Novel mutations in the BEST1 gene cause distinct retinopathies in two Chinese families

AIM:To describe the clinical heterogeneity of patients with novel mutations in BEST1.METHODS:All the members in the two Chinese families underwent detailed clinical evaluations including best-corrected visual acuity,slit-lamp examination,applanation tonometry,and dilated fundus examination.Fundus autofluorescence,fundus fluorescein angiography,spectral-domain optical coherence tomography,electrooculography,and electroretinogram were also performed.Genomic DNA was extracted from venous blood for all the participants.The targeted next-generation sequencing of inherited retinal disease-associated genes was conducted to identify the causative mutation.RESULTS:A novel BEST1 missense mutation c.41T>C(p.Leu14Ser) was identified in Family 1.It was co-segregated with the phenotype of best vitelliform macular dystrophy(BVMD) and bioinformatics analysis confirmed it was harmful.Another novel BEST1 frameshift mutation c.345_(3)46insGGCAAGGACG(p.Glu119Glyfs*116) and a novel USH2A missense mutation c.12560G>A,p.Arg4187 His were identified in family 2 with retinitis pigmentosa(RP),which might interact and lead to the phenotype of RP.CONCLUSION:Two novel mutations in the BEST1 gene in two unrelated families with distinct phenotypes and BEST1 mutation accompanied with USH2A mutation would result in RP,which could be enormously helpful in understanding the pathogenesis of the inherited retinal disease caused by a BEST1 mutation.

Bacterial outer membrane vesicles-based therapeutic platform eradicates triple-negative breast tumor by combinational photodynamic/chemo-/immunotherapy

Bacterial outer membrane vesicles(OMVs)are potent immuno-stimulating agents and have the potentials to be bioengineered as platforms for antitumor nanomedicine.In this study,OMVs are demonstrated as promising antitumor therapeutics.OMVs can lead to beneficial M2-to-M1 polarization of macrophages and induce pyroptosis to enhance antitumor immunity,but the therapeutic window of OMVs is narrow for its toxicity.We propose a bioengineering strategy to enhance the tumor-targeting ability of OMVs by macrophage-mediated delivery and improve the antitumor efficacy by co-loading of photosensitizer chlorin e6(Ce6)and chemotherapeutic drug doxorubicin(DOX)into OMVs as a therapeutic platform.We demonstrate that systemic injection of the DOX/Ce6-OMVs@M therapeutic platform,providing combinational photodynamic/chemo-/immunotherapy,eradicates triple-negative breast tumors in mice without side effects.Importantly,this strategy also effectively prevents tumor metastasis to the lung.This OMVs-based strategy with bioengineering may serve as a powerful therapeutic platform for a synergic antitumor therapy.

Targeting brain-derived neurotrophic factor in the treatment of neurodegenerative diseases:A review

Neurodegenerative diseases,marked by the gradual death of neurons,present a significant and growing public health challenge.Brain-derived neurotrophic factor(BDNF)is crucial for the survival,development,and synaptic plasticity of neurons.Studies have consistently demonstrated that perturbed BDNF communication pathways are associated with the development and progression of neurodegenerative conditions,underscoring their potential as therapeutic targets.This review aimed to summarize the existing findings regarding BDNF expression,metabolism,and signaling transduction.Furthermore,we reviewed the intricate roles of BDNF signaling pathways in neurodegenerative diseases,elucidating their contributions to disease onset and progression.The latest advancements in targeting BDNF for the treatment of neurodegenerative diseases,including the development of small molecules,nucleic acid-based therapeutics,and antibody-based approaches,were also summarized.Despite recent strides,challenges persist,including a lack of comprehensive understanding of BDNF modulation across diverse neurodegenerative contexts and the absence of clinically approved BDNF-targeted drugs.

Sinistral portal hypertension associated with pancreatic pseudocysts - ultrasonography findings: A case report

BACKGROUND Sinistral portal hypertension associated with pancreatic pseudocysts is rare,often caused by extrinsic compression of splenic vein,the follow-up examinations by ultrasonography for early diagnosis are quietly necessary since haematemesis,a life-threatening condition.Few studies have reported the ultrasonography findings of sinistral portal hypertension.CASE SUMMARY A 52-year-old man presented with acute abdominal pain after drinking,steatorrhea,weight loss and accidentally melena in the past 2 mo.He underwent ultrasound-guided fine needle aspiration in other hospital and diagnosed with pancreatic pseudocysts.Ultrasonography imaging,in our department,appeared as cystic heterogeneous hypoechoic area with the size of 4.7 cm×3.8 cm that located posterior to the body and tail of pancreas,adjacent to splenic vein associated with thrombosis resulted from compression.Spleen incrassated to approximately 7.3 cm,but no dilation of main portal vein was presented.Color Doppler Flow Imaging demonstrated the formation of splenic venous collateral,nevertheless no significantly flow signals was observed in splenic vein.Pulsed Doppler revealed that the peak velocity of splenic venous collateral was 18.4 cm/s with continuous waveform.Laparotomy confirmed sinistral portal hypertension associated with pancreatic pseudocysts,subsequently distal pancreatectomy combined with splenectomy and partial gastrectomy was performed.CONCLUSION It’s important clinically to know the ultrasound appearance of sinistral portal hypertension associated with pancreatic pseudocysts for sonographer and physician.

Application of imaging techniques in pancreaticobiliary maljunction

Imaging techniques are useful tools in the diagnosis and treatment of pancreaticobiliary maljunction(PBM).PBM is a precancerous lesion often relative to the disease of the pancreas and biliary tract,for example,cholecystolithiasis,protein plugs,and pancreatitis.For patients with PBM,early diagnosis and timely treatment are highly important,which is largely dependent on imaging techniques.The continuous development of imaging techniques,including endoscopic retrograde cholangiopancreatography,magnetic resonance cholangiopancreatography,computed tomography,ultrasound,and intraoperative cholangiography,has provided appropriate diagnostic and therapeutic tools for PBM.Imaging techniques,including non-invasive and invasive,have distinct advantages and disadvantages.The purpose of this paper is to review the application of various imaging techniques in the diagnosis and treatment of PBM.

Corrigendum to ‘Modeling colorectal tumorigenesis using the organoids derived from conditionally immortalized mouse intestinal crypt cells (ciMICs)’ [Genes Dis 8 (2021) 814-826]

The authors regret that an image assembly(copy/paste)error in Figure 3D,in which the image for the organoid of"Primary MiCs"group was erroneously duplicated with an image of primary MICs that was previously published.The corrected figure is shown below.As shown in the corrected Figure 3D,this error does not adversely impact the conclusion of the original work.The authors would like to apologise forany inconvenience caused.

Modeling colorectal tumorigenesis using the organoids derived from conditionally immortalized mouse intestinal crypt cells (ciMICs)

Intestinal cancers are developed from intestinal epithelial stem cells(ISCs)in intestinal crypts through a multi-step process involved in genetic mutations of oncogenes and tumor suppressor genes.ISCs play a key role in maintaining the homeostasis of gut epithelium.In 2009,Sato et al established a three-dimensional culture system,which mimicked the niche microenvironment by employing the niche factors,and successfully grew crypt ISCs into organoids or Mini-guts in vitro.Since then,the intestinal organoid technology has been used to delineate cellular signaling in ISC biology.However,the cultured organoids consist of heterogeneous cell populations,and it was technically challenging to introduce genomic changes into three-dimensional organoids.Thus,there was a technical necessity to develop a twodimensional ISC culture system for effective genomic manipulations.In this study,we established a conditionally immortalized mouse intestinal crypt(ciMIC)cell line by using a piggyBac transposon-based SV40 T antigen expression system.We showed that the ciMICs maintained long-term proliferative activity under two-dimensional niche factor-containing culture condition,retained the biological characteristics of intestinal epithelial stem cells,and could form intestinal organoids in three-dimensional culture.While in vivo cell implantation tests indicated that the ciMICs were non-tumorigenic,the ciMICs overexpressing oncogenic b-catenin and/or KRAS exhibited high proliferative activity and developed intestinal adenoma-like pathological features in vivo.Collectively,these findings strongly suggested that the engineered ciMICs should be used as a valuable tool cell line to dissect the genetic and/or epigenetic underpinnings of intestinal tumorigenesis.

Dissection-related carotid-cavernous fistula(CCF)following surgical revascularization of chronic internal carotid artery occlusion:a new subtype of CCF and proposed management

Background:The development of carotid-cavernous fistulas(CCFs)during surgical recanalization of chronic internal carotid artery occlusion(ICAO)may be secondary to severe ICA dissection rather than a focal tear of the cavernous ICA seen in typical traumatic CCFs.The purpose of this study is to investigate the causal relationship between the CCFs and severe ICA dissections and to characterize technical outcomes after treatment with stenting.Methods:Five patients underwent treatment with self-expanding stents due to intraprocedural CCF and ICA dissection following surgical removal of ICAO plaque.The stents were telescopically placed via true channel of the dissection.Safety of the procedure was evaluated with 30-day stroke and death rate.Procedural success was determined by the efficacy of CCF obliteration and ICAO recanalization with angiography.Results:All CCFs were associated with spiral and long segmental dissection from the cervical to cavernous ICA.After stenting,successful dissection reconstruction with TICI 3 was achieved in all patients,with complete(n=4)or partial CCF(n=1)obliteration.No patient had CCF syndrome,stroke,or death during follow-up of 6 to 37 months;but one patient had pulsatile tinnitus,which resolved 1 year later.Angiography at 6 to 24 months demonstrated CCF obliteration in all 5 patients and durable ICA patency in 4 patients.Conclusions:Intraprocedural CCFs with spiral and cervical-to-cavernous ICA dissection during ICAO surgery are dissection-related because of successful obliteration after stenting for dissection reconstruction.Self-expanding stenting through true channel of the dissection,serving as implanting stent-autograft,may be an optimal therapy for the atypical CCF complication from ICAO surgery.