New insights into ATR inhibition in muscle invasive bladder cancer:The role of apolipoprotein B mRNA editing catalytic subunit 3B

Background:Apolipoprotein B mRNA editing catalytic polypeptide(APOBEC),an endogenous mutator,induces DNA damage and activates the ataxia telangiectasia and Rad3-related(ATR)-checkpoint kinase 1(Chk1)pathway.Although cisplatin-based therapy is the mainstay for muscle-invasive bladder cancer(MIBC),it has a poor survival rate.Therefore,this study aimed to evaluate the efficacy of an ATR inhibitor combined with cisplatin in the treatment of APOBEC catalytic subunit 3B(APOBEC3B)expressing MIBC.Methods:Immunohistochemical staining was performed to analyze an association between APOBEC3B and ATR in patients with MIBC.The APOBEC3B expression in MIBC cell lines was assessed using real-time polymerase chain reaction and western blot analysis.Western blot analysis was performed to confirm differences in phosphorylated Chk1(pChk1)expression according to the APOBEC3B expression.Cell viability and apoptosis analyses were performed to examine the anti-tumor activity of ATR inhibitors combined with cisplatin.Results:There was a significant association between APOBEC3B and ATR expression in the tumor tissues obtained from patients with MIBC.Cells with higher APOBEC3B expression showed higher pChk1 expression than cells expressing low APOBEC3B levels.Combination treatment of ATR inhibitor and cisplatin inhibited cell growth in MIBC cells with a higher APOBEC3B expression.Compared to cisplatin single treatment,combination treatment induced more apoptotic cell death in the cells with higher APOBEC3B expression.Conclusion:Our study shows that APOBEC3B’s higher expression status can enhance the sensitivity of MIBC to cisplatin upon ATR inhibition.This result provides new insight into appropriate patient selection for the effective application of ATR inhibitors in MIBC.

遗传性出血性毛细血管扩张症致鼻出血1例

1临床资料患者,男,65岁,因反复鼻出血19年加重1个月,于2021-10-18收治入院。患者近19年来反复鼻出血,每次10~20 ml。19年前患者曾就诊于我科,给予鼻腔电凝止血等对症治疗,但术后半年开始无明显诱因下双侧鼻腔持续出血,多于每日夜间发作,交替性,出血量减少约为5~10 ml,均可自行止血。

Ataxia-telangiectasia mutated plays an important role in cerebellar integrity and functionality

Accumulating evidence indicates that ataxia-telangiectasia mutated kinase is critical for maintaining cellular homeostasis and that it has both nuclear and cytoplasmic functions.However,the functions of ataxia-telangiectasia mutated that when lost lead to cerebellar degeneration are still unknown.In this review,we first describe the role of ataxia-telangiectasia mutated in cerebellar pathology.In addition to its canonical nuclear functions in DNA damage response circuits,ataxia-telangiectasia mutated functions in various cytoplasmic and mitochondrial processes that are critically important for cellular homeostasis.We discuss these functions with a focus on the role of ataxia-telangiectasia mutated in maintaining the homeostatic redox state.Finally,we describe the unique functions of ataxia-telangiectasia mutated in various types of neuronal and glial cells including cerebellar granule neurons,astrocytes,and microglial cells.

Tranexamic acid may be a useful pharmacotherapy for endoscopically resistant small bowel angiodysplasia

Small bowel angiodysplasia(SBAD)is reported to account for nearly 50%of cases of small bowel bleeding.When SBAD occurs frequently,it is difficult to treat all the angiodysplasias endoscopically,and gastrointestinal bleeding often recurs.Hormone therapy,somatostatin analogs,thalidomide and vascular endothelial growth factor(VEGF)-neutralizing antibodies have been reported to reduce gastrointestinal angiodysplasia(GIAD)bleeding.However,there is no strong evidence to recommend them.Also,there are no guidelines for their use.Hereditary hemorrhagic telangiectasia(HHT)is a hereditary disease caused by abnormalities in VEGF,resulting in multiple GIADs.A treatment guideline has been created for GIAD in HHT,and the use of tranexamic acid,an antifibrinolytic agent,is the first recommendation pharmacotherapy for GIAD with gastrointestinal bleeding that is difficult to treat endoscopically.It has been reported that fibrinolysis is accelerated in GIAD patients who are not HHT,similar to HHT patients.The use of tranexamic acid for gastric antral vascular ectasia in GIAD has been reported to be useful.However,there are very few reports of its use for SBAD.There are concerns with tranexamic acid use regarding the development of thrombosis/embolism,but there are few reports of such side effects.Future clinical trials including tranexamic acid for SBAD are desired.

Multi-organ hereditary hemorrhagic telangiectasia:A case report

BACKGROUND Type 2 hereditary hemorrhagic telangiectasia(HHT)is a rare autosomal dominant disease and is associated with ALK1 gene mutations.Type 2 HHT patients primarily suffer from recurrent bleeding.There is currently no promising treatment.CASE SUMMARY A 5-year-old Chinese patient(III23)was admitted to Zhongshan Hospital for recurrent melena occurring over 2 mo.She had been experiencing epistaxis for years and had been diagnosed with idiopathic pulmonary hypertension 4 mo before presentation.Abdominal computed tomography examination showed hepatic arteriovenous malformation.Gene testing revealed a c.1121G>A mutation on the ALK1 gene.According to the international diagnostic criteria,this patient was diagnosed with HHT.In addition,8 more family members exhibited HHT symptoms to varying degrees.Gene testing in 5 family members(2 with HHT symptoms and 3 without HHT symptoms)revealed the ALK1 c.1121G>A mutation in the 2 family members with HHT symptoms.This missense mutation results in the substitution of arginine for glutamine at amino acid position 374(R374Q)in the conserved functional kinase domain of ALK1.Biological studies revealed that this mutation decreased the kinase activity of ALK1 and impeded the phosphorylation of its substrate Smad1.Moreover,the R374Q mutant downregulated the protein level of collagen-1,a fibrogenic factor,indicating abnormal fiber generation during vascular formation.CONCLUSION The R374Q mutant of ALK1 and its subsequent influence on fiber generation highly indicated its pathogenic role in this family with type 2 HHT.Detection of this gene mutation will facilitate early diagnosis of suspected type 2 HHT patients,and mechanistic studies will provide insights for future therapy.

Hereditary hemorrhagic telangiectasia involving portal venous system:A case report and review of the literature

BACKGROUND Hereditary hemorrhagic telangiectasia(HHT)is an autosomal dominant genetic disorder with an incidence of approximately 1 in 5000 in the general population.It is characterized by vasodilation,which affects specific organs,such as the skin,mucous membranes,brain,lungs,gastrointestinal tract,liver,and others.However,HHT rarely involves the portal venous system to cause serious clinical compli-cations.CASE SUMMARY A 68-year-old woman was admitted to the emergency department due to four consecutive days of abdominal pain and bloody stool and was subsequently diagnosed with HHT.Computed tomography angiography confirmed the presence of an arteriovenous fistula(AVFs).Considering this specific manifestation,whole exome sequencing was performed.After a comprehensive evaluation,a selective superior mesenteric artery embolization was prioritized to avoid intestinal ischemia.The postoperative symptoms of the patient were quickly relieved.Unfortunately,two months post-procedure the patient died from intestinal necrosis and abdominal infection related to remaining AVFs.CONCLUSION For patients with diffuse superior mesenteric AVFs,selective mesenteric arterial embolization may lead to positive short-term outcomes.

A Case Report of Concurrent Acne-Related Occurrence Complications: Telangiectasia, Post-Inflammatory Erythema, Post-Inflammatory Hyperpigmentation, and Atrophic and Hypertrophic Scars

Prior to his initial diagnosis, a 21-year-old male had been experiencing facial acne for two years and had been treated by a doctor in private practice. The patient visited our department because the clinical manifestations of mandibular acne did not improve. At the time of initial examination, telangiectasia (TE), post-inflammatory erythema (PIE), post-inflammatory hyperpigmentation (PIH), atrophic scars (ASs), and a hypertrophic scar (HS) with induration were observed on the right neck. We diagnosed this as an acne vulgaris complication. HS lesions were topically treated by injecting triamcinolone acetonide, and the patient was prescribed 8.1 g/day of oral Saireito (Japanese herb). Adapalene benzoyl peroxide gel and topical tacrolimus hydrate ointment were used to treat PIE and TE. Both HSs and PIE improved;however, TE and AS did not improve. Currently, the patient is under observation. We consider this to be a very rare concurrent occurrence of diverse complications of acne vulgaris, and present the following case study.

Rectitis Radiation a Problem of Therapeutic Management in Senegal about Two Cases

Radiotherapy occupies an important place in the management of cancers of the pelvic-perineal organs, it is at the origin of the fact of the ionizing radiations of radiation proctitis which is most often revealed by hematochezia. Diagnosis is based on rectoscopy which highlights a telengiectatic proctitis aspect. The standard treatment is endoscopic and based on argon plasma electrocoagulation. We report two cases of radiation proctitis occurring a few months after radiotherapy. Case number 1: A 76-year-old hypertensive patient known to have a history of cancer of the cervix treated with radiochemotherapy, she was received in an array of hematochezia of medium abundance;total colonoscopy found an aspect of telengiectatic proctitis making retain radiation proctitis. She had benefited from medical treatment, however, after a two-month follow-up, there was a recurrence of rectal bleeding despite medical treatment, due to the unavailability of endoscopic treatment based on argon plasma, surgical treatment of a type of protectomy had been carried out on postoperative follow-up was marked by a regression of hemorrhage with the occurrence of a. Case number 2: An 87-year-old patient, hypertensive, with a history of prostate adenocarcinoma 3 years ago treated with brachytherapy and hormone therapy;he was hospitalized with hematochesia. Rectosigmoidoscopy found an aspect of telengiectatic proctitis. The diagnosis of radiation proctitis had been retained and the patient had received medical treatment. The short-term evolution was marked by an amendment of the hematochezia with a long-term recurrence requiring endoscopic destruction via the diathermic loop of the telengiectatic lesions with good evolution without relapse after the procedure. Conclusion: Radiation proctitis is a major side effect of pelvic radiotherapy. Management is very difficult in our regions due to the unavailability of endoscopic means, in particular argon plasma.

Loss of BRCA1 expression leads to worse survival in patients with gastric carcinoma

AIM: To investigate the expression deficiency of key molecular markers in the homologous recombination pathway. METHODS: Expression loss of breast cancer type 1 susceptibility protein (BRCA1), ataxia telangiectasia mutated (ATM), ATM-Rad3-related (ATR), mediator of DNA damage checkpoint protein 1 (MDC1) and meiotic recombination 11 (Mre11) were correlated with their clinicopathological parameters in gastric cancer (GC). One hundred and twenty treatment-naive GC samples were formalin-fixed and paraffin-embedded into tissue blocks. Two representative cores from each block were extracted and constructed into tissue microarrays. Expression levels of BRCA1, ATM, ATR, MDC1 and Mre11 were determined using immunohistochemical analysis, and correlated with clinical parameters, including age, gender, Lauren subtype, tumor grades, clinical stage and overall survival.RESULTS: Expression loss of BRCA1, ATM, ATR, MDC1, and Mre11 was found in 21.4%, 20.2%, 21.0%, 11.1% and 4.6%, respectively, of interpretable cases. BRCA1 loss was significantly associated with patients of diffused subtype (intestinal vs diffused, 8.2% vs 31.7%, P = 0.001), higher tumor grade (Ⅰ/Ⅱ vs Ⅲ, 10.7% vs 20.5;Ⅰ/Ⅱ vs Ⅳ, 10.7% vs 54.5%, P = 0.047) and advanced clinical stage (Ⅰ/Ⅱ vs Ⅲ, 12.9% vs 16.9%;Ⅰ /Ⅱ vs Ⅳ, 12.9% vs 45.5%, P = 0.006). MDC1 loss was significantly associated with patients of diffused subtype (intestinal vs diffused, 0% vs 19.7%, P = 0.001) and higher tumor grade (Ⅰ/Ⅱ vs Ⅲ, 0% vs 12%;Ⅰ/Ⅱ vs Ⅳ, 0% vs 30.8%, P = 0.012). In addition, the survival time of the patients with expression loss of BRCA1 was significantly shorter than those with positive expression of BRCA1 (2-year survival rate, 32.4% vs 62.8%, P = 0.015). No correlations were found between clinicopathological parameters and expression loss of ATM, ATR and Mre11. CONCLUSION: Our results support the hypothesis that homologous recombination deficiency plays an important role in the progression of gastric carcinoma. Loss of expression of BRCA1 and MDC1 may serve as predictive factors in tumor development or progression in GC patients.

Pulmonary hypertension in hereditary haemorrhagic telangiectasia

Hereditary haemorrhagic telangiectasia(HHT) is an autosomal dominant inherited disorder characterised by vascular malformations in predominantly the brain,liverand lungs.Pulmonary hypertension(PH) is increasingly recognised as a severe complication of HHT.PH may be categorised into two distinct types in patients with HHT.Post-capillary PH most often results from a high pulmonary blood flow that accompanies the high cardiac output state associated with liver arteriovenous malformations.Less frequently,the HHT-related gene mutations in ENG or ACVRL1 appear to predispose patients with HHT to develop pre-capillary pulmonary arterial hypertension.Differentiation between both forms of PH by right heart catheterisation is essential,since both entities are associated with severe morbidity and mortality with different treatment options.Therefore all HHT patients should be referred to an HHT centre.

Macro-and microcirculation patterns of intrahepatic blood flow changes in patients with hereditary hemorrhagic telangiectasia

AIM To evaluated vascular dynamic processes in the liver of hereditary hemorrhagic telangiectasia(HHT) patients by ultrasound(US) considering quantitative analytic methods. METHODS The imaging features on US and contrast-enhanced ultrasound(CEUS) in 18 patients diagnosed with HHT were retrospectively analyzed. Regarding CEUS, realtime contrast harmonic imaging and sulfur hexafluoridefilled microbubbles were used. RESULTS HVa Ms were identified in all 18 patients. By US, the two major Caselitz criteria could be detected in 55.6% patients. "Color spots" were detected in 72.2% of the cases. Respecting sonographic grading criteria by Buscarini, grade 3 could be demonstrated most frequent(40%). By CEUS, all the patients showed quick and early hyperenhancement during the arterial phase. Significant lowest time to peak(TTP) and highest area under the curve(AUC) values were identified in the hepatic artery(TTP: 69.8%; AUC: 100%) and highest TTP and lowest AUC in the hepatic parenchyma and the portal vein. CONCLUSION For the first time we analyzed CEUS findings of a group of HHT patients regarding macro- and microcirculation. Our data demonstrate significant differences in TTP and AUC values in the four selected regions: hepatic artery, shunt region, portal vein and hepatic parenchyma.

A Novel ATM Antisense Transcript ATM-AS Positively Regulates ATM Expression in Normal and Breast Cancer Cells

Objective:The ataxia telangiectasia mutated(ATM)gene is a master regulator in cellular DNA damage response.The dysregulation of ATM expression is frequent in breast cancer,and is known to be involved in the carcinogenesis and prognosis of cancer.However,the underlying mechanism remains unclear.The bioinformatic analysis predicted a potential antisense transcript ATM-antisense(AS)from the opposite strand of the ATM gene.The purpose of this study was to identify ATM-AS and investigate the possible effect of ATM-AS on the ATM gene regulation.Methods:Single strand-specific RT-PCR was performed to verify the predicted antisense transcript ATM-AS within the ATM gene locus.qRT-PCR and Western blotting were used to detect the expression levels of ATM-AS and ATM in normal and breast cancer cell lines as well as in tissue samples.Luciferase reporter gene assays,biological mass spectrometry,ChIP-qPCR and RIP were used to explore the function of ATM-AS in regulating the ATM expression.Immunofluorescence and host-cell reactivation(HCR)assay were performed to evaluate the biological significance of ATM-AS in ATM-mediated DNA damage repair.Breast cancer tissue samples were used for evaluating the correlation of the ATM-AS level with the ATM expression as well as prognosis of the patients.Results:The ATM-AS significantly upregulated the ATM gene activity by recruiting KAT5 histone acetyltransferase to the gene promoter.The reduced ATM-AS level led to the abnormal downregulation of ATM expression,and impaired the ATM-mediated DNA damage repair in normal breast cells in vitro.The ATM-AS level was positively correlated with the ATM expression in the examined breast cancer tissue samples,and the patient prognosis.Conclusion:The present study demonstrated that ATM-AS,an antisense transcript located within the ATM gene body,is an essential positive regulator of ATM expression,and functions by mediating the binding of KAT5 to the ATM promoter.These findings uncover the novel mechanism underlying the dysregulation of the ATM gene in breast cancer,and enrich our understanding of how an antisense transcript regulates its host gene.

Bevacizumab and gastrointestinal bleeding in hereditary hemorrhagic telangiectasia

We report a case of severe, refractory gastrointestinal(GI) bleeding in a patient with hereditary hemorrhagic telangiectasia(HHT) whose massive transfusion dependence was lifted shortly after treatment with bevacizumab, an anti-vascular endothelial growth factor. The patient's bleeding had been refractory to repeated endoscopic interventions, tranexamic acid, and tamoxifen. However, following treatment with bevacizumab at 5 mg/kg every other week, nearly 300 units of packed red blood cell transfusions were avoided in one year's time. Despite its relatively high cost, bevacizumab may have a more active role in the management of severe GI bleeding in HHT if such remarkable response can be consistently demonstrated.

Interventional treatment of pulmonary arteriovenous malformations

Pulmonary arteriovenous malformations(PAVM) are congenital vascular communications in the lungs.They act as right to left shunts so that the blood running through these malformations is not oxygenated or filtered.These patients are typically hypoxaemic with exercise intolerance and are at high risk of paradoxical emboli to the brain and other organs.These malformations are most commonly seen in hereditary haemorrhagic telangiectasia(HHT)(Mb.Osler-Weber-Rendu syndrome).Nowadays,the generally accepted treatment strategy of first choice is embolization of the afferent arteries to the arteriovenous malformations.It is a minimally invasive procedure and at the same time a lung preserving treatment with a very high technical success,high effectiveness and low morbidity and mortality.Embolization prevents cerebral stroke and abscess as well as pulmonary haemorrhage and further raises the functional level.Embolization is a well-established method of treating PAVM,with a significant effect on oxygenation of the blood.Screening for PAVM in patients at risk is recommended,especially in patients with HHT.

Endoglin in liver fibrogenesis: Bridging basic science and clinical practice

Endoglin, also known as cluster of differentiation CD105, was originally identified 25 years ago as a novel marker of endothelial cells. Later it was shown that endoglin is also expressed in pro-fibrogenic cells including mesangial cells, cardiac and scleroderma fibroblasts, and hepatic stellate cells. It is an integral membranebound disulfide-linked 180 kDa homodimeric receptor that acts as a transforming growth factor-β(TGF-β) auxiliary co-receptor. In humans, several hundreds of mutations of the endoglin gene are known that give rise to an autosomal dominant bleeding disorder that is characterized by localized angiodysplasia and arteriovenous malformation. This disease is termed hereditary hemorrhagic telangiectasia type Ⅰ and induces various vascular lesions, mainly on the face, lips, hands and gastrointestinal mucosa. Two variants of endoglin(i.e., S- and L-endoglin) are formed by alternative splicing that distinguishes from each other in the length of their cytoplasmic tails. Moreover, a soluble form of endoglin, i.e.,sol-Eng, is shedded by the matrix metalloprotease-14 that cleaves within the extracellular juxtamembrane region. Endoglin interacts with the TGF-β signaling receptors and influences Smad-dependent and-independent effects. Recent work has demonstrated that endoglin is a crucial mediator during liver fibrogenesis that critically controls the activity of the different Smad branches. In the present review, we summarize the present knowledge of endoglin expression and function, its involvement in fibrogenic Smad signaling, current models to investigate endoglin function, and the diagnostic value of endoglin in liver disease.

Retinal circulation and its role in macular disorders in patients without systemic disease

AIM: To determine whether retinal circulatory changes play a role in the pathogenesis of macular disorders in patients who are otherwise healthy. METHODS: Patients with macular disorders that required angiographic imaging were included in this prospective case series. After a complete ocular exam,fluorescein angiography was performed using a standardized technique on the HRA-II(Heidelberg Engineering, Heidelberg, Germany) with special focus on the posterior pole. Only patients with good quality images were included in the analysis. Circulatory parameters recorded included the arm-choroid time,choroid-retinal artery, and finally the retinal artery-vein time. Zonal asymmetry(between the upper and lower zones divided by a line passing through the centre of the fovea) in transit times, if any was also noted. Appropriate statistical analysis was done. Circulation times were compared with age matched historical controls. Changes in retinal dye transit times relative to historical age matched controls, if any, were noted and compared between various disorders.RESULTS: A total of 156 eyes of 156 patients(120 males)were included in the study. Mean age: 49.14 ±14.93 y.Macular disorders studied were age related degeneration,polypoidal vasculopathy, central serous chorioretinopathy(CSCR) and parafoveal telangiectasia. Delayed circulation time was noted in CSCR patients only.CONCLUSION: CSCR patients appear to have delayed arterial filling, retinal circulatory disturbances do not seem to contribute to the pathogenesis of other macular disorders.

Bleeding and clotting in hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia(HHT) is arelatively common inherited vascular disorder that was first described in 1864, and is notable for epistaxis, telangiectasia, and arterial venous malformations. While genetic tests are available, the diagnosis remains clinical, and is based on the Curacao criteria. Patients with HHT are at increased risk for both bleeding and clotting events. Because of these competing complications, hematologists are often faced with difficult clinical decisions. While the majority of management decisions revolve around bleeding complications, it is not infrequent for these patients to require anticoagulation for thrombosis. Any anticoagulation recommendations must take into account the bleeding risks associated with HHT. Recent reviews have found that HHT patients can be safely anticoagulated, with the most frequent complication being worsened epistaxis. Large clinical trials have shown that factor Ⅱa and Ⅹa inhibitors have less intracranial bleeding than warfarin, and basic coagulation research has provided a possible mechanism. This article describes the anticoagulation dilemma posed when a 62-year-old female patient with a history of bleeding events associated with HHT was diagnosed with a pulmonary embolism. The subsequent discussion focuses on the approach to anticoagulation in the HHT patient, and addresses the role of the new oral anticoagulants.

Gastric angiodysplasia in a hereditary hemorrhagic telangiectasia type 2 patient

Hereditary hemorrhagic telangiectasia(HHT)is a rare autosomal-dominantly inherited disease that occurs in approximately one in 5000 to 8000 people.Clinical diagnosis of HHT is made when a person presents three of the following four criteria:family history,recurrent nosebleeds,mucocutaneous telangiectasis,and arteriovenous malformations(AVM)in the brain,lung,liver and gastrointestinal(GI)tract.Although epistaxis is themost common presenting symptom,AVMs affecting the lungs,brain and GI tract provoke a more serious outcome.Heterozygous mutations in endoglin,activin receptor-like kinase 1(ACVRL1;ALK1),and SMAD4,the genes involved in the transforming growth factor-βfamily signaling cascade,cause HHT.We report here the case of a 63 year-old male patient who presented melena and GI bleeding episodes,proven to be caused by bleeding from multiple gastric angiodysplasia.Esophagogastroduodenoscopy revealed multiple angiodysplasia throughout the stomach.Endoscopic argon plasma coagulation was performed to control bleeding from a gastric angiodysplasia.The patient has been admitted several times with episodes of hemoptysis and hematochezia.One year ago,the patient was hospitalized due to right-sided weakness,which was caused by left basal ganglia hemorrhage as the part of HHT presentation.In family history,the patient's mother and elder sister had died,due to intracranial hemorrhage,and his eldest son has been suffered from recurrent epistaxis for 20 years.A genetic study revealed a mutation in exon 3 of ALK1(c.199C>T;p.Arg67Trp)in the proband and his eldest son presenting epistaxis.

Role of octreotide in small bowel bleeding

Gastrointestinal bleeding accounts for a drastic negative impact on the quality of the patients’lives as it requires multiple diagnostic and therapeutic interventions to identify the source of the bleeding.Small bowel bleeding is the least common cause of gastrointestinal bleeding.However,it is responsible for the majority of complaints from patients with persisting or recurring bleeding where the primary source of bleeding cannot be identified despite investigation.A somatostatin analog known as octreotide is among the medical treatment modalities currently used to manage small bowel bleeding.This medication helps control symptoms of gastrointestinal bleeding by augmenting platelet aggregation,decreasing splanchnic blood flow,and antagonizing angiogenesis.In this review article,we will highlight the clinical efficacy of octreotide in small bowel bleeding and its subsequent effect on morbidity and mortality.