Vahlkampfia) erregten bis vor kurzem ärztliches Interesse lediglich als Verunreiniger von Bakterien-, Pilz-oder Zellkulturen. 1965 erschien die erste Publikation(16), die zeigte, daß sie dem Menschen auch gefährlich werden können. Schon 1958-61 wiesen Culbertson und sein Arbeitskreis (11-13) nach, daß sich mit Hartmanellen experimentell bei verschiedenen Tierarten (Mäusen, Affen) eine schwere, bei hinreichend massiver Infektion tödliche Meningoenzephalitis erzeugen läßt, und 1961 sprach Culbertson (12) davon, daß es die gleiche Krankheit wohl auch beim Menschen gebe. Schon 1965 bestätigte sich diese Vermutung, als Fowler und Carter (16) über vier Patienten berichteten. Symptome und Befunde Das beim Menschen hauptsächlich durch Naeglerien, weniger durch Hartmanellen hervorgerufene Krankheitsbild ist nach den bisherigen Beobachtungen recht einheitlich. Nach einem Prodromalstadium von 4-6 Tagen mit katarrhalischen Erscheinungen von seiten der oberen Luftwege, leichten Schluckbeschwerden und Anorexie beginnt die Krankheit abrupt mit Fieber, starken Kopfschmerzen (oft im Frontalbereich), Erbrechen, Unruhe und Schmerzen bei Augenbewegungen. Rasch zeigen sich Tachykardie, Nackensteifigkeit, allgemeine Reflexsteigerung und Hyperventilation. Häufig kommt es zu Persönlichkeitsveränderungen und so gut wie immer zu einer meist zunehmenden Trübung des Bewußtseins. Unter Krämpfen und ständigem Erbrechen tritt der Tod, meist in tief em Koma, in wenigen Tagen ein. Im Blut besteht eine deutliche Leukozytose; die Blutsenkung ist beschleunigt, der Augenhintergrund meist normal. Der Liquor ist trübe, flockig, leicht xanthochrom, der Liquordruck erhöht. Die Pandy-Reaktion ist stark positiv. Die Zellzahl liegt um 1000-2000/mm3, meist handelt K. Brass
Background: Dysregulated signaling through GPCRs is implicated in oncogenic RAS signaling in breast cancer (BC). The complex regulatory mechanisms that link RAS nodes can trigger an adaptive response (e.g. resistance) when a single RAS node is inhibited. Inhibition of multiple RAS nodes may thus be required to achieve durable antitumor responses. To identify patients with dysregulated RAS signaling tumors that may respond to RAS node inhibitors, an assay using an impedance biosensor was developed. The CELsignia RAS Activity Test measures GPCR-initiated signaling activity and PI3K, mTOR, and BCL's role in transducing this activity in live tumor cells. The current study set out to characterize the prevalence of dysregulated RAS signaling initiated through a GPCR in HER2-negative BC patients and the role played by PI3K, mTOR and BCL. Methods: Fresh tumor specimens from 69 HER2- BC patients were used to derive tumor cell samples. Dynamic live cell response to a GPCR agonist (LPA), a PI3K-α inhibitor (GDC-0077), a pan-PI3K inhibitor (copanlisib), a pan-PI3K/mTOR inhibitor (gedatolisib), and a BCL inhibitor (navitoclax) was measured using an xCELLigence impedance biosensor (Agilent Technologies). From these responses, the gross amount of GPCR-initiated signaling and corresponding participation of PI3K-α, all Class 1 PI3K-isoforms, mTORC1, and BCL was quantified and converted to a signaling score. Correlative analyses using FACS markers (RPS6, AKT, ERK, caspase 3) were performed. Results: Hyperactive RAS signaling (RASs+) initiated by GPCR pathways was found in 16 of 69 (23.1%; 95% CI=15%-34%) tumors. The signaling scores were bimodally distributed; for the 16 RASs+ and the 53 RASs- patient tumors, the mean scores were 486 (SD 248) and 91 (SD 73), respectively. For the 16 RASs+ tumors, inhibition of all Class 1 PI3K-isoforms attenuated, on average, 71% of the GPCR signaling, while inhibition of PI3K-α alone had only a nominal inhibitory effect. When mTOR inhibition was combined with pan-PI3K inhibition, GPCR signaling was further attenuated by 14%. The most complete attenuation of RAS-signaling occurred when PI3K, mTOR, and BCL were simultaneously inhibited. Early apoptosis markers (RPS6, AKT, ERK, caspase 3) were found most significantly in RASs+ tumors with pan-PI3K/mTOR inhibition and to a greater degree with pan-PI3K/mTOR/BCL inhibition. No apoptosis markers were found in RASs- tumors regardless of which RAS node was inhibited. Conclusions: These findings suggest that a significant sub-group of BC patients have a RAS-involved oncogenic driver that is responsive ex vivo to pan-PI3K/mTOR and pan-PI3K/mTOR/BCL inhibitors. A clinical trial to evaluate treatment response of this patient sub-group to combined PI3K/mTOR or PI3K/mTOR/BCL inhibitors is warranted. Citation Format: Salmaan Khan, Adrish Sen, Catherine Kuzmicki, Ian MacNeil, Aaron Broege, Sarah Mutka, Kelly Brass, Ky McCracken, Laura Milligan, Katja Kotke, Brian Sullivan, Lance Laing. Sub-group of HER2-negative breast cancer patients with hyperactive RAS network signaling identified: Dynamic pathway activity test identifies patients that may benefit from PI3K/mTOR or PI3K/mTOR/BCL inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 342.
Routine histological investigations of the lungs of 38 children led to the discovery during the second half of 1970 of 4 cases of pulmonary aspergillosis in hospitalized children between 3 1/2 weeks and 2 years of age. Those cases represented 10.5% of all children, autopsiated during this period with an hospitalization period of more than 7 days. In two cases Aspergillus filaments did not invade pulmonary tissue, but in the two other cases Aspergillus mycelium had invaded the walls of adjacent pulmonary arteries with resultant arteritis, thrombosis and hemorrhagic infarction. The author believes, that the mycoses were acquired by inhalation of contaminated air. But he can not base this supposition of factual evidence.
e13000 Background: Biological factors other than PIK3CA status, such as aberrant GPCR-linked signaling, may be important to measure when identifying patients eligible for PI3K inhibitors. A new assay, the CELx PI3K test, using an impedance biosensor was developed to measure ex vivo live tumor cell response to specific S1P agonists and PI3K antagonists to diagnose breast tumors with PI3K-involved hyperactive signaling. This study set out to: 1) compare CELx PI3K test results and xenograft results using cell lines with PIK3CA mutations; and 2) assess whether PI3K-involved hyperactive S1P signaling is found in PIK3CA WT breast cancer patient tumors. Methods: A panel of 17 fresh HER2-/PIK3CA WT tumor cells from breast cancer patients and three PIK3CA mutated breast tumor cell lines were obtained. Live cell response to an S1P agonist, PI3K-α antagonist (alpelisib), PI3K-γ antagonist (IPI-549), and a pan-PI3K inhibitor (taselisib) were measured using an xCELLigence RTCA impedance biosensor. From these responses, PI3K-involved signaling was quantified and characterized as normal or abnormal using a previously determined cutpoint. For the xenograft study, 16 NSG mice were injected with HCC1954 PIK3CA mutated breast cancer cells and randomly assigned to either the control or taselisib group (10 mg/kg). Results: Four of the 17 PIK3CA WT tumor cells had abnormal levels of combined PI3K-α and PI3K-γ signaling. Only one of the three PIK3CA mutated breast tumor cell lines (BT20) had abnormal levels of PI3K-α and pan-PI3K involved signaling. The HCC1954 cell line had normal PI3K-α and abnormal pan-PI3K signaling. CAL-51 reported normal PI3K-α and pan-PI3K signaling. The normal levels of PI3K-α signaling found in the HCC1954 and CAL-51 cell lines correlated with previously reported xenograft studies that found alpelisib had no anti-tumor effect. The xenograft study reported here using HCC1954 cells found taselisib induces a significant anti-tumor effect (T/C ratio = 0.21; p = 0.009; t-test). Conclusions: A sub-set of PIK3CA WT patient breast cancer tumors had abnormal PI3K-involved signaling comparable to levels found in PI3KCA mutated cell lines. Abnormal pan-PI3K signaling and normal PI3K-α signaling in the HCC1954 cell line correlated with xenograft results. This study thus suggests that measurement of PI3K-involvement in hyperactive S1P signaling in live patient breast cancer cells may provide a means to identify breast cancer patients who may or may not benefit from treatment with PI3K inhibitors.
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