Pan-cancer analysis and in vitro validation of the oncogenic and prognostic roles of AURKA in human cancers

BackgroundAurora kinase A (AURKA) plays a pivotal role in regulating cell mitosis and tumor progression. However, its prognostic significance across diverse cancer types remains relatively unexplored.MethodsWe conducted a comprehensive analysis of AURKA expression in various cancers using data from The Cancer Genome Atlas, Genotype-Tissue Expression, and The Human Protein Atlas databases. Our investigation encompassed an exploration of the associations between AURKA expression and clinical characteristics, shedding light on potential functional roles of AURKA. Additionally, we delved into the relationship between AURKA and the tumor microenvironment. To substantiate the role of AURKA, we carried out in vitro experiments in esophageal adenocarcinoma (EAC), prostate cancer (PRAD), and pancreatic cancer (PAAD) cells.ResultsOur analysis revealed that AURKA is prominently overexpressed in a majority of the cancer types under investigation. Elevated AURKA expression correlated closely with poorer prognosis and advanced tumor stages. AURKA was found to be associated with key pathways involved in the cell cycle and arachidonic acid metabolism. Moreover, AURKA expression exhibited significant correlations with immunoregulatory genes and immune cell profiles. Notably, in vitro experiments demonstrated that silencing AURKA expression resulted in reduced cell viability in EAC, PRAD, and PAAD cells, as well as a decrease in clone formation, cell cycle elongation, diminished cell invasion and reduced spheroid size in EAC cells (OE33 and OE19).ConclusionOur study elucidates the oncogenic role of AURKA and underscores its prognostic value across a spectrum of cancers, including EAC. These findings suggest that AURKA holds promise as a predictive biomarker for EAC and various other tumor types

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Energy Estimation of Cosmic Rays with the Engineering Radio Array of the Pierre Auger Observatory

The Auger Engineering Radio Array (AERA) is part of the Pierre Auger Observatory and is used to detect the radio emission of cosmic-ray air showers. These observations are compared to the data of the surface detector stations of the Observatory, which provide well-calibrated information on the cosmic-ray energies and arrival directions. The response of the radio stations in the 30 to 80 MHz regime has been thoroughly calibrated to enable the reconstruction of the incoming electric field. For the latter, the energy deposit per area is determined from the radio pulses at each observer position and is interpolated using a two-dimensional function that takes into account signal asymmetries due to interference between the geomagnetic and charge-excess emission components. The spatial integral over the signal distribution gives a direct measurement of the energy transferred from the primary cosmic ray into radio emission in the AERA frequency range. We measure 15.8 MeV of radiation energy for a 1 EeV air shower arriving perpendicularly to the geomagnetic field. This radiation energy -- corrected for geometrical effects -- is used as a cosmic-ray energy estimator. Performing an absolute energy calibration against the surface-detector information, we observe that this radio-energy estimator scales quadratically with the cosmic-ray energy as expected for coherent emission. We find an energy resolution of the radio reconstruction of 22% for the data set and 17% for a high-quality subset containing only events with at least five radio stations with signal.Comment: Replaced with published version. Added journal reference and DO

Measurement of the Radiation Energy in the Radio Signal of Extensive Air Showers as a Universal Estimator of Cosmic-Ray Energy

We measure the energy emitted by extensive air showers in the form of radio emission in the frequency range from 30 to 80 MHz. Exploiting the accurate energy scale of the Pierre Auger Observatory, we obtain a radiation energy of 15.8 \pm 0.7 (stat) \pm 6.7 (sys) MeV for cosmic rays with an energy of 1 EeV arriving perpendicularly to a geomagnetic field of 0.24 G, scaling quadratically with the cosmic-ray energy. A comparison with predictions from state-of-the-art first-principle calculations shows agreement with our measurement. The radiation energy provides direct access to the calorimetric energy in the electromagnetic cascade of extensive air showers. Comparison with our result thus allows the direct calibration of any cosmic-ray radio detector against the well-established energy scale of the Pierre Auger Observatory.Comment: Replaced with published version. Added journal reference and DOI. Supplemental material in the ancillary file

Funktionelle Untersuchungen am Acyl-CoA-Synthetase-5-abhängigen Lipidmetabolismus des humanen Darmepithels

The amounts of lipids within the western style diet have increased massively within the last decades. Considering this fact, it has become more and more relevant to deal with such diseases that are demonstrably associated with the phenomenon. In particular, the increasing incidences of gastrointestinal pathogeneses such as colorectal cancer or the chronic inflammatory bowel diseases seem to be functionally linked to the altered fatty acid uptake. The intestine is the central organ of the lipid resorption and therefore it is essential to understand the mechanisms involved within the metabolism of these nutrients. Here, the initial step is the activation of the long chain fatty acids to acyl-CoA thioester. This reaction is catalyzed by a group of enzymes called the long chain acyl-CoA synthetases (ACSLs). Today there are five different isoforms of ACSL described within the human and rodent organism of which the ACSL5 dominates the intestinal mucosa and has unique localization on the outer mitochondrial membrane. Within the enterocyte, there also exists some evidence that this enzyme is involved in the regulation of the cell’s maturation as well as survival by sensitizing it to apoptosis. But after all, the available information about the intestinal ACSL5 is still meager. Thus, the principle goal of the current studies was the characterization of the ACSL5 within the human digestive tract. By using an in vitro model based on cell culture experiments it was supposed to gain further information about the ACSL5’s position in the enterozytic lipid metabolism and the putative interactions with other functional signal pathways. The lipid metabolism was inhibited at different positions: Orlistat blocked the endogenous fatty acid synthesis while Etomoxir stopped the fatty acid transport into the mitochondrion as compartment of the beta-oxidation. After treatment the cells’ ACSL5 was examined by several methods including qRT-PCR, Western blotting and enzyme activity assay. ACSL5 was up regulated on the mRNA- as well as the proteomic level. Furthermore the enzymatic activity increases, too. Beyond this, molecular genetic examinations reveal possible ACSL5 dependent regulated genes like the free-fatty acid-receptors 2 and 3 (FFAR2 and 3) or Mortalin (HSPA9), a member of the so-called heat shock protein 70 (Hsp70) family. This supposes on the one hand a predominant catabolic function of ACSL5 within the enterocyte. On the other hand the association with the mitochondrial Mortalin demonstrates a potential clue to cellular stress caused by ACLS5 activity. Regarding putative functional connections between ACSL5 and apoptosis, it came out that proapoptotic genes such as Caspase 8 and Bid were also increased under treatment. These results show that ACSL5’s induction might stimulates the cell towards apoptosis. Microscopical observation supported this presumption: High levels of Orlistat led to a disruption in cell growth. Transmission electron microscopy however could not show an ACSL5 associated alteration. In summary, these experimental data evidence a much more complex role of the enterozytic ACSL5 than expected. It is not just the key player within the lipid metabolism, but also seems to be involved in other functional pathways which regulate the cell’s homeostasis. First hints show a putative influence on the apoptosis and other ACSL5-related regulated molecules

Surgical treatment of esophageal cancer-Indicators for quality in diagnostics and treatment

Background Within the framework of the quality initiative of the German Society for General and Visceral Surgery (DGAV) a review article was compiled based on a systematic literature search. Recommendations for the current diagnostics and treatment of esophageal cancer were also elaborated. Methods The systematic literature search was carried out in March 2019 according to the PRISMA criteria using the MEDLINE databank. The recommendations were formulated based on a consensus in the DGAV. Results and conclusion Operations below the currently valid minimum quantity threshold should no longer be carried out. There are many indications that the minimum quantity in Germany should be raised to >= 20 resections/year/hospital in order to comprehensively improve the quality. Prehabilitation programs with endurance, strength and intensive breathing training as well as nutritional therapy improve patient outcome. The current treatment of esophageal cancer is stage-dependent and incorporates endoscopic resection of (sub)mucosal low-risk tumors (T1m1-3 or T1sm1 low risk), primary esophagectomy of submucosal high-risk tumors (T1a), submucosal cancer (T1sm2-3) and T2N0 tumors, multimodal treatment with neoadjuvant chemoradiotherapy or perioperative chemotherapy and operations for advanced stages. Esophagectomy is nowadays carried out in one stage as a so-called hybrid procedure (laparoscopy and muscle-preserving thoracotomy) or as a total minimally invasive operation (laparoscopy and thoracoscopy

Outcome of prophylactic endoscopic vacuum therapy for high-risk anastomosis after esophagectomy

Background: Endoscopic vacuum therapy (EVT) has become an established procedure for the treatment of anastomotic leaks (AL) in upper gastrointestinal surgery. A novel approach is the use of EVT for preventing leaks in high-risk anastomosis. The aim of this study was to analyze the outcome of prophylactic EVT (pEVT) in patients receiving surgical revision of the anastomosis after oncological Ivor-Lewis esophagectomy (ILE) due to AL. Material and methods: Between June 2016 and February 2019, all patients who underwent anastomotic revision after ILE due to a confirmed AL were included. The primary outcome was the success rate of pEVT, which was defined as absence of an AL after revision. Secondary outcome parameters were duration of treatment, inflammatory levels, and ICU/hospital stay. Results: Twenty-one patients underwent anastomotic revision due to an AL. The cause of the AL was ischemia in nine patients (42.9%) and non-ischemia (other) in 12 patients (57.1%). PEVT was performed in 14 patients (66.6%). The overall success rate of pEVT was five out of 14 patients (35.7%). Conclusions: Prophylactic EVT cannot prevent a re-leak in patients with high-risk anastomosis due to surgical revision of an AL after oncological ILE. However, pEVT might help to control the clinical condition of these patients