancer in adults. Both UM and CM originate from melanocytes and exhibit an aggressive growth pattern with high rates of metastasis and mortality. The integral membrane glycoprotein beta-secretase 2 (BACE2), an enzyme that cleaves amyloid precursor protein into amyloid beta peptide, has been reported to play a vital role in vertebrate pigmentation and metastatic melanoma. However, the role of BACE2 in ocular melanoma remains unclear. In this study, we showed that BACE2 was significantly upregulated in ocular melanoma, and inhibition of BACE2 significantly impaired tumor progression both in vitro and in vivo. Notably, we identified that transmembrane protein 38B (TMEM38B), whose expression was highly dependent on BACE2, modulated calcium release from endoplasmic reticulum (ER). Inhibition of the BACE2/TMEM38B axis could trigger exhaustion of intracellular calcium release and inhibit tumor progression. We further demonstrated that BACE2 presented an increased level of N-methyladenosine (mA) RNA methylation, which led to the upregulation of BACE2 mRNA. To our knowledge, this study provides a novel pattern of BACE2-mediated intracellular calcium release in ocular melanoma progression, and our findings suggest that mA/BACE2/TMEM38b could be a potential therapeutic axis for ocular melanoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymthe.2021.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178445PMC
June 2021

Clinical characteristics and germline mutation spectrum of RB1 in Chinese patients with retinoblastoma: A dual-center study of 145 patients.

Exp Eye Res 2021 04 23;205:108456. Epub 2021 Jan 23.

Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address:

Retinoblastoma (Rb) is the most common primary intraocular childhood malignancy and one of the main causes of blindness in children. In China, most tumors are diagnosed at an advanced stage and have relatively poor outcomes compared to developed countries. Here, we aimed to update the clinical manifestations and RB transcriptional corepressor 1 (RB1) mutation spectrum in Chinese Rb patients. Medical charts of 184 eyes in 145 Chinese Rb patients belonging to unrelated families were reviewed. Genomic DNA was isolated from peripheral blood of the patients and their parents. Mutation analysis of whole coding regions, promoter regions and flanking splice sites in the RB1 gene was performed. In addition, multiplex ligation-dependent probe amplification (MLPA) was done to detect gross aberrations. Germline RB1 mutations were observed in 37.2% (54/145) of Rb patients. RB1-mutated patients presented with earlier age of diagnosis (p = 0.019), with a significantly larger proportion of bilateral cases (p = <0.001) and secondary malignancies (p = 0.027) relative to those without RB1 mutations. For ocular clinical presentations, RB1-mutated retinoblastomas presented with a larger proportion of ectropion uveae (p = 0.017) and iris neovascularization (p = 0.001). These RB1 mutations comprised of 13 (24.1%) nonsense mutation, 13 (24.1%) splicing mutations, 11 (20.4%) frameshift deletions, 11 (20.4%) gross mutations, 3 (5.6%) missense mutations, 2 (3.7%) promoter mutations and 1 (1.9%) non-frameshift deletion. In addition, 8 novel RB1 mutations were identified. These germline RB1 mutations were not related to age at diagnosis or laterality. Here, we provide a comprehensive spectrum of RB1 germline mutations in Chinese Rb patients and describe correlations between RB1 mutations and clinical presentations. Our study also provides new evidence that will inform management and genetic counselling of Rb patients and families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exer.2021.108456DOI Listing
April 2021

BMP9 promotes cutaneous wound healing by activating Smad1/5 signaling pathways and cytoskeleton remodeling.

Clin Transl Med 2021 01;11(1):e271

Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ctm2.271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809598PMC
January 2021

Generation of onco-enhancer enhances chromosomal remodeling and accelerates tumorigenesis.

Nucleic Acids Res 2020 12;48(21):12135-12150

Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P. R. China.

Chromatin remodeling impacts the structural neighborhoods and regulates gene expression. However, the role of enhancer-guided chromatin remodeling in the gene regulation remains unclear. Here, using RNA-seq and ChIP-seq, we identified for the first time that neurotensin (NTS) serves as a key oncogene in uveal melanoma and that CTCF interacts with the upstream enhancer of NTS and orchestrates an 800 kb chromosomal loop between the promoter and enhancer. Intriguingly, this novel CTCF-guided chromatin loop was ubiquitous in a cohort of tumor patients. In addition, a disruption in this chromosomal interaction prevented the histone acetyltransferase EP300 from embedding in the promoter of NTS and resulted in NTS silencing. Most importantly, in vitro and in vivo experiments showed that the ability of tumor formation was significantly suppressed via deletion of the enhancer by CRISPR-Cas9. These studies delineate a novel onco-enhancer guided epigenetic mechanism and provide a promising therapeutic concept for disease therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gkaa1051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708045PMC
December 2020

Uveal melanoma: progress in molecular biology and therapeutics.

Ther Adv Med Oncol 2020 22;12:1758835920965852. Epub 2020 Oct 22.

Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Huangpu District, Shanghai 200001, China.

Uveal melanoma (UM) is the most common intraocular malignancy in adults. So far, no systemic therapy or standard treatment exists to reduce the risk of metastasis and improve overall survival of patients. With the increased knowledge regarding the molecular pathways that underlie the oncogenesis of UM, it is expected that novel therapeutic approaches will be available to conquer this disease. This review provides a summary of the current knowledge of, and progress made in understanding, the pathogenesis, genetic mutations, epigenetics, and immunology of UM. With the advent of the omics era, multi-dimensional big data are publicly available, providing an innovation platform to develop effective targeted and personalized therapeutics for UM patients. Indeed, recently, a great number of therapies have been reported specifically for UM caused by oncogenic mutations, as well as other etiologies. In this review, special attention is directed to advancements in targeted therapies. In particular, we discuss the possibilities of targeting: GNAQ/GNA11, PLCβ, and CYSLTR2 mutants; regulators of G-protein signaling; the secondary messenger adenosine diphosphate (ADP)-ribosylation factor 6 (ARF6); downstream pathways, such as those involving mitogen-activated protein kinase/MEK/extracellular signal-related kinase, protein kinase C (PKC), phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR), Trio/Rho/Rac/Yes-associated protein, and inactivated BAP1; and immune-checkpoint proteins cytotoxic T-lymphocyte antigen 4 and programmed cell-death protein 1/programmed cell-death ligand 1. Furthermore, we conducted a survey of completed and ongoing clinical trials applying targeted and immune therapies for UM. Although drug combination therapy based on the signaling pathways involved in UM has made great progress, targeted therapy is still an unmet medical need.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1758835920965852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586035PMC
October 2020

Endoscopy-guided diode laser-assisted transcaruncular StopLoss Jones tube implantation for canalicular obstructions in primary surgery.

Graefes Arch Clin Exp Ophthalmol 2020 Dec 6;258(12):2809-2817. Epub 2020 Oct 6.

Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

Purpose: To introduce and evaluate a minimally-invasive endoscopy-guided transcaruncular laser-assisted StopLoss Jones tube (SLJT) implantation technique for severe canalicular obstructions in primary surgeries.

Methods: We retrospectively identified 12 adult patients (12 eyes) with severe epiphora secondary to long-segment canalicular obstructions. All the 12 eyes underwent an endoscopy-guided transcaruncular SLJT implantation with an 810-nm diode laser's assistance as the primary surgical approach. Surgical and functional success rates, intraoperative and postoperative complications, as well as the need for secondary surgery, are evaluated.

Results: Primary surgical success was achieved in 11 of the 12 cases (92%); one patient (8%) required secondary surgery to replace an SLJT with a shorter one. Ultimately, all cases showed well-placed functioning tubes. Three of the 12 cases (25%) presented conjunctival scarring, conjunctival granulation tissue, with or without tube-associated irritation of the ocular surface. We observed no sink-in, extrusion, nor crack of the tube. Complete functional success was achieved in 83%, and moderate functional success in 17% of all patients. The functionally unsuccessful outcome was not present in this study.

Conclusion: Endoscopy-guided transcaruncular diode laser-assisted SLJT implantation seems to be a promising minimally invasive approach for primary treatment of severe canalicular dacryostenosis. This novel technique shows high functional success rates. It seems to avoid the risk of tube malposition and extrusion, septal and turbinate injury, nasal adhesion, drainage failure, ethmoiditis, postoperative bleeding, and cutaneous scars.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00417-020-04942-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677269PMC
December 2020

Evaluation of changes in choroidal thickness after implantable collamer lens surgery in high myopia patients with graves' Ophthalmopathy (inactive phase).

BMC Ophthalmol 2020 Aug 25;20(1):344. Epub 2020 Aug 25.

Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Background: To evaluate the safety and effectiveness of the Visian Implantable Collamer Lens (ICL) implantation in high myopic patients with inactive Graves' ophthalmopathy (GO) by observing the changes of choroidal thickness (CT).

Methods: Eight patients (16 eyes) with high myopia accompanied with inactive GO were selected as the experimental group (group A) and 18 high myopic patients (36 eyes) without GO were selected as a control group (group B). The outcomes of uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BCVA), safety index, efficacy index, intraocular pressure (IOP), vault, corneal endothelial count, and choroidal thickness (CT) were observed. The values of CT were measured using swept-source optical coherence tomography (SS-OCT) scans.

Results: The UCVA and BCVA in all operated eyes were better than that before surgery. The postoperative safety index and efficacy index were 1.23 and 1.19 in the group A, respectively, and 1.26 and 1.21 in the group B, respectively. In both groups, foveal CT increased significantly in high myopic patients at 2 h and at 3 months after surgery, compared to preoperative values. The same tendencies were observed in the inner nasal and outer nasal regions. Compared with patients without GO, the increase of CT was more obvious in GO patients, 2 h postoperatively (P = 0.006) and 3 months postoperatively (P = 0.011).

Conclusions: The ICL implantation is safe and effective in high myopic patients with inactive GO. Subfoveal and nasal CT may be useful parameters for monitoring the activity of GO patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12886-020-01612-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446171PMC
August 2020

An Artificial CTCF Peptide Triggers Efficient Therapeutic Efficacy in Ocular Melanoma.

Mol Ther Oncolytics 2020 Sep 9;18:317-325. Epub 2020 Jul 9.

Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, P.R. China.

Although CCCTC binding factor (CTCF) has been demonstrated to play a variety of often contradictory roles in tumorigenesis, little is known about its function in the tumorigenesis of ocular melanoma. Here, we generated two artificial CTCF peptides (Decoy-CTCFs) combining the zinc finger domain of wild-type CTCF and artificial marker region. This Decoy-CTCF retained the DNA binding region but lost the functional regions of wild-type CT Transferring artificial CTCF into ocular melanoma cells suppressed proliferation and migration in the tumor cells, while no effect was observed in normal cells. Intriguingly, we first showed that decoy-CTCF inhibited tumorigenesis by preventing the histone acetyltransferase EP300 from binding to the promoter of Thus was a novel oncogene in the tumorigenesis of ocular melanoma. These studies provide efficient decoy CTCF-based therapeutic concept in malignant ocular melanoma and reveal the potential mechanism underlying decoy-based tumor therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.omto.2020.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394857PMC
September 2020

BMP9 attenuates occurrence of venous malformation by maintaining endothelial quiescence and strengthening vessel walls via SMAD1/5/ID1/α-SMA pathway.

J Mol Cell Cardiol 2020 10 28;147:92-107. Epub 2020 Jul 28.

Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address:

Venous malformation (VM) is a type of vascular morphogenic defect in humans with an incidence of 1%. Although gene mutation is considered as the most common cause of VM, the pathogenesis of those without gene mutation remains to be elucidated. Here, we aimed to explore the relation of bone morphogenetic protein 9 (BMP9) and development of VM. At first, we found serum and tissue BMP9 expression in VM patients was significantly lower than that in healthy subjects, detected via enzyme-linked immunosorbent assay. Next, with wound healing assay, transwell assay and tube formation assay, we discovered BMP9 could inhibit migration and enhance tube formation activity of human umbilical vein endothelial cells (HUVECs) via receptor activin receptor-like kinase 1 (ALK1). Besides, BMP9 improved the expression of structural proteins alpha-smooth muscle actin (α-SMA) and Desmin in human umbilical vein smooth muscle cells (HUVSMCs) via activation of the SMAD1/5-ID1 pathway, determined by RNA-based next-generation sequencing, qPCR, immunofluorescence and western blotting. Intriguingly, this effect could be blocked by receptor ALK1 inhibitor, SMAD1/5 inhibitor and siRNAs targeting ID1, verifying the BMP9/ALK1/SMAD1/5/ID1/α-SMA pathway. Meanwhile, knocking out BMP9 in C57BL/6 mice embryo led to α-SMA scarcity in walls of lung and mesenteric vessels, as well as walls of small trachea. BMP9-/- zebrafish also exhibited abnormal vascular maturity, indicating a critical role of BMP9 in vascular maturity and remodeling. Finally, a VM mice model revealed that BMP9 might have therapeutic effect in VM progression. Our study discovered that BMP9 might inhibit the occurrence of VM by strengthening the vessel wall and maintaining endothelium quiescence. These findings provide promising evidences of new therapeutic targets that might be used for the management of VM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yjmcc.2020.07.010DOI Listing
October 2020

A novel LncRNA transcript, RBAT1, accelerates tumorigenesis through interacting with HNRNPL and cis-activating E2F3.

Mol Cancer 2020 07 15;19(1):115. Epub 2020 Jul 15.

Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.

Background: Long non-coding RNAs (lncRNAs) have been identified as important epigenetic regulators that play critical roles in human cancers. However, the regulatory functions of lncRNAs in tumorigenesis remains to be elucidated. Here, we aimed to investigate the molecular mechanisms and potential clinical application of a novel lncRNA, retinoblastoma associated transcript-1 (RBAT1), in tumorigenesis.

Methods: RBAT1 expression was determined by real-time PCR in both retinoblastoma (Rb) and bladder cancer (BCa) cell lines and clinical tissues. Chromatin isolation using RNA purification (ChIRP) assays were performed to identify RBAT1-interacting proteins. Patient-derived xenograft (PDX) retinoblastoma models were established to test the therapeutic potential of RBAT1-targeting GapmeRs.

Results: Here, we found that RBAT1 expression was significantly higher in Rb and BCa tissues than that in adjacent tissues. Functional assays revealed that RBAT1 accelerated tumorigenesis both in vitro and in vivo. Mechanistically, RBAT1 recruited HNRNPL protein to E2F3 promoter, thereby activating E2F3 transcription. Therapeutically, GapmeR-mediated RBAT1 silencing significantly inhibited tumorigenesis in orthotopic xenograft retinoblastoma models derived from Rb cell lines and Rb primary cells.

Conclusions: RBAT1 overexpression upregulates a known oncogene, E2F3, via directly recruiting HNPNPL to its promoter and cis-activating its expression. Our finding provides a novel mechanism of lncRNA biology and provides potential targets for diagnosis and treatment of Rb and BCa.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12943-020-01232-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362570PMC
July 2020

A novel variant in GPAA1, encoding a GPI transamidase complex protein, causes inherited vascular anomalies with various phenotypes.

Hum Genet 2020 Dec 12;139(12):1499-1511. Epub 2020 Jun 12.

Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639, Zhizaoju Road, Huangpu District, Shanghai, 200001, China.

Vascular anomalies (VAs), comprising wide subtypes of tumors and malformations, are often caused by variants in multiple tyrosine kinase (TK) receptor signaling pathways including TIE2, PIK3CA and GNAQ/11. Yet, a portion of individuals with clinical features of VA do not have variants in these genes, suggesting that there are undiscovered pathogenic factors underlying these patients and possibly with overlapping phenotypes. Here, we identified one rare non-synonymous variant (c.968A > G) in the seventh exon of GPAA1 (Glycosylphosphatidylinositol Anchor Attachment Protein 1), shared by the four affected members of a large pedigree with multiple types of VA using whole-exome sequencing. GPAA1 encodes a glycosylphosphatidylinositol (GPI) transamidase complex protein. This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum (ER). We showed such variant led to scarce expression of GPAA1 protein in vascular endothelium and induced a localization change from ER membrane to cytoplasm and nucleus. In addition, expressing wild-type GPAA1 in endothelial cells had an effect to inhibit cell proliferation and migration, while expressing variant GPAA1 led to overgrowth and overmigration, indicating a loss of the quiescent status. Finally, a gpaa1-deficient zebrafish model displayed several types of developmental defects as well as vascular dysplasia, demonstrating that GPAA1 is involved in angiogenesis and vascular remodeling. Altogether, our results indicate that the rare coding variant in GPAA1 (c.968A > G) is causally related to familial forms of VAs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00439-020-02192-wDOI Listing
December 2020

The role of mitochondrial dynamics in human cancers.

Am J Cancer Res 2020 1;10(5):1278-1293. Epub 2020 May 1.

Department of Ophthalmology, Ninth People's Hospital of Shanghai, Shanghai Jiao Tong University School of Medicine Shanghai, China.

Mitochondria are crucial cellular organelles. Under extracellular stimulations, mitochondria undergo constant fusion and fission dynamics to meet different cellular demands. Mitochondrial dynamics is regulated by specialized proteins and lipids. Dysregulated mitochondrial dynamics has been linked to the initiation and progression of diverse human cancers, affecting aspects such as cancer metastasis, drug resistance and cancer stem cell survival, suggesting that targeting mitochondrial dynamics is a potential therapeutic strategy. In the present review, we summarize the molecular mechanisms underlying fusion and fission dynamics and discuss the effects of mitochondrial dynamics on the development of human cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269774PMC
May 2020

Dinutuximab Synergistically Enhances the Cytotoxicity of Natural Killer Cells to Retinoblastoma Through the Perforin-Granzyme B Pathway.

Onco Targets Ther 2020 8;13:3903-3920. Epub 2020 May 8.

Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.

Purpose: Conventional chemotherapy and enucleation usually fail to cure advanced retinoblastoma. We investigated the retinoblastoma immune microenvironment and the efficacy of the combination of dinutuximab and CD16-expressing NK-92MI (NK-92MI) cells on retinoblastoma cells in this study.

Patients And Methods: Immunohistochemistry and flow cytometry (FC) were performed to assess the expression level of GD2 in retinoblastoma tissues and cells. Gene set enrichment analysis (GSEA), immunohistochemisrztry and immunocytochemistry were conducted to assess the retinoblastoma immune microenvironment and the integrity of the blood-retinal barrier (BRB). After overexpressing CD16 in NK-92MI cells, fluorescence-activated cell sorting (FACS) was applied to select the positive subpopulation. LDH assays and FC were used to detect LDH release and apoptosis in retinoblastoma cells subjected to a combination of dinutuximab and NK-92MI cells. Finally, the release of perforin-granzyme B and the expression of CD107a in NK-92MI stimulated by retinoblastoma cells were assessed via enzyme-linked immunosorbent assays (ELISAs) and FC in the presence of dinutuximab or an isotype control.

Results: GD2 was heterogeneously expressed in retinoblastoma tissues and cell lines and positively correlated with proliferation and staging. GSEA revealed the immunosuppressive status of retinoblastoma microenvironment. The immune cell profile of retinoblastoma tissues and vitreous bodies suggested BRB destruction. LDH release and apoptosis in retinoblastoma cells caused by NK-92MI cells were significantly enhanced by dinutuximab. Finally, the release of perforin-granzyme B and the expression of CD107a in NK-92MI cells stimulated by retinoblastoma cells were obviously increased by dinutuximab.

Conclusion: This study indicates that retinoblastoma impairs the integrity of the BRB and contributes to dysregulated immune cell infiltrates. GD2 is a specific target for natural killer (NK) cell-based immunotherapy and that the combination of dinutuximab and NK-92MI cells exerts potent antitumor effects through antibody-dependent cell-mediated cytotoxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/OTT.S228532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218403PMC
May 2020

Nomogram for Preoperative Estimation of Orbit Invasion Risk in Periocular Squamous Cell Carcinoma.

Front Oncol 2020 30;10:564. Epub 2020 Apr 30.

Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.

Orbital invasion occurs in some periocular squamous cell carcinoma (SCC), compromising surgical outcomes, and prognoses of patients. To date, however, there are no validation studies on the clinical features related to orbital invasion in patients with periocular SCC. To explore clinical features that may be associated with orbital invasion and build a model for predicting the risk of orbital invasion. In this retrospective mono-center case-control study, 90 patients with periocular SCC were treated at the Ninth People's Hospital Shanghai Jiao Tong University School of Medicine from January 2005 to August 2019. "Case" is defined as a SCC patient with orbit invasion prior to operation. "Exposure" is defined as the different sites of lesion. Clinical features, including "time to relapse after surgery," were collected. Multivariate logistic regression analysis was applied to identify the independent risk clinical features associated with orbital invasion, which was then incorporated into a nomogram. Of the 90 patients included in this study, 33 patients (36.7%) had orbital invasion. 14 of the 33 orbit-invasive patients had local recurrence, while 11 of 57 orbit non-invasive patients had local recurrence, suggesting that orbital invasion is a risk factor for local recurrence. The multivariate binary logistic regression indicated that the lesions at the medial canthus [odds ratio (OR), 5.024, 95% CI, 1.409-17.912, = 0.013], the age at diagnosis (10-years intervals; OR, 0.590, 95% CI, 0.412-0.844, = 0.004), and bleeding in the lesion (OR, 3.480, 95% CI, 1.254-9.660, = 0.017) were three preoperative clinical features significantly associated with orbital invasion. For periocular SCC, lesions at the medial canthus, the younger age of the patients at diagnosis, and bleeding in the lesion were the three main clinical features associated with orbital invasion. The risk score model for orbital invasion can act as a supportive tool for optimized clinical evaluation and treatment decisions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.00564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203342PMC
April 2020
-->