Epigenetic drug library screening reveals targeting DOT1L abrogates NAD+synthesis by reprogramming H3K79 methylation in uveal melanoma / 药物分析学报

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.

Research on Performance Evaluation of Clinical Physicians Based on Medical Big Data / 中国医院管理

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.

FBXO38 regulates ocular melanoma proliferation through the PI3K-Akt signaling pathway / 上海交通大学学报（医学版）

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.

Graves′ ophthalmopathy: emphasis on assessment / 中华内分泌代谢杂志

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.

Thinking of medical major setting under the background of "New Medicine" / 中华医学教育探索杂志

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.

"4+4" Clinical Medicine Program: comparison and thinking on the model of America and Shanghai Jiao Tong University School of Medicine / 中华医学教育探索杂志

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.

Exploration and practice of clinical medicine "4+4" program for the cultivation model of innovative talents: taking Shanghai Jiao Tong University School of Medicine as an example / 中华医学教育探索杂志

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.

Pay attention to the research on the mechanism of retinoblastoma and the methods of diagnosis and treatment / 中华眼底病杂志

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.

Association between neurosensory abnormalities and dry eye / 中华实验眼科杂志

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.

The importance of basic research and drug development for thyroid-associated ophthalmopathy / 中华实验眼科杂志

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.

Classification and treatment of orbital venous malformations: an updated review / 医学前沿

Orbital venous malformation (OVM) is a congenital vascular disease. As a common type of vascular malformation in the orbit, OVM may result in vision deterioration and cosmetic defect. Classification of orbital vascular malformations, especially OVMs, is carried out on the basis of different categories, such as angiogenesis, hemodynamics, and locations. Management of OVM is complicated and challenging. Treatment approaches include sclerotherapy, laser therapy, embolization, surgical resection, and radiotherapy. A satisfactory outcome can be achieved only by selecting the appropriate treatment according to lesion characteristics and following the sequential multi-method treatment strategy. This article summarizes the current classification and treatment advances in OVM.

Modified levator lengthening for thyroid-associated ophthalmopathy related upper eyelid retraction / 上海交通大学学报（医学版）

Objective · To improve the surgical procedure of correcting upper eyelid retraction.Methods · Patients suffering upper eyelid retraction of 2-5 mm caused by thyroid-associated ophthalmopathy were treated with modified levator lengthening technique in Shanghai Ninth People's Hospital (Shanghai Jiao Tong University School of Medicine,China) from July 2013 to December 2014.Results· Of the 34 patients underwent the modified levator lengthening surgery for upper eyelid retraction correction,there were 7 males and 27 females.After 6 months,upper eyelid retraction got fully resolved in 25 cases and partly improved in 9 cases.The palpebral fissure height demonstrated an average decrease of 3.7 mm (P=0.000).Patient's ocular discomfort such as photophobia and tearing were either cured or improved.Conclusion · Modified levator lengthening surgery can effectively correct upper eyelid retraction,improve the patient's appearance and cure their ocular discomfort.

A research on three-dimensional reconstruction of nasolacrimal duct in lacrimal surgery / 生物医学工程学杂志

In this paper, we present a new method which can reconstruct the three-dimensional model of nasolacrimal duct. We firstly resampled the volume data along nasolacrimal duct direction, then segmented the nasolacrimal duct into slices, and finally, completed the 3D reconstruction from the two-D contours. Using this method, we can not only reconstruct normal nasolacrimal duct, but also reconstruct catagmatic nasolacrimal duct. It overcomes the current shortcomings of some traditional methods. Consequently, the technology proposed is of great significance in computer aided technique and surgical planning related to ophthalmonogy.

Electrical stimulation promotes BDNF expression in spinal cord neurons through Ca(2+)- and Erk-dependent signaling pathways.

Brief electrical stimulation has been shown to be effective in promoting neuronal regeneration following peripheral nerve injury. These effects are thought to be mediated largely by the upregulation of the expression of brain-derived neurotrophic factor (BDNF) in spinal cord neurons. However, the molecular mechanisms by which electrical stimulation can promote BDNF expression are not known. The mechanism involved in BDNF expression after electrical stimulation was explored in this study. Immunohistochemistry and Western blotting were used to test BDNF expression. Confocal microscopy was utilized to study intracellular Ca(2+) volume. Immunohistochemistry and Western blotting confirmed that brief electrical stimulation increased BDNF expression in spinal cord neurons both in vivo and in vitro. Treatment of cultured neurons with nifedipine, an inhibitor of voltage-gated calcium channels, significantly reduced the BDNF increase produced by electrical stimulation, and an inhibitor of Erk completely abolished the effect of electrical stimulation. Levels of BDNF expression in the presence of the Erk inhibitor were lower that in unstimulated and untreated controls, indicating that Erk activation is required to maintain baseline levels of BDNF. Confocal microscopy using a Ca(2+)-sensitive fluorochrome revealed that electrical stimulation is accompanied by an increase in intracellular Ca(2+) levels; the increase was partly blocked by nifedipine. These findings argue that electrical stimulation increases BDNF expression in spinal cord neurons by activating a Ca(2+)- and Erk-dependent signaling pathways.

On the curriculum construction of medical students' occupational career planning / 中华医学教育探索杂志

The curriculum construction of medical students' occupational career planning has its own character. Principles of curriculum construction siuh as practical object, professional content and target-oriented organization should be sticked to and four aspects of curriculum construction such as target,content, organization and evaluation. are discussed in detail.

Clinical application of superficial temporal artery island flap in the reconstruction of eyelid and periorbital defect / 眼科研究

Serious defect of eyelid and periorbital tissue affects the appearance of patients and closure-eye function.Application of superficial temporal artery island flap to repair the defected tissue is considered to be an available method to reconstruct eyelid and periorbital tissue.ObjectiveThis study aims to investigate the indication,safety and effectivity of reconstructing the serious defect of eyelid and periorbital tissue by forward flow flap.MethodsEighteen eyes of 18 cases with serious eyelid and periorbital tissue defect were reconstructed by covering the defect zone with superficial temporal artery to form forward flow flap.The flap was made along the distribution of superficial temporal artery with the size over the tissue detect area and transferred to lesion via subcutaneous tunnel.The follow-up time was 6 months.Survival status of flap,plastic condition of lesion and surgical treatment were discussed.ResultsAmong 18 cases with eyelid and periorbital defect,the flaps were survived in 16 cases with the satisfactory repairing appearance,showing nice color,soft texture and normal sensation after plastic surgery.Reconstructed eyelids closed well.One case showed the temporary obstruction of venous refluence in early stage after operation and remained distal epidermal necrosis.Reoperation was performed in 6 patients because of flap hypertrophy and showed a successful outcome.One patients occurred the failure of plastic flap due to hypertrophy and underwent free-flap transplantation in 3 months following the first surgery and obtained a ultimately flap survival.ConclusionThe superficial temporal artery forward flow flap offers a stable and reliable blood supplying and provides adequate tissue of excellent color and texture match.It is an ideal and available flap for the reconstruction of serious eyelid and periorbital tissue defect.

The effect mechanism of pharmacological vitreolysis with plasmin and hyaluronidase / 眼科研究

Background Many ophthalmologists have proved that the intravitreal injection of plasmin can safely induce posterior vitreous detachment(PVD),but if it can generate the complete PVD need further to seek confirmation.Researches showed that the safe dose and toxicity dose of dispase are very near,so its application is limited.Whether hyaluronidase can induce PVD is still in controversy.Objective This study is to clarity the mechanism of pharmacological vitreolysis with plasmin and hyaluronidase.Methods Plasmin 4μmol/L,2μmol/L and 1μmol/L,plasmin 1μmol/L+ hyaluronidase 20μmol/L,hyaluronidase alone were intravitreally injected in lateral eye of 4 clean New Zealand white rabbits respectively,and 0.1mL BSS was injected as control group.Electron immunocytochemical technique was used to detect the laminin and fibronectin of interface between vitreous and retina in 7 days after intravitreal injection.Other 14 eyes of 7 clean New Zealand white rabbits were used in this study.Plasmin 1μmol/L + hyaluronidase 20μmol/L was intravitreally injected in the lateral eyes,and only plasmin 1μmol/L was injected in the fellow eyes.Plasmin activity in vitreous was evaluated in 15 and 30 minutes,1 hour,2,3,6,12 hours after intravitreal injection.The use of animals followed the Regulations for the Administration of Affair Concerning Experimental Animals by State Science and Technology Commission.Results The amounts of laminin and fibronectin in the vitreoretinal interface were decreased in 4μmol/L plasmin group,2μmol/L plasmin group,1μmol/L plasmin group,1μmol/L plasmin+20μmol/L hyaluronidase group compared with control group(P＜0.01).No significant difference was seen in the density of gold particles of anti FN between 20μmol/L hyaluronidase group and control group (P＞0.05).The change of amounts of fibronectin in the vitreoretinal interface was similar to that of laminin.Plasmin activity remained the highest level 1 hour after injection and thereafter gradually decreased and extincted in 12 hours and presented the same trend between plasmin 1μmol/L+hyaluronidase 20μmol/L group and only plasmin 1μmol/L group.Conclusion The mechanism of pharmacological vitreolysis is to dissolve laminin and fibronectin in the interface between vitreous and retina and therefore induce PVD.Combination of plasmin with hyaluronidase can increase the efficiency of pharmacological vitreolysis.The optimum selection of drug in inducing PVD should consider not only its role of lysis laminin and fibronectin but also the role of liquefying the vitreous.

The effect of cyclopentolate cycloplegic on the refraction measurement in adult guinea pigs / 眼科

Objective To investigate the effect of cyclopentolate cycloplegic on the refraction measurement in adult guinea pigs. Design Experimental study.Participants 24 eyes of 12(10 weeks) adult guinea pigs.Methods 12 animals were randomly examined thrice by streak retinoscopy pre and post mydriasis.1%cyclopentolate hydrochloride was topically administrated to the eye every five minutes for three times.Main Outcome Measures The eye refraction of guinea pigs included the scope,cylinder and the equivalent power.Results The average refraction of guinea pigs in pre-mydriasis and post-mydriasis were 1.92?0.79 D and 2.08?0.79 D respectively. The average refraction that included the scope,cylinder and the equivalent power all showed no significant difference between pre and post mydriasis.The effect of mydriasis and measure time points on the refraction that included the scope,cylinder and the equivalent scope showed no significant difference either.Conclusions The effect of 1%cyclopentolate cycloplegic on adult guinea pigs in refraction is limited.The refraction of adult guinea pig can be measured naturally without cyclopentolate cycloplegic administrated.

Treatment of nasolacrimal duct obstruction / 眼科

Dacryocystorhinostomy(DCR) has been regarded as the gold standard for the treatment of nasal lacrimal duct obstruction for over a hundred years.Currently,the treatment of nasolacrimal duct obstruction has grown along with the advances in endoscopic techniques developing and in-depth understanding of the mechanisms of lacrimal drainage.Endoscopic dacryocystorhinostomy,endolacrimal laser and intubation,lacrimal endoscopic recanalization and lacrimal bypass surgery have been employed to substitute for external DCR as treatment for nasolaerimal duct obstruction.The endoscope,laser and minimally invasive techniques provide higher successful rates with minimal wounds,lower rates of both recurrence and complications and allow quicker recovery after surgery.

A study on the relationship of the electroretinographic scotopic b-wave amplitude to flash intensity / 眼科

The dark adapted electroretinogram was recorded in 30 eyes of New Zealand rabbits and 30 normal eyes of human volunteers.With the visual electrophy- siologic recording system,each eye being tested with intensities of a range of 5 log units,to study the intensity-response function of the scotopic b- wave of electroretinogram.It was found that the intensity-response function of the scotopic b-wave was a sigmoidal curve which fitted to the Naka- Rushton Equation:R/Rmax=I~n/(I~n+K~n)only at low to moderate flash luminances:at high flash lumi- nances,a second limb appeared in the function,which represented a complex combination of the rod system response and the cone system response.