Better Safe Than Sorry! Automated Identification of Functionality-Breaking Security-Configuration Rules

Insecure default values in software settings can be exploited by attackers to compromise the system that runs the software. As a countermeasure, there exist security-configuration guides specifying in detail which values are secure. However, most administrators still refrain from hardening existing systems because the system functionality is feared to deteriorate if secure settings are applied. To foster the application of security-configuration guides, it is necessary to identify those rules that would restrict the functionality. This article presents our approach to use combinatorial testing to find problematic combinations of rules and machine learning techniques to identify the problematic rules within these combinations. The administrators can then apply only the unproblematic rules and, therefore, increase the system's security without the risk of disrupting its functionality. To demonstrate the usefulness of our approach, we applied it to real-world problems drawn from discussions with administrators at Siemens and found the problematic rules in these cases. We hope that this approach and its open-source implementation motivate more administrators to harden their systems and, thus, increase their systems' general security.Comment: Peer-reviewed version accepted for publication at the 4th ACM/IEEE International Conference on Automation of Software Test (AST 2023), May 15--16, 2023, Melbourne, A

An In Vitro Analysis of TKI-Based Sequence Therapy in Renal Cell Carcinoma Cell Lines

The tyrosine kinase inhibitor (TKI) cabozantinib might impede the growth of the sunitinibresistant cell lines by targeting MET and AXL overexpression in metastatic renal cell carcinoma (mRCC). We studied the role of MET and AXL in the response to cabozantinib, particularly following long-term administration with sunitinib. Two sunitinib-resistant cell lines, 786-O/S and Caki-2/S, and the matching 786-O/WT and Caki-2/WT cells were exposed to cabozantinib. The drug response was cell-line-specific. The 786-O/S cells were less growth-inhibited by cabozantinib than 786-O/WT cells (p-value = 0.02). In 786-O/S cells, the high level of phosphorylation of MET and AXL was not affected by cabozantinib. Despite cabozantinib hampering the high constitutive phosphorylation of MET, the Caki-2 cells showed low sensitivity to cabozantinib, and this was independent of sunitinib pretreatment. In both sunitinib-resistant cell lines, cabozantinib increased Src-FAK activation and impeded mTOR expression. The modulation of ERK and AKT was cell-line-specific, mirroring the heterogeneity among the patients. Overall, the MET- and AXL-driven status did not affect cell responsiveness to cabozantinib in the second-line treatment. The activation of Src-FAK might counteract cabozantinib activity and contribute to tumor survival and may be considered an early indicator of therapy response

Exponentially fast Thinning of Nanoscale Films by Turbulent Mixing

Films are nanoscopic elements of foams, emulsions and suspensions, and form a paradigm for nanochannel transport that eventually tests the limits of hydrodynamic descriptions. Here, we study the collapse of a freestanding film to its equilibrium. The generation of nanoscale films usually is a slow linear process; using thermal forcing we find unprecedented dynamics with exponentially fast thinning. The complex interplay of thermal convection, interface and gravitational forces yields optimal turbulent mixing and transport. Domains of collapsed film are generated, elongated and convected in a beautiful display of chaotic mixing. With a timescale analysis we identify mixing as the dominant dynamical process responsible for exponential thinning.Comment: accepted for publication in Phys. Rev. Let

Primary Tumor Resection Decelerates Disease Progression in an Orthotopic Mouse Model of Metastatic Prostate Cancer

Radical prostatectomy in oligometastatic prostate cancer is a matter of intense debate. Besides avoiding local complications, it is hypothesized that primary tumor resection may result in better oncological outcomes. The aim of our study was to analyze the effect of primary tumor resection on disease progression in an orthotopic prostate cancer mouse model. First, the optimal time point for primary tumor resection, when metastases have already occurred, but the primary tumor is still resectable, was determined as 8 weeks after inoculation of 5 × 105 LuCaP136 cells. In a second in vivo experiment, 64 mice with metastatic prostate cancer were randomized into two groups, primary tumor resection or sham operation, and disease progression was followed up for 10 weeks. The technique of orthotopic primary tumor resection was successfully established. Compared with the sham operation group, mice with primary tumor resection showed a significantly longer survival (p < 0.001), a significantly slower PSA increase (p < 0.01), and a lower number of lung metastases (p = 0.073). In conclusion, primary tumor resection resulted in slower disease progression and longer survival in an orthotopic mouse model of metastatic prostate cancer. In future studies, this model will be used to unravel the molecular mechanisms of primary tumor/metastasis interaction in prostate cancer

Last Resort from Nursing Shortage? Comparative Cost Analysis of Open vs. Robot-Assisted Partial Nephrectomies with a Focus on the Costs of Nursing Care

Despite perioperative advantages, robot-assisted surgery is associated with high costs. However, the lower morbidity of robotic surgery could lead to a lower nursing workload and cost savings. In this comparative cost analysis of open retroperitoneal versus robot-assisted transperitoneal partial nephrectomies (PN), these possible cost savings, including other cost factors, were quantified. Therefore, patient, tumor characteristics, and surgical results of all PN within two years at a tertiary referral center were retrospectively analyzed. The nursing effort was quantified by the local nursing staff regulation and INPULS® intensive care and performance-recording system. Out of 259 procedures, 76.4% were performed robotically. After propensity score matching, the median total nursing time (2407.8 vs. 1126.8 min, p < 0.001) and daily nursing effort (245.7 vs. 222.6 min, p = 0.025) were significantly lower after robotic surgery. This resulted in mean savings of EUR 186.48 in nursing costs per robotic case, in addition to savings of EUR 61.76 due to less frequent administrations of erythrocyte concentrates. These savings did not amortize the higher material costs for the robotic system, causing additional expenses of EUR 1311.98 per case. To conclude, the nursing effort after a robotic partial nephrectomy was significantly lower compared to open surgery; however, this previously unnoticed savings mechanism alone could not amortize the overall increased costs

Characterization of CD147, CA9, and CD70 as Tumor-Specific Markers on Extracellular Vesicles in Clear Cell Renal Cell Carcinoma

Extracellular vesicles (EVs) are secreted by healthy and tumor cells and are involved in cell–cell communication. Tumor-released EVs could represent a new class of biomarkers from liquid biopsies. The aim of this study was to identify tumor-specific EV markers in clear cell renal carcinoma (ccRCC) using cell lines and patient-derived tissue samples. EVs from ccRCC cell lines (786-O, RCC53, Caki1, and Caki2) and patient tissues were isolated via ultracentrifugation. EVs were characterized using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting using exosome and putative tumor markers (epithelial cell adhesion molecule (EpCAM), carbonic anhydrase 9 (CA9), CD70, CD147). The tumor markers were verified using immunohistochemistry. CA9 was expressed in Caki2 cells and EVs, and CD147 was found in the cells and EVs of all tested ccRCC cell lines. In tumor tissues, we found an increased expression of CA9, CD70, and CD147 were increased in cell lysates and EV fractions compared to normal tissues. In contrast, EpCAM was heterogeneously expressed in tumor samples and positive in normal tissue. To conclude, we developed an effective technique to isolate EVs directly from human tissue samples with high purity and high concentration. In contrast to EpCAM, CA9, CD70, and CD147 could represent promising markers to identify tumor-specific EVs in ccRCC

Organ-Specific Uptake of Extracellular Vesicles Secreted by Urological Cancer Cells

Extracellular vesicles (EVs) secreted by cancer cells have been shown to take a pivotal part in the process of local and systemic tumor progression by promoting the formation of a supportive local tumor microenvironment and preparing premetastatic niches in distant organ systems. In this study, we analyzed the organ-specific uptake of EVs secreted by urological cancer cells using an innovative in-vivo approach. EVs from benign and malignant prostate, kidney, and bladder cells were isolated using ultracentrifugation, fluorescence-labeled and injected intravenously in immunodeficient mice. After 12 or 24 h, the animals were sacrificed, their organs were harvested and analyzed for the presence of EVs by high-resolution fluorescence microscopy. Across all entities, EVs were taken up fast (12 h > 24 h), and EVs from malignant cells were taken up more efficiently than EVs from benign cells. Though not entirely organ-specific, EVs were incorporated in different amounts, depending on the entity (prostate: lung > liver > brain; kidney: brain > lung > liver; bladder: lung > liver > brain). EV uptake in other organs than lung, liver, brain, and spleen was not observed. Our results suggest a role of EVs in the formation of premetastatic niches and an organotropism in EV uptake, which have to be examined in more detail in further studies

The metastatic potential of seminomatous germ cell tumours is associated with a specific microRNA pattern

Background Seminomatous germ cell tumours (SGCT) are the most frequent malignancy in young men. Reliable prognostic biomarkers for the prediction of metastasis at diagnosis and the risk of relapse in clinical stage I (CSI) are lacking. Adjuvant therapies carry a risk of overtreatment, whereas salvage therapies have a risk of high toxicities. Thus, the identification of reliable prognostic biomarkers is highly desirable to identify patients who will benefit from early adjuvant treatment. MicroRNAs (miRNAs) regulate tumour development and progression, and their potential as biomarkers has already been proven in a variety of malignancies. Objectives The aim of our study was to define a specific miRNA expression pattern that discriminates metastatic from non‐metastatic primary SGCT. Materials and methods Total RNA was isolated from 24 formalin‐fixed paraffin‐embedded (FFPE) primary SGCT tumours (10 non‐metastatic, five metachronously and nine synchronously metastatic) and from 10 normal testicular tissue samples. Microarray analysis was performed for global miRNA expression profiling. The results were validated by quantitative real‐time polymerase chain reaction (qRT‐PCR). Statistical analysis was performed using SPSS. Results Microarray analyses revealed a specific miRNA pattern that distinguishes metastatic from non‐metastatic SGCT. Sixty‐three miRNAs were differentially expressed in metastatic compared to non‐metastatic tumours (P < .01). Microarray results were confirmed by qRT‐PCR for three out of five selected miRNAs (miR‐29c‐5p, miR‐506‐3p and miR‐371a‐5p; P < .05). All five miRNAs (miR‐29c‐5p, miR‐506‐3p, miR‐1307‐5p, miR‐371a‐5p and miR‐371a‐3p) showed differential expression between tumour and normal tissues (P < .05). Conclusion Metastatic primary SGCTs are characterized by a specific miRNA expression pattern. Therefore, specific miRNAs could represent a new tool to predict the metastatic potential in SGCT patients

Cancer-associated fibroblasts stimulate primary tumor growth and metastatic spread in an orthotopic prostate cancer xenograft model

The unique microenvironment of the prostate plays a crucial role in the development and progression of prostate cancer (PCa). We examined the effects of cancer-associated fibroblasts (CAFs) on PCa progression using patient-derived fibroblast primary cultures in a representative orthotopic xenograft model. Primary cultures of CAFs, non-cancer-associated fibroblasts (NCAFs) and benign prostate hyperplasia-associated fibroblasts (BPHFs) were generated from patient-derived tissue specimens. These fibroblasts were coinjected together with cancer cells (LuCaP136 spheroids or LNCaP cells) in orthotopic PCa xenografts to investigate their effects on local and systemic tumor progression. Primary tumor growth as well as metastatic spread to lymph nodes and lungs were significantly stimulated by CAF coinjection in LuCaP136 xenografts. When NCAFs or BPHFs were coinjected, tumor progression was similar to injection of tumor cells alone. In LNCaP xenografts, all three fibroblast types significantly stimulated primary tumor progression compared to injection of LNCaP cells alone. CAF coinjection further increased the frequency of lymph node and lung metastases. This is the first study using an orthotopic spheroid culture xenograft model to demonstrate a stimulatory effect of patient-derived CAFs on PCa progression. The established experimental setup will provide a valuable tool to further unravel the interacting mechanisms between PCa cells and their microenvironment