AIM: Activating mutations in the epidermal growth factor receptor (EGFR) are predominantly detected in pulmonary adenocarcinoma and have been reported in small cell lung cancer (SCLC) for decades. This retrospective single-center study aimed to determine the frequency and types of EGFR mutations in SCLC in Taiwan. METHODS: This study comprises a consecutive cohort of 161 patients histologically diagnosed with SCLC between January 1992 and August 2014 at the Department of Pathology in Keelung Chang Gung Memorial Hospital, Taiwan. Archived formalin-fixed paraffin-embedded sections from 71 patients were eligible for molecular analysis. EGFR mutation analysis was performed using a fully-automated IdyllaTM EGFR Mutation Test and confirmed a comparable result through Qiagen Therascreen® EGFR RGQ PCR. In addition, EGFR gene copy number was assessed in EGFR-mutated tumors by fluorescence in situ hybridization (FISH). RESULTS: Mutational status of the EGFR gene was successfully analyzed in 63 specimens by both IdyllaTM and Qiagen platforms. Both methods detected L858R point mutation in exon 21 in an 81-year-old female and a 47-year-old male non-smoker. Both tumors show no concurrent EGFR gene amplification. The overall agreement between results obtained with the IdyllaTM EGFR Mutation Test and Qiagen Therascreen® EGFR RGQ PCR was 100% Conclusions. Our results showed that EGFR mutation is a rare mutation type in a consecutive series of de novo SCLC. Furthermore, the performance of IdyllaTM EGFR Mutation Test and Qiagen Therascreen® EGFR RGQ PCR on archived paraffin sections of limited quantities is available with the high agreement of results.

• MeSH
• erbB receptory genetika   MeSH
• formaldehyd MeSH
• hybridizace in situ fluorescenční MeSH
• lidé MeSH
• malobuněčný karcinom plic * genetika   MeSH
• mutace MeSH
• mutační analýza DNA metody   MeSH
• nádory plic * diagnóza   MeSH
• nemalobuněčný karcinom plic * diagnóza   MeSH
• parafín MeSH
• retrospektivní studie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Accumulated evidence suggests that the endosymbiotic Trichomonasvirus (TVV) may play a role in the pathogenesis and drug susceptibility of Trichomonas vaginalis. Several reports have shown that extracellular vesicles (EVs) released from TVV-positive (TVV+) trichomonads can modulate the immune response in human vaginal epithelial cells and animal models. These results prompted us to examine whether EVs released from TVV+ isolates contained TVV. We isolated small extracellular vesicles (sEVs) from six T. vaginalis isolates that were either TVV free (ATCC 50143), harbored a single (ATCC 30236, ATCC 30238, T1), two (ATCC PRA-98), or three TVV subspecies (ATCC 50148). The presence of TVV subspecies in the six isolates was observed using reverse transcription-polymerase chain reaction (RT-PCR). Transmission electron microscopy (TEM) confirmed the presence of cup-shaped sEVs with a size range from 30-150 nm. Trichomonas vaginalis tetraspanin (TvTSP1; TVAG_019180), the classical exosome marker, was identified in all the sEV preparations. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed that all the sEVs isolated from TVV+ isolates contain viral capsid proteins derived from the same TVV subspecies in that isolate as demonstrated by RT-PCR. To provide more comprehensive information on the TVV subspecies population in other T. vaginalis isolates, we investigated the distribution of TVV subspecies in twenty-four isolates by mining the New-Generation Sequencing (NGS) RNAseq datasets. Our results should be beneficial for future studies investigating the role of TVV on the pathogenicity of T. vaginalis and the possible transmission of virus subspecies among different isolates via sEVs.

• MeSH
• chromatografie kapalinová MeSH
• dvouvláknová RNA MeSH
• extracelulární vezikuly * genetika   MeSH
• RNA-viry * genetika   MeSH
• tandemová hmotnostní spektrometrie MeSH
• Trichomonas vaginalis * genetika   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) comprises ∼10% to 15% of childhood ALL cases, many of which respond exquisitely to tyrosine kinase inhibitors (TKIs), for example, imatinib in PDGFRB-rearranged ALL. However, some cases developed drug resistance to TKIs and the mechanisms are poorly understood. In this study, we identified a novel PDGFRB fusion gene, namely AGGF1-PDGFRB, and functionally characterized its oncogenic potential in vitro. Further genomic profiling of longitudinally collected samples during treatment revealed the emergence of a mutation, PDGFRBC843G , which directly conferred resistance to all generations of ABL TKIs, including imatinib, dasatinib, nilotinib, and ponatinib. PDGFRB-mutant leukemia cells are highly sensitive to multitarget kinase inhibitor CHZ868, suggesting potential therapeutic options for some patients resistant to ABL TKIs. In summary, we describe a complex clonal evolution pattern in Ph-like ALL and identified a novel PDGFRB point mutation that drives leukemia relapse after ABL TKI treatment.

• MeSH
• akutní lymfatická leukemie farmakoterapie   genetika   metabolismus   patologie   MeSH
• angiogenní proteiny genetika   MeSH
• chemorezistence genetika   MeSH
• fúzní onkogenní proteiny MeSH
• inhibitory proteinkinas farmakologie   terapeutické užití   MeSH
• lidé MeSH
• mutace * MeSH
• nádorové buněčné linie MeSH
• předškolní dítě MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• recidiva MeSH
• růstový faktor odvozený z trombocytů - receptor beta genetika   MeSH
• sekvenování celého genomu MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

• MeSH
• finanční podpora výzkumu jako téma MeSH
• Helicobacter pylori účinky léků   MeSH
• infekce vyvolané Helicobacter pylori komplikace   patologie   MeSH
• kombinace amoxicilinu a kyseliny klavulanové aplikace a dávkování   terapeutické užití   MeSH
• lidé MeSH
• metronidazol aplikace a dávkování   terapeutické užití   MeSH
• nádory žaludku diagnóza   prevence a kontrola   MeSH
• omeprazol aplikace a dávkování   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• randomizované kontrolované studie MeSH

Cíl Přestože již bylo prokázáno, že inhibitory tyrosinkináz (tyrosine kinase inhibitor, TKI) receptoru epidermálního růstového faktoru (epidermal growth factor receptor, EGFR) jsou u pacientů s adenokarcinomem plic s aktivující mutací EGFR účinnější než u pacientů s tímto genem divokého typu, je v první skupině přítomno zhruba 30 % pacientů, kteří na TKI neodpovídají. Molekulární základ této zásadní heterogenity odpovědí není znám. Naším cílem bylo najít molekulární aberace, které na celogenomové úrovni přispívají k progresi onemocnění, a určit prognostickou signaturu specifi ckou pro pacienty s aktivující mutací EGFR. Pacienti a metody Nejprve jsme pomocí microarray pro vysokodenzitní komparativní genomovou hybridizaci (high-density array comparative genomic hybridization) v souboru 138 tkání adenokarcinomu prozkoumali molekulární rozdíly mezi nádory s aktivující mutací EGFR a nádory s genem divokého typu. Potom jsme u jiné nezávislé skupiny 114 pacientů validovali klinický význam alterací počtu kopií (copy-number alteration, CNA) pro predikci celkového přežití a přežití bez známek onemocnění (disease-free survival, DFS). V posledním kroku jsme u 23 pacientů s mutací EGFR léčených EGFR TKI zkoumali spojení mezi CNA a odpovědí na EGFR-TKI. Výsledky Určili jsme chromosomové oblasti s rozdíly v CNA mezi nádory s aktivující mutací EGFR a nádory divokého typu a zjistili jsme přítomnost vysoké míry shlukování aberací na chromosomu 7p. Klastr šesti reprezentativních genů na chromosomu 7p předpovídal celkové přežití a přežití bez známek onemocnění pacientů s aktivující mutací EGFR, ale ne u pacientů s genem divokého typu. Důležité je zjištění, že současná přítomnost většího počtu genů se zvýšenou hodnotou CNA v tomto klastru u pacientů s aktivující mutací EGFR korelovala s méně příznivou odpovědí na EGFR-TKI. Závěr Naše výsledky významným způsobem přispívají k objasnění příčin heterogenních odpovědí pacientů s aktivující mutací EGFR na léčbu EGFR-TKI. Mohly by přispět ke zlepšení léčby pacientů v této populaci.

PURPOSE: Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been proven more effective for patients with lung adenocarcinoma with EGFR-activating mutation rather than wild type, the former group still includes approximately 30% nonresponders. The molecular basis of this substantial response heterogeneity is unknown. Our purpose was to seek molecular aberrations contributing to disease progression at the genome-wide level and identify the prognostic signature unique to patients with EGFR-activating mutation. PATIENTS AND METHODS: We first investigated the molecular differences between tumors with EGFR-activating mutation and wild-type tumors by conducting high-density array comparative genomic hybridization on a collection of 138 adenocarcinoma tissues. We then used an independent group of 114 patients to validate the clinical relevance of copy-number alterations (CNAs) in predicting overall and disease-free survival. Finally, focusing on 23 patients with EGFR mutation receiving EGFR-TKI treatment, we investigated the association between CNAs and response to EGFR-TKIs. RESULTS: We identified chromosome regions with differential CNAs between tumors with EGFR-activating mutation and wild-type tumors and found the aberration sites to cluster highly on chromosome 7p. A cluster of six representative chromosome 7p genes predicted overall and disease-free survival for patients with EGFR-activating mutation but not for those with wild type. Importantly, simultaneous presence of more genes with increased CNAs in this cluster correlated with less favorable response to EGFR-TKIs in patients with EGFR-activating mutation. CONCLUSION: Our results shed light on why responses to EGFR-TKIs are heterogeneous among patients with EGFR-activating mutation. They may lead to better patient management in this population.

• MeSH
• adenokarcinom farmakoterapie   genetika   MeSH
• chromozomální aberace MeSH
• DNA nádorová genetika   MeSH
• erbB receptory genetika   MeSH
• financování organizované MeSH
• genom lidský MeSH
• genová dávka MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy, pár 7 genetika   MeSH
• míra přežití MeSH
• mutace genetika   MeSH
• mutační analýza DNA MeSH
• nádory plic farmakoterapie   genetika   MeSH
• následné studie MeSH
• nemalobuněčný karcinom plic farmakoterapie   genetika   MeSH
• polymerázová řetězová reakce MeSH
• prognóza MeSH
• senioři MeSH
• srovnávací genomová hybridizace MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH

BACKGROUND: Prior comparisons of brain arteriovenous malformations (AVMs) treated using stereotactic radiosurgery (SRS) with or without embolization were inherently flawed, due to differences in the pretreatment nidus volumes. OBJECTIVE: To compare the outcomes of embolization and SRS, vs SRS alone for AVMs using pre-embolization malformation features. METHODS: We retrospectively reviewed International Radiosurgery Research Foundation AVM databases from 1987 to 2018. Patients were categorized into the embolization and SRS (E + SRS) or SRS alone (SRS-only) cohorts. The 2 cohorts were matched in a 1:1 ratio using propensity scores. Primary outcome was defined as AVM obliteration. Secondary outcomes were post-SRS hemorrhage, all-cause mortality, radiologic and symptomatic radiation-induced changes (RIC), and cyst formation. RESULTS: The matched cohorts each comprised 101 patients. Crude AVM obliteration rates were similar between the matched E + SRS vs SRS-only cohorts (48.5% vs 54.5%; odds ratio = 0.788, P = .399). Cumulative probabilities of obliteration at 3, 4, 5, and 6 yr were also similar between the E + SRS (33.0%, 46.4%, 56.2%, and 60.8%, respectively) and SRS-only (32.9%, 46.2%, 56.0%, and 60.6%, respectively) cohorts (subhazard ratio (SHR) = 1.005, P = .981). Cumulative probabilities of radiologic RIC at 3, 4, 5, and 6 yr were lower in the E + SRS (25.0%, 25.7%, 26.7%, and 26.7%, respectively) vs SRS-only (45.3%, 46.2%, 47.8%, and 47.8%, respectively) cohort (SHR = 0.478, P = .004). Symptomatic and asymptomatic embolization-related complication rates were 8.3% and 18.6%, respectively. Rates of post-SRS hemorrhage, all-cause mortality, symptomatic RIC, and cyst formation were similar between the matched cohorts. CONCLUSION: This study refutes the prevalent notion that AVM embolization negatively affects the likelihood of obliteration after SRS.

• MeSH
• dospělí MeSH
• intrakraniální arteriovenózní malformace terapie   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• radiochirurgie metody   MeSH
• retrospektivní studie MeSH
• terapeutická embolizace metody   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Embolization of brain arteriovenous malformations (AVMs) using ethylene-vinyl alcohol copolymer (Onyx) embolization may influence the treatment effects of stereotactic radiosurgery (SRS) differently than other embolysates. OBJECTIVE: To compare the outcomes of pre-SRS AVM embolization with vs without Onyx through a multicenter, retrospective matched cohort study. METHODS: We retrospectively reviewed International Radiosurgery Research Foundation AVM databases from 1987 to 2018. Embolized AVMs treated with SRS were selected and categorized based on embolysate usage into Onyx embolization (OE + SRS) or non-Onyx embolization (NOE + SRS) cohorts. The 2 cohorts were matched in a 1:1 ratio using de novo AVM features for comparative analysis of outcomes. RESULTS: The matched cohorts each comprised 45 patients. Crude AVM obliteration rates were similar between the matched OE + SRS vs NOE + SRS cohorts (47% vs 51%; odds ratio [OR] = 0.837, P = .673). Cumulative probabilities of obliteration were also similar between the OE + SRS vs NOE + SRS cohorts (subhazard ratio = 0.992, P = .980). Rates of post-SRS hemorrhage, all-cause mortality, radiation-induced changes, cyst formation, and embolization-associated complications were similar between the matched cohorts. Sensitivity analysis for AVMs in the OE + SRS cohort embolized with Onyx alone revealed a higher rate of asymptomatic embolization-associated complications in this subgroup compared to the NOE + SRS cohort (36% vs 15%; OR = 3.297, P = .034), but the symptomatic complication rates were similar. CONCLUSION: Nidal embolization using Onyx does not appear to differentially impact the outcomes of AVM SRS compared with non-Onyx embolysates. The embolic agent selected for pre-SRS AVM embolization should reflect both the experience of the neurointerventionalist and target of endovascular intervention.

• MeSH
• dospělí MeSH
• intrakraniální arteriovenózní malformace terapie   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• polyvinyly terapeutické užití   MeSH
• radiochirurgie * MeSH
• retrospektivní studie MeSH
• terapeutická embolizace metody   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Acute lymphoblastic leukemia expressing the gamma delta T-cell receptor (γδ T-ALL) is a poorly understood disease. We studied 200 children with γδ T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. γδ T-ALL diagnosed in children under 3 years of age was extremely high-risk and enriched for genetic alterations that result in both LMO2 activation and STAG2 inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping, resulting in deregulation of gene expression associated with T-cell differentiation. High-throughput drug screening identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which can be targeted by poly(ADP-ribose) polymerase inhibition. These data provide a diagnostic framework for classification and risk stratification of pediatric γδ T-ALL. Significance: Patients with acute lymphoblastic leukemia expressing the gamma delta T-cell receptor under 3 years old or measurable residual disease ≥1% at end of induction showed dismal outcomes and should be classified as having high-risk disease. The STAG2/LMO2 subtype was enriched in this very young age group. STAG2 inactivation may perturb chromatin conformation and cell differentiation and confer vulnerability to poly(ADP-ribose) polymerase inhibition.

• MeSH
• adaptorové proteiny signální transdukční * genetika   metabolismus   MeSH
• dítě MeSH
• genová přestavba MeSH
• kojenec MeSH
• lidé MeSH
• lymfoblastická leukemie-lymfom z prekurzorových T-buněk genetika   patologie   MeSH
• předškolní dítě MeSH
• proteiny buněčného cyklu genetika   metabolismus   MeSH
• proteiny s doménou LIM * genetika   MeSH
• protoonkogenní proteiny MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR.

• MeSH
• genotyp MeSH
• lidé MeSH
• missense mutace MeSH
• myši MeSH
• nádory prsu genetika   MeSH
• protein BRCA2 genetika   MeSH
• riziko MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• substituce aminokyselin MeSH
• zárodečné mutace MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

• MeSH
• androgeny * genetika   MeSH
• celogenomová asociační studie * MeSH
• genetická predispozice k nemoci MeSH
• jednonukleotidový polymorfismus MeSH
• ledviny MeSH
• lidé MeSH
• lidské chromozomy X genetika   MeSH
• responzivní elementy MeSH
• tetraspaniny genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH