- Malignant Peritoneal Mesothelioma in an Infant With Familial ATM Mutations. [Journal Article]
- JPJ Pediatr Hematol Oncol 2018 Aug 17
- Ataxia-telangiectasia (A-T), an autosomal recessive disorder characterized by progressive neurological dysfunction, oculocutaneous telangiectasia, immunodeficiency, and cancer susceptibility, is caus...
Ataxia-telangiectasia (A-T), an autosomal recessive disorder characterized by progressive neurological dysfunction, oculocutaneous telangiectasia, immunodeficiency, and cancer susceptibility, is caused by mutations in the ATM gene. A previous study of 4 A-T patients identified 2 rare homozygous missense mutations residing on the same allele of the ATM gene: c.1514T>C and c.1547T>C, which were shown to decrease ATM levels and increase T-cell acute lymphoblastic leukemia predisposition. We studied 5 patients from 2 consanguineous Bedouin families of the same tribe, presenting with A-T. Whole-exome sequencing data identified the 2 aforementioned mutations in ATM, which segregated within all family members as expected of autosomal recessive heredity. Interestingly, one individual was diagnosed with malignant peritoneal mesothelioma (MPM), an extremely rare neoplasm in pediatric patients. Here, we describe a case of a 4-month-old infant homozygous for the 2 ATM mutations, who developed MPM and died by the age of 2 years. To the best of our knowledge, this is the first case of peritoneal mesothelioma in an infant bearing ATM mutations, and one of the youngest pediatric mesotheliomas described. Thus, the risk of MPM might be considered in the follow-up of A-T patients, and ATM mutations sought in cases of early-onset MPM.
- Histone Ubiquitination by the DNA Damage Response Is Required for Efficient DNA Replication in Unperturbed S Phase. [Journal Article]
- MCMol Cell 2018 Jul 24
- Chromatin ubiquitination by the ubiquitin ligase RNF168 is critical to regulate the DNA damage response (DDR). DDR deficiencies lead to cancer-prone syndromes, but whether this reflects DNA repair de...
Chromatin ubiquitination by the ubiquitin ligase RNF168 is critical to regulate the DNA damage response (DDR). DDR deficiencies lead to cancer-prone syndromes, but whether this reflects DNA repair defects is still elusive. We identified key factors of the RNF168 pathway as essential mediators of efficient DNA replication in unperturbed S phase. We found that loss of RNF168 leads to reduced replication fork progression and to reversed fork accumulation, particularly evident at repetitive sequences stalling replication. Slow fork progression depends on MRE11-dependent degradation of reversed forks, implicating RNF168 in reversed fork protection and restart. Consistent with regular nucleosomal organization of reversed forks, the replication function of RNF168 requires H2A ubiquitination. As this novel function is shared with the key DDR players ATM, γH2A.X, RNF8, and 53BP1, we propose that double-stranded ends at reversed forks engage classical DDR factors, suggesting an alternative function of this pathway in preventing genome instability and human disease.
- Photodynamic therapy for rosacea in Chinese patients. [Journal Article]
- PPPhotodiagnosis Photodyn Ther 2018 Aug 14
- CONCLUSIONS: ALA-PDT is an effective and safe approach for the treatment of rosacea of erythematotelangiectatic or papulopustular types, to control clinical manifestations and reduce subjective symptoms.
- Polo-like kinase 1 inhibitor BI 6727 induces DNA damage and exerts strong antitumor activity in small cell lung cancer. [Journal Article]
- CLCancer Lett 2018 Aug 14; 436:1-9
- The prognosis of small cell lung cancer (SCLC) is poor despite its good initial response to chemotherapy. Polo-like kinase 1 (PLK1) is a crucial mitotic regulator that is overexpressed in many tumors...
The prognosis of small cell lung cancer (SCLC) is poor despite its good initial response to chemotherapy. Polo-like kinase 1 (PLK1) is a crucial mitotic regulator that is overexpressed in many tumors, and its overexpression is associated with tumor aggressiveness and a poor prognosis. However, its role in SCLC is still poorly characterized. Based on immunohistochemistry findings, the PLK1 protein is expressed at higher levels in SCLC tumor samples than in normal lung tissue samples. The selective PLK1 inhibitor BI 6727 significantly induced the inhibition of proliferation and apoptosis in a dose-dependent manner in SCLC cell lines. FACS analysis showed an increase in the population of cells in the G2/M phase, followed by DNA damage and the consequent activation of the ataxia telangiectasia and Rad3-related (ATR)/ataxia telangiectasia mutated (ATM)-Chk1/Chk2 checkpoint pathway. In addition, BI 6727 treatment resulted in clearly attenuated growth and apoptosis in NCI-H446 xenografts. The level of histone H2AX phosphorylation at serine-139 (γH2AX) was markedly increased both in vitro and in vivo. Our findings indicate that BI 6727 has therapeutic potential for SCLC patients.
- Next-generation sequencing reveals mutational accordance between cell-free DNA from plasma, malignant pleural effusion and ascites and directs targeted therapy in a gastric cancer patient. [Journal Article]
- CBCancer Biol Ther 2018 Aug 17; :1-6
- Cell-free DNA (cfDNA) has been a research hotspot in molecular tumor profiling. In advanced gastric cancer patients, malignant pleural effusion (MPE) and ascites provide a wealth of tumor cells that ...
Cell-free DNA (cfDNA) has been a research hotspot in molecular tumor profiling. In advanced gastric cancer patients, malignant pleural effusion (MPE) and ascites provide a wealth of tumor cells that can be investigated. Here we conducted next-generation sequencing (NGS) on matched cfDNA from plasma, MPE and ascites from a stage-IV gastric cancer patient to identify potential therapeutic targets. In all three samples, we detected an amplification in the cellular-mesenchymal to epithelial transition factor (MET) gene, a truncation mutation in SMAD3 (p.R368X), and four ataxia telangiectasia-mutated gene (ATM) variants, including a missense mutation (p.E2351A), an in-frame deletion (p.NPAVIM2353delinsK), a frame-shift deletion (p.D1758fs) and an ATM- BPI fold containing family B member 1 (BPIFB1) gene fusion. In contrast, we detected amplification of TEK only in malignant ascites. The patient was subjected to Crizotinib to counter MET amplification. Our study demonstrates high accordance in mutational spectra of matched cfDNA from plasma, MPE and ascites, and suggests that it is feasible to utilize these tumor sources in clinical decision-making.
- Fluorescence Lifetime Imaging Ophthalmoscopy: A Novel Way to Assess Macular Telangiectasia Type 2. [Journal Article]
- OROphthalmol Retina 2018; 2(6):587-598
- CONCLUSIONS: FLIO detects retinal changes in patients with MacTel with high contrast, presenting a distinctive signature that is a characteristic finding of the disease. The non-invasive properties of this novel imaging modality provide a valuable addition to clinical assessment of early changes in the disease that could lead to more accurate diagnosis of MacTel.
- European Reference Network For Rare Vascular Diseases (VASCERN) Outcome Measures For Hereditary Haemorrhagic Telangiectasia (HHT). [Journal Article]
- OJOrphanet J Rare Dis 2018 Aug 15; 13(1):136
- Hereditary haemorrhagic telangiectasia (HHT) is a multisystemic vascular dysplasia that leads to nosebleeds, anaemia due to blood loss, and arteriovenous malformations (AVMs) in organs such as the lu...
Hereditary haemorrhagic telangiectasia (HHT) is a multisystemic vascular dysplasia that leads to nosebleeds, anaemia due to blood loss, and arteriovenous malformations (AVMs) in organs such as the lungs, liver and brain. HHT is estimated to affect 85,000 European citizens, but most health care providers have limited prior HHT exposure or training.Outcome Measures were developed and implemented by the HHT Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN), in order to maximise the number of patients receiving good care. The measures specifically target areas where optimal management reduces morbidity and mortality in HHT patients, and were designed to be robust to emerging new evidence. Thresholds are the percentage of patients in particular settings who have been recommended screening, or provided with written advice. The 5 Outcome Measures cover (1) pulmonary AVM screening; (2) written nosebleed advice, (3) assessment of iron deficiency; (4) antibiotic prophylaxis prior to dental and surgical procedures for patients with pulmonary AVMs, and (5) written advice on pregnancy. They are not a blueprint for detailed HHT management, but are suitable for all clinicians to be aware of and implement.In summary, these 5 Outcome Measures provide metrics to identify healthcare providers of good care, and encourage care improvement by all healthcare providers.
- 2-year follow-up of Lung transplantation as a treatment of Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease) - a case report. [Journal Article]
- ARAdv Respir Med 2018 Aug 15
- CONCLUSIONS: Lung transplantation is a viable therapeutic option for patients with HHT, as there are reports of other patients, who have benefited from lung transplantation after other therapeutic options were exhausted.
- Soluble endoglin regulates expression of angiogenesis-related proteins and induction of arteriovenous malformations in a mouse model of hereditary hemorrhagic telangiectasia. [Journal Article]
- DMDis Model Mech 2018 Aug 14
- Endoglin is a transmembrane glycoprotein expressed in vascular endothelium that plays a key role in angiogenesis. Mutations in the endoglin gene (ENG) cause Hereditary Hemorrhagic Telangiectasia type...
Endoglin is a transmembrane glycoprotein expressed in vascular endothelium that plays a key role in angiogenesis. Mutations in the endoglin gene (ENG) cause Hereditary Hemorrhagic Telangiectasia type 1 (HHT1), characterized by arteriovenous malformations (AVMs) in different organs. These vascular lesions derive from abnormal processes of angiogenesis where aberrant vascular remodeling leads to focal loss of capillaries. Current treatments for HHT1 include anti-angiogenic therapies. Interestingly, a circulating form of endoglin (also known as soluble endoglin, sEng), proteolytically released from the membrane-bound protein and displaying anti-angiogenic activity, has been described in several endothelial-related pathological conditions. Using human and mouse endothelial cells, we find that sEng downregulates several pro-angiogenic and pro-migratory proteins involved in angiogenesis. However, this effect is much reduced in endothelial cells that lack endogenous transmembrane endoglin, suggesting that the anti-angiogenic activity of sEng is dependent on the presence of endogenous transmembrane endoglin protein. In fact, sEng partially restores the phenotype of endoglin-silenced endothelial cells back to that of normal endothelial cells. Moreover, using an established neonatal retinal model of HHT1 with depleted endoglin in the vascular endothelium, sEng treatment decreases the number of AVMs and has a normalizing effect on the vascular phenotype with respect to vessel branching, vascular density and migration of the vascular plexus towards the retinal periphery. Taken together these data show that circulating sEng can influence vascular development and AVMs by modulating angiogenesis and that its effect on endothelial cells depends on expression of endogenous endoglin.
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- Palbociclib enhances radiosensitivity of hepatocellular carcinoma and cholangiocarcinoma via inhibiting ataxia telangiectasia-mutated kinase-mediated DNA damage response. [Journal Article]
- EJEur J Cancer 2018 Aug 10; 102:10-22
- CONCLUSIONS: Our findings provide a novel combination strategy against liver cancer cells. Clinical trials using palbociclib as an adjuvant in RT are warranted.