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Medulloblastoma (MB), the most common malignant pediatric brain tumor and a leading cause of childhood mortality, is stratified into four primary subgroups, WNT (wingless), SHH (sonic hedgehog), group 3, and group 4. Patients with group 3 tumors have the poorest prognosis. Loss of 17p13.3, which houses the tumor suppressor gene miR-1253, is a frequent high-risk feature of group 3 tumors.. In this study, we show that miR-1253 levels can disrupt iron homeostasis, induce oxidative stress and lipid peroxidation, triggering an iron-mediated form of cell death called ferroptosis. In silico and in vitro analyses of group 3 tumors revealed deregulation of ABCB7, a mitochondrial iron transporter and target of miR-1253, and GPX4, a critical regulator of ferroptosis. Restoration of miR-1253 levels in group 3 cell lines resulted in downregulation of ABCB7 and GPX4, consequently increasing cytosolic and mitochondrial labile iron pools, reducing glutathione levels, in turn, resulting in mitochondrial oxidative stress and lipid peroxidation. Together, these events accelerated cancer cell death. Treating miR-1253-expressing cancer cells with cisplatin potentiated cell death by further elevating oxidative stress, depleting glutathione levels, and augmenting lipid peroxidation, with added inhibitory effects on cell viability and colony formation. Treatment with a ferroptosis inhibitor (ferrostatin-1) lead to recovery from the cytotoxic effects of this combination therapy. Together, these findings reveal a novel role for miR-1253 in enhancing ferroptosis to attenuate group 3 tumor cell growth. Our studies provide a proof-of-concept for using miR-based therapeutics to augment current chemotherapeutics in high-risk tumors. Leveraging the tumor-suppressive properties of miRNAs as adjuncts to chemotherapy may provide a promising alternative to current therapeutic strategies.

Medulloblastoma (MB), the most common malignant pediatric brain tumor, is a leading cause of childhood mortality. Of the four primary subgroups, patients with group 3 tumors have the poorest prognosis. Loss of chromosome 17p is a high-risk feature associated with poor outcomes in group 3 tumors. We recently elucidated the tumor suppressive properties of a novel miR, miR-1253, on the terminal end of 17p. In further exploring its anti-neoplastic effects, we discovered that miR-1253 can disrupt iron homeostasis, causing oxidative stress and inducing lipid peroxidation. These concurrent events are capable of triggering an iron-mediated form of cell death called ferroptosis. Notably, our in silico interrogation of ferroptosis regulator genes (FRGs) in group 3 tumors revealed high expression of genes associated with iron transport and glutathione metabolism. These included mitochondrial iron transporters and GPX4, a critical regulator of ferroptosis. Restoration of miR-1253 expression in group 3 cell lines resulted in specific downregulation of ABCB7, an iron-sulfur cluster exporter, and GPX4. Consequently, cytosolic and mitochondrial labile iron pools rose, glutathione levels declined, and mitochondrial oxidative stress and lipid peroxidation were induced. These events were recapitulated by ABCB7 knockdown and potentiated cell death. Treating miR-1253-expressing cancer cells with cisplatin, a group 3 MB chemotherapeutic agent with ferroptotic properties, further elevated oxidative stress, depleted glutathione levels, and augmented lipid peroxidation, with added inhibitory effects on cell viability and colony formation. Treatment with a ferroptosis inhibitor (ferrostatin-1) lead to recovery from the cytotoxic effects of this combination therapy. Our studies highlight a novel mechanism for group 3 MB pathogenesis via ferroptosis regulation and provide a proof-of-concept for exploiting group 3 MB tumor vulnerability to iron imbalance as a novel treatment strategy.

Targeting the anti-tumor immune response via the B7 family of immune-regulatory checkpoint proteins has revolutionized cancer treatment and resulted in punctuated responses in patients. B7-H3 has gained recent attention given its prominent deregulation and immunomodulatory role in a multitude of cancers. Numerous cancer studies have firmly established a strong link between deregulated B7-H3 expression and poorer outcomes. B7-H3 has been shown to augment cancer cell survival, proliferation, metastasis, and drug resistance by inducing an immune evasive phenotype through its effects on tumor-infiltrating immune cells, cancer cells, cancer-associated vasculature, and the stroma. Given the complex interplay between each of these components of the tumor microenvironment, a deeper understanding of B7-H3 signaling properties is inherently crucial to developing efficacious therapies that can target and inhibit these cancer-promoting interactions. This review delves into the various ways B7-H3 acts as an immunomodulator to facilitate immune evasion and promote tumor growth and spread. With post-transcriptional and post-translational modifications giving rise to different active isoforms coupled with recent discoveries of its putative receptors, B7-H3 can perform diverse functions. Here, we first discuss the dual co-stimulatory/co-inhibitory functions of B7-H3 in the context of normal physiology and cancer. We then discuss the crosstalk facilitated by B7-H3 between stromal components and tumor cells that promote tumor growth and metastasis in different populations of tumor cells, associated vasculature, and the stroma. Concurrently, we highlight therapeutic strategies that can exploit these interactions and their associated limitations, concluding with a special focus on the promise of next-gen in silico-based approaches to small molecule inhibitor drug discovery for B7-H3 that may mitigate these limitations.

Across the molecular spectrum of medulloblastoma (MB), group 3 (G3) tumors are the most aggressive with

Amongst the 4 subgroups of medulloblastoma (MB), tumors falling into group 3 are the most aggressive and associated with increased incidence of aberrations on chromosome 17p, c-Myc amplification, metastases at diagnosis, and rapid tumor relapse. Thus, patients with group 3 tumors suffer the worst prognosis with a 5-year survival rate of

Background: Malpositioned central venous access devices (CVADs) can lead to significant patient injury including central vein thrombosis and dysrhythmias. Intra-cavitary electrocardiography (IC ECG) has been recommended by peak professional bodies as an accurate alternative for bedside CVAD insertion, to reduce risk of malposition and allowing immediate use of the device. Our objective was to compare the effect of IC ECG on CVAD malposition compared to traditional institutional practice for CVAD placement. Methods: Randomised controlled trial of IC ECG CVAD insertion verses traditional CVAD insertion (surface landmark measurement with post insertion x ray). Patient recruitment was from December 2016 to July 2018. The setting was a 900-bed tertiary referral hospital based in South Western Sydney, Australia. Three hundred and forty-four adult patients requiring CVAD insertion for intravenous therapy, were enrolled and randomly allocated (1:1 ratio) to either IC-ECG ( n = 172) or traditional ( n = 172) CVAD insertion. Our primary outcome of interest was the rate of catheters not requiring repositioning after insertion (ready for use). Secondary outcomes were comparison of procedure time and cost. Results: Of the 172 patients allocated to the IC ECG method, 170 (99%) were ready for use immediately compared to 139 of the 172 (81%) in the traditional insertion group (difference, 95% confidence interval (CI): 18%, 11.9–24.1%). The total procedure time was mean 15 min (SD 8 min) for IC ECG and mean 36 min (SD 17 min) for traditional CVAD insertion (difference–19.9 min (95% CI–14.6 to −34.4). IC ECG guided CVAD insertion had a cost reduction of AUD $62.00 per procedure. Conclusions: Using IC-ECG resulted in nearly no requirement for post-insertion repositioning of CVADs resulting in savings in time and cost and virtually eliminating the need for radiographic confirmation. Trial registration: This trial is registered at the Australian New Zealand Clinical Trials Registry ( http://www.anzctr.org.au ). The registration number is ACTRN12620000919910.

Scedosporium apiospermum is a common environmental mold which is increasingly reported in the literature as a cause of infection, particularly in the immunocompromised patient population. We present a case of malignant otitis externa due to S apiospermum, complicated by spread of infection causing skull base osteomyelitis, internal carotid artery vasculitis and subsequent stroke. Despite the multiple complications encountered, prompt diagnosis and initiation of appropriate antifungal treatment resulted in patient survival. Multiple imaging modalities were used to aid the establishment of the diagnosis in this complex case and highlight the radiological findings associated with skull base osteomyelitis and its possible complications. Keywords: Skull base osteomyelitis, Malignant otitis externa, Mycotic aneurysm, Scedosporium apiospermum, Fungal infection

Medulloblastoma (MB), the most frequent malignant pediatric brain tumor is subdivided into four primary subgroups, i.e. wingless-type (WNT), sonic hedgehog (SHH), group 3, and group 4. Haploinsufficiency of chromosome 17p13.3 and c-myc amplification distinguish high-risk group 3 tumors, which are associated with rapid metastasis, recurrence and early mortality. We sought to identify the role of miR-212, which resides on chromosome 17p13.3, in the pathophysiology of group 3 MB. RNA expression analyses revealed dramatically reduced levels of miR-212 in group 3 tumors and cell lines mainly through epigenetic silencing via histone modifications (deacetylation). Restoring in vitro miR-212 expression reduced tumor cell proliferation, colony formation, wound healing, migration and invasion with decreased p-AKT and p-ERK levels in group 3 MB cell lines. Interestingly, a shift in differential c-myc phosphorylation (from serine-62 to threonine-58) was also discovered with miR-212 expression, resulting in reduced total c-myc levels, concurrent with elevated cellular apoptosis. In turn, pro-apoptotic binding partners of c-myc, i.e. Bin-1 and P19ARF, were upregulated in these cells. These findings were recapitulated in stable inducible miR-212 expressing tumor cells. Using a combination of transcriptomic data and a dual luciferase assay, we isolated an important oncogenic target of miR-212, i.e, NFIB, a nuclear transcription factor implicated in metastasis and recurrence. Increased expression of NFIB was confirmed in group 3 tumors, with poor survival shown in high NFIB-expressing patients. As prior, transient NFIB silencing in vitro reduced not only tumor cell proliferation, colony formation, wound healing, migration and invasion, but also medullosphere formation along with decreased expression of stem cell markers (Nanog, Oct4, Sox2, CD133), confirming its role in tumor recurrence possibly via augmenting tumor stemness. Taken together, these results substantiate the tumor suppressive role of miR-212 in group 3 MB and provide a potential new oncogenic target implicated in tumor recurrence, NFIB.

Medulloblastoma (MB), the most common malignant pediatric brain tumor and a leading cause of childhood mortality, is stratified into four primary subgroups, i.e. SHH (sonic hedgehog), WNT (wingless), and non-SHH/WNT groups 3 and 4, the latter representing high-risk MB. Haploinsufficiency of 17p13.3, which houses the tumor suppressor gene miR-1253, characterizes high-risk tumors. Despite improvements in targeted therapies, a limited proportion of these patients survive the disease. Capitalizing on the tumor suppressive properties of miRNAs as adjuncts to chemotherapy provides a promising alternative to current therapeutic strategies. In this study, we explored the potentiating effects of miR-1253 on cisplatin cytotoxicity in group 3 MB. First, in silico and in vitro analyses revealed an upregulation of ABCB7, a mitochondrial iron transporter and putative target of miR-1253, in MB cell lines and group 3 MB tumors. Overexpression of miR-1253 resulted in downregulation of ABCB7 and GPX4, a critical ferroptosis regulator, which consequently increased labile mitochondrial iron pool and, in turn, mitochondrial ROS (mtROS). Complementarily, we demonstrated, using CRISPR knockdown of ABCB7, ferroptosis induction with downregulation of GPx4 expression, liberation of free iron, mtROS generation and lipid peroxidation. Cisplatin is reported as an inducer of both apoptosis and ferroptosis-mediated cancer cell death. Therapeutically, the combination of miR-1253 and cisplatin led to an additive effect on cell viability, colony formation, apoptosis, and ROS generation. In turn, treatment with mtROS inhibitor (MnTBAP) and ferroptosis inhibitor (Ferrostatin) lead to partial recovery from the cytotoxic effects of this combination therapy. These studies identify an miR-1253-induced ferroptosis pathway targeting the ABCB7/GPX4/mtROS axis in group 3 MB. They further provide proof-of-concept in using miR-based therapeutics to augment treatment efficacy of current chemotherapeutics in the treatment of high-risk tumors.

Considerable effort has gone into improving the performance and reliability of the SAAO’s 74-inch telescope. This included replacing the telescope encoders, refining the pointing model and increasing the telescope throughput. The latter involved re-aluminising the primary and formulating a procedure to ensure optimal alignment of the telescope mirrors. To this end, we developed the necessary hardware and techniques to ensure that such alignment is achieved and maintained, particularly following re-aluminising of the mirrors. In essence, the procedure involves: placing a Taylor Hobson Alignment Telescope on the mechanical rotation axis of the 74-inch (which we define to be the optical axis, since the Cassegrain instruments attach to the associated turntable), then adjusting the tip/tilt of the secondary mirror to get it onto that axis and, lastly, adjusting the tip/tilt of the primary mirror to eliminate coma. An eyepiece (or wavefront camera) is installed at the Cassegrain port for this final step since comatic star images indicate the need to tip/tilt the primary mirror to align it to the secondary. Tuning out any brightness gradients seen in an out-of-focus image of a bright star may also be used for feedback when adjusting the tip/tilt of the primary mirror to null coma.

A computer-based instructional workstation (IWS) is a means to: 1) integrate computer, video, and optical data storage technology into a single instructional system, 2) enable students to learn how to manage information and resolve problems by using the new technology available to them, and 3) help preservice and inservice teachers learn how to use these forms of technology to teach subject matter and information management skills. This workstation is a “problem-centered, information management” instructional system, suitable for individuals or small groups. It combines a microcomputer; video tape, video disc, and CD-ROM players; a video camera; and a printer with productivity, educational, and custom-designed software. An instructional workstation enables teachers and media specialists to focus on educational intents, processes and outcomes without the restrictions of discrete technologies. The system is flexible enough to provide multiple options in task selection, information presentation, and performance evaluation.

The poor state of security on the Internet calls for more effective ways to protect networked systems from attacks. One solution is to be able to counter attack with offensive capabilities. With attacker information available, companies find themselves in a dilemma-counter attack for immediate self-defense, retaliate for future deterrence, inform the appropriate law enforcement authorities, or do nothing. We examine justification for the hack back self-defense and deterrence arguments in the context Of current technology and legal framework. This paper extends discussion of issues surrounding using offensive capabilities for defensive purposes to the civilian/commercial Internet context beyond information warfare.

A honeypot is a decoy computer system designed to look like a legitimate system an intruder will want to break into while, unbeknownst to the intruder, they are being covertly observed. Honeypots are effective precisely because attackers do not know if they are there and where they will be. However, honeypots are also a controversial technique; they essentially bait and capture intruders skirting the fine line between keeping attackers out of a network versus inviting them in. Little legal precedent has been established. Some see them as unfair entrapment tools while others see them as an effective data gathering and deterrence mechanism. This paper attempts to flush out the issues on both sides of a technique that may become ubiquitous in the future.

The state of security on the Internet is bad and becoming worse. One reaction to this state of affairs is a behavior termed "Ethical Hacking" which attempts to proactively increase security protection by identifying and patching known security vulnerabilities on systems owned by other parties. Ethical hackers may beta test unreleased software, stress test released software, and scan networks of computers for vulnerabilities. Previous work has emphasized ethical hacking as an altruistic behavior but we find ethical hackers act rationally, in self-interest, to secure systems that are within their own community (sometimes for pay)-networked systems are only as secure as the weakest system within perimeter defenses.

Deploying VPNs (Virtual Private Networks), especially in a large-scale environment, requires much planning. Based on actual implementation experience, we propose a layered framework that can be used to distribute VPN deliverables among different workgroups. Despite the perception that a VPN is not a customizable solution, we conclude there is a broad range of VPN options available with corresponding trade-offs. This framework supports advanced planning to maximize trade-offs depending on individualized requirements.

The use of virtual private networks is increasing rapidly primarily due to security concerns. As the result of analyzing actual corporate VPN strategies, we identify a common vulnerability we name "distributed weakness in VPNs". Specifically we describe a simple routing attack that can be launched against VPN tunnel endpoints with significant implications. We close with a solution to protect against exploitation of this vulnerability.

This paper presents a layered VPN planning framework for organizations based on actual implementation experience. Specifically, we describe security issues corresponding to five distinct layers of analysis: (1) VPN technology; (2) firewalls; (3) legacy networks; (4) survivability; and (5) legacy applications. There is a broad spectrum of VPN options available with each having its own strengths, weaknesses, and vulnerabilities. It is anticipated that no single VPN solution will supplant others but instead a diversity of choices will continue to emerge thus increasing the value of an advanced planning framework.

Mathematical methods of assessing the spatial autocorrelation associated with individual tree characteristics in forest stands were identified. These measures were used to investigate the spatial autocorrelation of discrete tree characteristics including the species, product, and defect classifications. With the exception of the species classification, none of the discrete tree characteristics examined showed any evidence of significant (α = 0.05) levels of spatial autocorrelation in loblolly pine stands. The significant autocorrelation of the species classification was probably due to past stand history or microsite variability rather than overall stand conditions such as age, density, or percent pine. The relationship between the level of spatial autocorrelation associated with basal area and several descriptive stand characteristics was also examined. No strong relationships were identified but trends were noticed between the autocorrelation measures and measures of stand competition such as basal area and crown competition factor. The measures of spatial association indicate positive autocorrelation between the characteristics of neighboring trees at very low levels of competition with the autocorrelation becoming increasingly negative as competition increases. At extremely high levels of competition, the spatial autocorrelation measures become positive again, reflecting the stagnated condition of the stand. Methods were developed, using the measures of spatial autocorrelation, to assign characteristics to individual trees in computer generated stands. These methods, applicable for discrete or continuous characteristics; assign the characteristics to individual trees depending on the spatial location of the individual tree and the locations and characteristics of its neighbors. Ph. D.