Influence of Anti-Infective Periodontal Therapy on Subgingival Microbiota Evaluated by Chair-Side Test Compared to qPCR-A Clinical Follow-Up Study.

A chair-side test (CST) for five periodontal pathogens (Aggregatibacter actinomycetemcomitans, A.a.; Porphyromonas gingivalis, P.g.; Prevotella intermedia, P.i.; Treponema denticola, T.d.; Tannerella forsythia, T.f.) was compared with qPCR in a previous clinical study on 100 periodontitis patients at first diagnosis (T0). Following non-surgical treatment alone (SRP) or in combination with systemic or local antibiotics, 74 patients (57.4 ± 13.5 years) were again tested at the same sites from 14 to 24 months after T0. Bacterial elimination (%; compared to T0) was determined for each single species and compared between both test systems. In all patients, all five pathogens could not be fully eliminated regardless of therapy or test method. Tested with CST, the mean elimination ranged from 90% for SRP + Amoxicillin/Metronidazole to 59.13% for SRP only. The corresponding qPCR values were 30% and 29.6%. Only A.a. was eradicated in 100% by SRP + Amoxicillin/Metronidazole tested by CST, and it was 80% when qPCR was the test method. CST agreed with qPCR in 98.7% in the detection of A.a., and 74.3%, 78.4%, 73.0%, and 48.7% for P.g., P.i., T.d., and T.f., respectively. Neither conventional treatment nor the additional use of antibiotics-even with the correct indication-could completely eradicate the tested pathogens or prevent pocket reinfection

Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer

Activation of MAPK signaling via BRAF mutations may limit the activity of EGFR inhibitors in EGFR-mutant lung cancer patients. However, the impact of BRAF mutations on the selection and fitness of emerging resistant clones during anti-EGFR therapy remains elusive. We tracked the evolution of subclonal mutations by whole-exome sequencing and performed clonal analyses of individual metastases during therapy. Complementary functional analyses of polyclonal EGFR-mutant cell pools showed a dose-dependent enrichment of BRAF(V600E) and a loss of EGFR inhibitor susceptibility. The clones remain stable and become vulnerable to combined EGFR, RAF, and MEK inhibition. Moreover, only osimertinib/trametinib combination treatment, but not monotherapy with either of these drugs, leads to robust tumor shrinkage in EGFR-driven xenograft models harboring BRAF mutations. These data provide insights into the dynamics of clonal evolution of EGFR-mutant tumors and the therapeutic implications of BRAF(V600E) co-mutations that may facilitate the development of treatment strategies to improve the prognosis of these patients

Influence of Anti-Infective Periodontal Therapy on Subgingival Microbiota Evaluated by Chair-Side Test Compared to qPCR—A Clinical Follow-Up Study

A chair-side test (CST) for five periodontal pathogens (Aggregatibacter actinomycetemcomitans, A.a.; Porphyromonas gingivalis, P.g.; Prevotella intermedia, P.i.; Treponema denticola, T.d.; Tannerella forsythia, T.f.) was compared with qPCR in a previous clinical study on 100 periodontitis patients at first diagnosis (T0). Following non-surgical treatment alone (SRP) or in combination with systemic or local antibiotics, 74 patients (57.4 ± 13.5 years) were again tested at the same sites from 14 to 24 months after T0. Bacterial elimination (%; compared to T0) was determined for each single species and compared between both test systems. In all patients, all five pathogens could not be fully eliminated regardless of therapy or test method. Tested with CST, the mean elimination ranged from 90% for SRP + Amoxicillin/Metronidazole to 59.13% for SRP only. The corresponding qPCR values were 30% and 29.6%. Only A.a. was eradicated in 100% by SRP + Amoxicillin/Metronidazole tested by CST, and it was 80% when qPCR was the test method. CST agreed with qPCR in 98.7% in the detection of A.a., and 74.3%, 78.4%, 73.0%, and 48.7% for P.g., P.i., T.d., and T.f., respectively. Neither conventional treatment nor the additional use of antibiotics—even with the correct indication—could completely eradicate the tested pathogens or prevent pocket reinfection.</jats:p

Untersuchung des Einflusses von Wasser in Druckuebertragungsmedien auf die Fluessigkeitsalterung und den Bauteilverschleiss Abschlussbericht. Vorhaben Nr. 51. Beginn der Arbeiten: 1.4.1979. Ende der Arbeiten: 31.3.1982

TIB: RA 2383 (94) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

CD74-NRG1 fusions are oncogenic in vivo and induce therapeutically tractable ERBB2:ERBB3 heterodimerization

NRG1 fusions are recurrent somatic genome alterations occurring across several tumor types, including invasive mucinous lung adenocarcinomas and pancreatic ductal adenocarcinomas and are potentially actionable genetic alterations in these cancers. We initially discovered CD74-NRG1 as the first NRG1 fusion in lung adenocarcinomas, and many additional fusion partners have since been identified. Here, we present the first CD74-NRG1 transgenic mouse model and provide evidence that ubiquitous expression of the CD74-NRG1 fusion protein in vivo leads to tumor development at high frequency. Furthermore, we show that ERBB2:ERBB3 heterodimerization is a mechanistic event in transformation by CD74-NRG1 binding physically to ERBB3 and that CD74-NRG1–expressing cells proliferate independent of supplemented NRG1 ligand. Thus, NRG1 gene fusions are recurrent driver oncogenes that cause oncogene dependency. Consistent with these findings, patients with NRG1 fusion-positive cancers respond to therapy targeting the ERBB2:ERBB3 receptors

Targeting EGFR Ex20 mutant lung cancer with the wild type sparing kinase inhibitor PRB001.

e14718 Background: The majority of EGFR mutant tumors can be effectively treated with targeted drugs. Lung adenocarcinoma patients with EGFR Ex20 insertion mutations, however, lack safe and potent treatment options. These genetic alterations share homology with HER2 Ex20 insertion mutations and perturb the ATP binding pocket in a way that limits accessibility through currently available tyrosine kinase inhibitors. Second-generation EGFR inhibitors are partially active in EGFR Ex20 mutant models but their potent activity against wild type (WT) EGFR and the resulting adverse effects largely prohibit the clinical use of these drugs. To address this medical need, we developed PRB001, a novel EGFR kinase inhibitor. Methods: We facilitated protein X-ray crystallography to guide the development of small molecule inhibitors with high potency against EGFR/HER2 Ex20 mutant kinases and low activity against WT EGFR. Iterative compound optimization involved biochemical profiling concerning inhibition and binding kinetics, cellular profiling as well as mouse pharmacokinetic and mouse efficacy studies. Results: PRB001 exhibits potent activity against EGFR/HER2 Ex20 insertion mutations, in genetically engineered Ba/F3 cell line models and patient derived cell lines. At the same time, PRB001 exhibits a 10-100 fold lower activity against WT EGFR in several cellular models. Our data indicate that PRB001 and its derivatives display a therapeutic window for an effective treatment of EGFR Ex20 mutant tumors with a limited toxicity profile. Mouse xenograft experiments support these results, showing that, in contrast to second-generation EGFR inhibitors, PRB001 does not inhibit WT EGFR and does not lead to loss of weight of treated animals at effective doses of 90 mg/kg daily. Conclusions: Our data support the notion that PRB001 effectively kills a wide range of EGFR Ex20 mutant cellular models and together with its safety profile builds a basis for the development of a mutant-selective and clinically effective tyrosine kinase inhibitor. </jats:p

CD74-NRG1 Fusions Are Oncogenic In Vivo and Induce Therapeutically Tractable ERBB2:ERBB3 HeterodimerizationCD74-NRG1 Gene Fusion as a Bona Fide Oncogene

NRG1 fusions are recurrent somatic genome alterations occurring across several tumor types, including invasive mucinous lung adenocarcinomas and pancreatic ductal adenocarcinomas and are potentially actionable genetic alterations in these cancers. We initially discovered CD74-NRG1 as the first NRG1 fusion in lung adenocarcinomas, and many additional fusion partners have since been identified. Here, we present the first CD74-NRG1 transgenic mouse model and provide evidence that ubiquitous expression of the CD74-NRG1 fusion protein in vivo leads to tumor development at high frequency. Furthermore, we show that ERBB2:ERBB3 heterodimerization is a mechanistic event in transformation by CD74-NRG1 binding physically to ERBB3 and that CD74-NRG1-expressing cells proliferate independent of supplemented NRG1 ligand. Thus, NRG1 gene fusions are recurrent driver oncogenes that cause oncogene dependency. Consistent with these findings, patients with NRG1 fusion-positive cancers respond to therapy targeting the ERBB2:ERBB3 receptors

CD74-NRG1 Fusions Are Oncogenic <i>In Vivo</i> and Induce Therapeutically Tractable ERBB2:ERBB3 Heterodimerization

Abstract NRG1 fusions are recurrent somatic genome alterations occurring across several tumor types, including invasive mucinous lung adenocarcinomas and pancreatic ductal adenocarcinomas and are potentially actionable genetic alterations in these cancers. We initially discovered CD74-NRG1 as the first NRG1 fusion in lung adenocarcinomas, and many additional fusion partners have since been identified. Here, we present the first CD74-NRG1 transgenic mouse model and provide evidence that ubiquitous expression of the CD74-NRG1 fusion protein in vivo leads to tumor development at high frequency. Furthermore, we show that ERBB2:ERBB3 heterodimerization is a mechanistic event in transformation by CD74-NRG1 binding physically to ERBB3 and that CD74-NRG1–expressing cells proliferate independent of supplemented NRG1 ligand. Thus, NRG1 gene fusions are recurrent driver oncogenes that cause oncogene dependency. Consistent with these findings, patients with NRG1 fusion-positive cancers respond to therapy targeting the ERBB2:ERBB3 receptors.</jats:p

MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer

MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients