Objective·To investigate the effect of F-box only protein 38(FBXO38)on the ocular melanoma proliferation and the potential regulatory pathway.Methods·Human skin cutaneous melanoma A375 and human uveal melanoma OMM2.3 cell lines with FBXO38 knockdown and overexpression were constructed by FBXO38 short hairpin RNA(shRNA)and FBXO38 overexpression plasmids respectively.Knockdown and overexpression efficiency of FBXO38 at transcription and protein levels were verified by using quantitative real-time PCR(qRT-PCR)and Western blotting.The effects of FBXO38 on melanoma cell proliferation were detected through clonal formation assay,BrdU immunofluorescence staining and CCK8 cell proliferation assay.By using The Cancer Genome Atlas(TCGA)database,differentially expressed genes were analyzed in the high and low expression groups of FBXO38.Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment was performed to reveal the signaling pathways associated with FBXO38.CCK8 cell proliferation assay was used to detect the inhibition rates of the signaling pathway inhibitors on cells with different FBXO38 expression levels.qRT-PCR and Western blotting were used to detect whether the signaling pathway was activated after knocking down FBXO38.Results·qRT-PCR and Western blotting verified that mRNA and protein expression levels of FBXO38 in FBXO38 knockdown A375 and OMM2.3 cell lines decreased compared with the control group,while the expression levels of FBXO38 in the overexpression cell lines increased compared with wild type group(P＜0.05).Clonal formation assay,BrdU immunofluorescence staining and CCK8 cell proliferation assay showed that FBXO38 knockdown significantly enhanced the proliferation of A375 and OMM2.3 cells(P＜0.05),while overexpression of FBXO38 inhibited melanoma cell proliferation(P＜0.05).Enrichment analysis showed that in skin cutaneous melanoma and uveal melanoma,FBXO38 expression influenced the phosphoinositide 3-kinase/protein kinase B(PI3K-Akt)pathway activation.Compared with those in the control group,the inhibition rates of P13K inhibitor LY294002 and mTOR1 inhibitor Everolimus in the FBXO38 knockdown group significantly improved(P＜0.05),while their inhibition rates of the overexpression group significantly decreased compared with those of control cells(P＜0.05).Western blotting results showed that after knocking down FBXO38,expression levels of PTEN,P21 and P53 proteins decreased,while expression level of MDM2 protein increased.The qRT-PCR results showed a significant decrease in P53 transcription level(P＜0.05)and a significant increase in MDM2 transcription level in FBXO38 knockdown cells(P＜0.05).Conclusion·FBXO38 plays a role in regulating the proliferation of ocular melanoma,and this regulatory effect is related to the PI3K-Akt signaling pathway.

Uveal melanoma(UM)is the most frequent and life-threatening ocular malignancy in adults.Aberrant histone methylation contributes to the abnormal transcriptome during oncogenesis.However,a comprehensive understanding of histone methylation patterns and their therapeutic potential in UM remains enigmatic.Herein,using a systematic epi-drug screening and a high-throughput transcriptome profiling of histone methylation modifiers,we observed that disruptor of telomeric silencing-1-like(DOT1L),a methyltransferase of histone H3 lysine 79(H3K79),was activated in UM,especially in the high-risk group.Concordantly,a systematic epi-drug library screening revealed that DOT1 L inhibitors exhibited salient tumor-selective inhibitory effects on UM cells,both in vitro and in vivo.Combining Cleavage Under Targets and Tagmentation(CUT&Tag),RNA sequencing(RNA-seq),and bioinformatics analysis,we identified that DOT1 L facilitated H3K79 methylation of nicotinate phosphoribosyltransferase(NAPRT)and epigenetically activated its expression.Importantly,NAPRT served as an oncogenic accel-erator by enhancing nicotinamide adenine dinucleotide(NAD+)synthesis.Therapeutically,DOT1L inhi-bition epigenetically silenced NAPRT expression through the diminishment of dimethylation of H3K79(H3K79me2)in the NAPRT promoter,thereby inhibiting the malignant behaviors of UM.Conclusively,our findings delineated an integrated picture of the histone methylation landscape in UM and unveiled a novel DOT1L/NAPRT oncogenic mechanism that bridges transcriptional addiction and metabolic reprogramming.

Objective It combines medical big data and machine learning techniques to explore clinical outcomes based clinical physician performance evaluation method.Methods The non-negative principal component analysis(NPCA)was used in cases.Based on the non-negative sparse principal component analysis(NSPCA),a comprehen-sive index fitting was performed on 11 clinical performance indicators of 170 clinicians treating cardiovascular diseases.At the same time,confidence intervals were constructed based on root cause assessment techniques to calculate the range of indicators for each clinician.Results The coincidence rate of outpatient discharge diagnosis,the rate of grade A healing of surgical incision,the proportion of surgical patients,the rate of 3-day diagnosis,the proportion of third-grade and fourth-grade surgery,the completion of surgery and the number of operations were significant in dis-tinguishing the work performance of clinicians.However,the average length of hospital stays before surgery,the rate of unplanned readmission within 30 days,the average length of hospital stays of discharged patients,the main diag-nosis and cure/improvement,and the number of patients admitted were not significant in distinguishing the clinical work performance of clinicians.The overall work performance of all clinicians can be ranked through comprehensive index fitting,and the further evaluation of high,middle and low performance of each specific index can reveal the potential reconstruction dimensions of each clinician.Conclusion It utilizes machine learning techniques to achieve a comprehensive evaluation of clinical performance,utilizing medical big data as the foundation.It holds the potential to provide important support for a more scientific and objective assessment of clinical performance.

Retinoblastoma (RB) is the most serious eye disease that causes blindness, disability and death in infant. Loss of tumor suppressor gene RB1 leads to tumorigenesis of RB. With continuous innovation and development of new methods, the management of retinoblastoma has experienced a dramatic change from enucleation, external radiotherapy, intravenous chemotherapy, to intra-arterial chemotherapy combined with local treatment, enabling a more favorable outcome for survival, salvage and vision. However, the pathogenesis of RB is unclear in many aspects, the rate of eyeball removal in children with advanced RB remains high, and the innovation of new treatment are needed to be further promoted. Therefore, the key to improve the overall treatment level of RB is to pay attention to the study on pathogenesis, early diagnosis and treatment, as well as strengthen multi-center clinical trials and translational medicine research.

National education, medical industry demand and external environment all put forward the demand of training "medical + X" compound medical talents. In recent years, the development of "medical + X" has provided a foundation for the establishment of related majors in the undergraduate stage. This paper analyzes the current situation of medical interdisciplinary development at home and abroad, summarizes the existing "medical + X" training model at the undergraduate level, and argues that the new "medical + X" majors should be supported by optimizing the system design and focusing on the interdisciplinary frontier. At the same time, the setting of new majors of "Medical + X" should also pay attention to the three characteristics of livelihood, faculty and employment.

Learning from the clinical medicine program of North American medical schools, Shanghai Jiao Tong University School of Medicine (SJTUSM) has taken the lead in carrying out the "4+4" program of clinical medicine specialty in China since 2002, recruiting outstanding non-medical graduates to study for four years of medical courses. After 20 years of practice, SJTUSM has accumulated a series of effective school-running experience with Chinese characteristics, but there are also problems and puzzles. Based on the analysis and comparison of the "4+4" Clinical Medicine Program of SJTUSM with leading medical schools in the United States, such as Harvard Medical College and Stanford University Medical College, this paper discusses the training objectives, enrollment methods and scale, curriculum setting, degree-granting standards, etc. SJTUSM needs to strengthen the educational reform, improve the enrollment methods and curriculum system, strengthen the characteristics of compound talents training, and rationally balance the training of clinical and scientific research ability, so as to help promote the "4+4" clinical medical talents training mode to excellent.

Since the enrollment in 2002, the cultivation model of "4+4" program of clinical medicine in Shanghai Jiao Tong University School of Medicine has been continuously explored and practiced. With the goal of cultivating high-level compound outstanding medical innovative talents with multi-disciplinary cross-capacity, through strengthening the heuristic teaching, establishing the medical-engineering cross-course, emphasizing the training of scientific research ability, and taking teaching reform in the basic clinical single-circulation organ system integration course, we have established a talent training system with the characteristics of Shanghai Jiao Tong University School of Medicine, which is characterized by "thick foundation, strong practice, re-transformation, shaping norms, and international integration", and intend to make further exploration in the field of post-graduation education convergence.

Graves′ ophthalmopathy(GO) is an autoimmune disease closely related to thyroid diseases. Clinical manifestations of GO are various, making it hard to be diagnozed and treated. There are a number of treatments available clinically, however etiological treatment remains scarce. The choice of treatment, the evaluation of therapeutic effect and the prediction of patients′ outcomes should be rooted in the evaluation of patients′ condition. In this review, the clinical characteristics of GO were analyzed, and key points of assessment including risk factors, clinical activity, disease severity, quality of life and psychological status were also proposed. Clinicians are encouraged to shed more focus on the assessment of GO.

Dry eye affects a large number of people worldwide.A vicious cycle involving multiple factors tends to be implicated in its pathophysiology.Tear secretion is regulated by the sympathetic and parasympathetic nervous systems.Corneal nerve fibers secrete neurotransmitters and neuropeptides, which together participate in the maintenance of ocular surface homeostasis.Abnormal neuromodulation can cause abnormal tear secretion and a disruption of ocular surface homeostasis, leading to dry eye.The persistent abnormal tear film in dry eye can damage the normal repair system of ocular surface and leave the ocular surface and the lacrimal gland in a chronic inflammatory state.The cornea in dry eye patients is more sensitive to temperature change and mechanical stimulation than in healthy individuals.Symptomatic eye pain may be related to the effect of chronic inflammation on the corneal pain signal pathway.In vivo confocal microscopy and corneal esthesiometry can be used to evaluate the corneal nerve morphology and function in dry eye patients.This may ead to a more comprehensive treatment of dry eyes through the use of nerve related factors to nourish the cornea and the stimulation of neural pathways or related neural receptors to increase tear secretion.This study reviewed the relationship between neurosensory abnormalities and dry eye.

Thyroid-associated ophthalmopathy (TAO) is an organ specific autoimmune disease with complex pathogenesis.In recent years, great progress has been made in the pathogenesis of TAO primarily in immune and molecular mechanism aspects, including related autoantigens, lymphocytes, inflammatory factors, and autoimmune target tissue, that is, the role and biological behavior of orbital fibroblasts.Accordingly, various biological agents and immunosuppressive agents have emerged in an endless stream and have shown good effects and safety in clinical trials.Some important researches seem to be promising, but many novel therapies still are not extensively applied in clinical practice up to now.Therefore, it is of great significance to strengthen the basic research of TAO, fully understand its pathogenesis, research and develop more targeting drugs and precise clinical diagnosis and management of TAO, as well as improve the prognosis of patients.