An orthotopic prostate cancer model for new treatment development using syngeneic or patient-derived tumors.

BACKGROUND: There are limited preclinical orthotopic prostate cancer models due to the technical complexity of surgical engraftment and tracking the tumor growth in the mouse prostate gland. Orthotopic xenografts recapitulate the tumor microenvironment, tumor stromal interactions, and clinical behavior to a greater extent than xenografts grown at subcutaneous or intramuscular sites. METHODS: This study describes a novel micro-surgical technique for orthotopically implanting intact tumors pieces from cell line derived (transgenic adenocarcinoma mouse prostate [TRAMP]-C2) or patient derived (neuroendocrine prostate cancer [NEPC]) tumors in the mouse prostate gland and monitoring tumor growth using magnetic resonance (MR) imaging. RESULTS: The TRAMP-C2 tumors grew rapidly to a predetermined endpoint size of 10 mm within 3 weeks, whereas the NEPC tumors grew at a slower rate over 7 weeks. The tumors were readily detected by MR and confidently identified when they were approximately 2-3 mm in size. The tumors were less well-defined on CT. The TRAMP-C2 tumors were characterized by amorphous sheets of poorly differentiated cells similar to a high-grade prostatic adenocarcinoma and frequent macroscopic peritoneal and lymph node metastases. In contrast, the NEPC's displayed a neuroendocrine morphology with polygonal cells arranged in nests and solid sheets and high count. There was a local invasion of the bladder and other adjacent tissues but no identifiable metastases. The TRAMP-C2 tumors were more hypoxic than the NEPC tumors. CONCLUSIONS: This novel preclinical orthotopic prostate cancer mouse model is suitable for either syngeneic or patient derived tumors and will be effective in developing and advancing the current selection of treatments for patients with prostate cancer.

Living Naked in the Cold: New Insights into Metabolic Feasibility in Primeval Cultures.

The people of three primeval cultures lived naked or nearly naked in regions where they experienced air temperatures of ± 5 degrees Celsius during cold seasons. These were the Australian Aboriginal peoples, the Bushmen of southern Africa, and the Yamana and the Alakaluf of Tierra del Fuego. Recent meta-analyses of data on human metabolic rate and metabolic endurance enable a quantitative demonstration of feasibility: Thermoregulation at winter air temperatures while naked was feasible in the three cultures for significantly longer than 50-180 days per year (sufficient for the duration of winter). Considering the life histories of the people, their estimated, time-averaged daily (24 hours) metabolic rates in winter were 2.6 times basal-similar to the highest daily rates empirically measured in extant peoples. Although the primeval peoples' way of life was metabolically expensive, it was as feasible as the lifestyles of peoples in today's world who live at the upper bound of the metabolically possible.

Abscisic acid supports colonization of Eucalyptus grandis roots by the mutualistic ectomycorrhizal fungus Pisolithus microcarpus.

The pathways regulated in ectomycorrhizal (EcM) plant hosts during the establishment of symbiosis are not as well understood when compared to the functional stages of this mutualistic interaction. Our study used the EcM host Eucalyptus grandis to elucidate symbiosis-regulated pathways across the three phases of this interaction. Using a combination of RNA sequencing and metabolomics we studied both stage-specific and core responses of E. grandis during colonization by Pisolithus microcarpus. Using exogenous manipulation of the abscisic acid (ABA), we studied the role of this pathway during symbiosis establishment. Despite the mutualistic nature of this symbiosis, a large number of disease signalling TIR-NBS-LRR genes were induced. The transcriptional regulation in E. grandis was found to be dynamic across colonization with a small core of genes consistently regulated at all stages. Genes associated to the carotenoid/ABA pathway were found within this core and ABA concentrations increased during fungal integration into the root. Supplementation of ABA led to improved accommodation of P. microcarpus into E. grandis roots. The carotenoid pathway is a core response of an EcM host to its symbiont and highlights the need to understand the role of the stress hormone ABA in controlling host-EcM fungal interactions.

Domain Feature Mapping with YOLOv7 for Automated Edge-Based Pallet Racking Inspections.

Pallet racking is an essential element within warehouses, distribution centers, and manufacturing facilities. To guarantee its safe operation as well as stock protection and personnel safety, pallet racking requires continuous inspections and timely maintenance in the case of damage being discovered. Conventionally, a rack inspection is a manual quality inspection process completed by certified inspectors. The manual process results in operational down-time as well as inspection and certification costs and undiscovered damage due to human error. Inspired by the trend toward smart industrial operations, we present a computer vision-based autonomous rack inspection framework centered around YOLOv7 architecture. Additionally, we propose a domain variance modeling mechanism for addressing the issue of data scarcity through the generation of representative data samples. Our proposed framework achieved a mean average precision of 91.1%.

A Dynamic Multi-Mobile Agent Itinerary Planning Approach in Wireless Sensor Networks via Intuitionistic Fuzzy Set.

In recent research developments, the application of mobile agents (MAs) has attracted extensive research in wireless sensor networks (WSNs) due to the unique benefits it offers, such as energy conservation, network bandwidth saving, and flexibility of open usage for various WSN applications. The majority of the proposed research ideas on dynamic itinerary planning agent-based algorithms are efficient when dealing with node failure as a result of energy depletion. However, they generate inefficient groups for MAs itineraries, which introduces a delay in broadcasting data return back to the sink node, and they do not consider the expanding size of the MAs during moving towards a sequence of related nodes. In order to rectify these research issues, we propose a new Graph-based Dynamic Multi-Mobile Agent Itinerary Planning approach (GDMIP). GDMIP works with "Directed Acyclic Graph" (DAG) techniques and distributes sensor nodes into various and efficient group-based shortest-identified routes, which cover all nodes in the network using intuitionistic fuzzy sets. MAs are restricted from moving in the predefined path and routes and are responsible for collecting data from the assigned groups. The experimental results of our proposed work show the effectiveness and expediency compared to the published approaches. Therefore, our proposed algorithm is more energy efficient and effective for task delay (time).

Posttraumatic stress disorder in nurses caring for patients with COVID-19.

ABSTRACT: Little is known about the psychological impact of trauma from pandemics such as the COVID-19 pandemic. This article explores a descriptive study on the impact of COVID-19 and the prevalence of posttraumatic stress disorder among RNs caring for patients with COVID-19.

Towards rabies elimination in the Asia-Pacific region: From theory to practice.

Rabies is a major neglected zoonotic disease and causes a substantial burden in the Asian region. Currently, Pacific Oceania is free of rabies but enzootic areas throughout southeast Asia represent a major risk of disease introduction to this region. On September 25-26, 2019, researchers, government officials and related stakeholders met at an IABS conference in Bangkok, Thailand to engage on the topic of human rabies mediated by dogs. The objective of the meeting was focused upon snowballing efforts towards achieving substantial progress in rabies prevention, control and elimination within Asia by 2030, and thereby to safeguard the Pacific region. Individual sessions focused upon domestic animal, wildlife and human vaccination; the production and evaluation of quality, safety and efficacy of existing rabies biologics; and the future development of new products. Participants reviewed the progress to date in eliminating canine rabies by mass vaccination, described supportive methods to parenteral administration by oral vaccine application, considered updated global and local approaches at human prophylaxis and discussed the considerable challenges ahead. Such opportunities provide continuous engagement on disease management among professionals at a trans-disciplinary level and promote new applied research collaborations in a modern One Health context.

Hardware-Intrinsic Multi-Layer Security: A New Frontier for 5G Enabled IIoT.

The introduction of 5G communication capabilities presents additional challenges for the development of products and services that can fully exploit the opportunities offered by high bandwidth, low latency networking. This is particularly relevant to an emerging interest in the Industrial Internet of Things (IIoT), which is a foundation stone of recent technological revolutions such as Digital Manufacturing. A crucial aspect of this is to securely authenticate complex transactions between IIoT devices, whilst marshalling adversarial requests for system authorisation, without the need for a centralised authentication mechanism which cannot scale to the size needed. In this article we combine Physically Unclonable Function (PUF) hardware (using Field Programmable Gate Arrays-FPGAs), together with a multi-layer approach to cloud computing from the National Institute of Standards and Technology (NIST). Through this, we demonstrate an approach to facilitate the development of improved multi-layer authentication mechanisms. We extend prior work to utilise hardware security primitives for adversarial trojan detection, which is inspired by a biological approach to parameter analysis. This approach is an effective demonstration of attack prevention, both from internal and external adversaries. The security is further hardened through observation of the device parameters of connected IIoT equipment. We demonstrate that the proposed architecture can service a significantly high load of device authentication requests using a multi-layer architecture in an arbitrarily acceptable time of less than 1 second.

Bio-Inspired Approaches to Safety and Security in IoT-Enabled Cyber-Physical Systems.

Internet of Things (IoT) and Cyber-Physical Systems (CPS) have profoundly influenced the way individuals and enterprises interact with the world. Although attacks on IoT devices are becoming more commonplace, security metrics often focus on software, network, and cloud security. For CPS systems employed in IoT applications, the implementation of hardware security is crucial. The identity of electronic circuits measured in terms of device parameters serves as a fingerprint. Estimating the parameters of this fingerprint assists the identification and prevention of Trojan attacks in a CPS. We demonstrate a bio-inspired approach for hardware Trojan detection using unsupervised learning methods. The bio-inspired principles of pattern identification use a Spiking Neural Network (SNN), and glial cells form the basis of this work. When hardware device parameters are in an acceptable range, the design produces a stable firing pattern. When unbalanced, the firing rate reduces to zero, indicating the presence of a Trojan. This network is tunable to accommodate natural variations in device parameters and to avoid false triggering of Trojan alerts. The tolerance is tuned using bio-inspired principles for various security requirements, such as forming high-alert systems for safety-critical missions. The Trojan detection circuit is resilient to a range of faults and attacks, both intentional and unintentional. Also, we devise a design-for-trust architecture by developing a bio-inspired device-locking mechanism. The proposed architecture is implemented on a Xilinx Artix-7 Field Programmable Gate Array (FPGA) device. Results demonstrate the suitability of the proposal for resource-constrained environments with minimal hardware and power dissipation profiles. The design is tested with a wide range of device parameters to demonstrate the effectiveness of Trojan detection. This work serves as a new approach to enable secure CPSs and to employ bio-inspired unsupervised machine intelligence.

Correction: Targeting CXCL12/CXCR4 and myeloid cells to improve the therapeutic ratio in patient-derived cervical cancer models treated with radio-chemotherapy.

Since the publication of this paper, the authors have reported that an incorrect version of Figure 1 was presented. The correct version of Figure 1 is provided.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Targeting CXCL12/CXCR4 and myeloid cells to improve the therapeutic ratio in patient-derived cervical cancer models treated with radio-chemotherapy.

BACKGROUND: The CXCL12/CXCR4 chemokine pathway is involved in cervical cancer pathogenesis and radiation treatment (RT) response. We previously reported that radiochemotherapy (RTCT) and concurrent administration of the CXCR4 inhibitor plerixafor improved primary tumour response. The aims of this study were to determine optimal sequencing of RTCT and plerixafor, the mechanisms responsible for improved response and the effect of plerixafor on late intestinal toxicity. METHODS: Orthotopic cervical cancer xenografts were treated with RTCT (30 Gy in 2 Gy fractions and cisplatin) with or without concurrent, adjuvant or continuous plerixafor. The endpoints were growth delay and molecular and immune cell changes at the end of treatment. Late intestinal toxicity was assessed by histologic examination of the rectum 90 days after a single 20 Gy fraction. RESULTS: RTCT increased CXCL12/CXCR4 signalling and the intratumoral accumulation of myeloid cells; the addition of plerixafor mitigated these effects. All of the RTCT and plerixafor arms showed prolonged tumour growth delay compared to RTCT alone, with the adjuvant arm showing the greatest improvement. Plerixafor also reduced late intestinal toxicity. CONCLUSION: Adding Plerixafor to RTCT blunts treatment-induced increases in CXCL12/CXCR4 signalling, improves primary tumour response and reduces intestinal side effects. This combination warrants testing in future clinical trials.

Diagnostics in the veterinary field: The role in health surveillance and disease identification.

An international workshop, held in Wiesbaden, Germany on 15-17 May 2019 provided an overview of existing and new methods and approaches to diagnostics in animal health and their benefits and challenges. The variability in quality and authority review of test kits across the world is a concern for the reliability of test results and the decisions that are based on the diagnostic data. In countries or regions without regulatory oversight, there is an urgent need for international harmonisation of quality requirements and licensing procedures. This would increase the validity of the diagnostic methods and allow mutual recognition of test results within the network of official control laboratories and amongst animal health officials. Regional cooperation, as well as the OIE Laboratory Network, should be used to support licensing procedures, pool resources for serum and sample banks, survey outbreak responses, and coordinate research and development of new veterinary diagnostics. The end-users must have clear information on a test's performance, limitations, and interpretation of results.

Achieving scientific and regulatory success in implementing non-animal approaches to human and veterinary rabies vaccine testing: A NICEATM and IABS workshop report.

This two-day workshop, co-sponsored by NICEATM and IABS-NA, brought together over 60 international scientists from government, academia, and industry to advance alternative methods for human and veterinary Rabies Virus Vaccine (RVV) potency testing. On day one, workshop presentations focused on regulatory perspectives related to in vitro potency testing, including recent additions to the European Pharmacopoeia (5.2.14) that provide a scientific rationale for why in vivo methods may be less suitable for vaccine quality control than appropriately designed in vitro methods. Further presentations reviewed the role of the consistency approach to manufacturing and vaccine batch comparison to provide supportive data for the substitution of existing animal-based methods with in vitro assays. In addition, updates from research programs evaluating and validating RVV glycoprotein (G) quantitation by ELISA as an in vitro potency test were presented. On the second day, RVV stakeholders participated in separate human and veterinary vaccine discussion groups focused on identifying potential obstacles or additional requirements for successful implementation of non-animal alternatives to the in vivo potency test. Workshop outcomes and proposed follow up activities are discussed herein.

Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress.

Tumor cells gain a survival/growth advantage by adapting their metabolism to respond to environmental stress, a process known as metabolic transformation. The best-known aspect of metabolic transformation is the Warburg effect, whereby cancer cells up-regulate glycolysis under aerobic conditions. However, other mechanisms mediating metabolic transformation remain undefined. Here we report that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific metabolic enzyme, may participate in metabolic transformation. CPT1C expression correlates inversely with mammalian target of rapamycin (mTOR) pathway activation, contributes to rapamycin resistance in murine primary tumors, and is frequently up-regulated in human lung tumors. Tumor cells constitutively expressing CPT1C show increased fatty acid (FA) oxidation, ATP production, and resistance to glucose deprivation or hypoxia. Conversely, cancer cells lacking CPT1C produce less ATP and are more sensitive to metabolic stress. CPT1C depletion via siRNA suppresses xenograft tumor growth and metformin responsiveness in vivo. CPT1C can be induced by hypoxia or glucose deprivation and is regulated by AMPKα. Cpt1c-deficient murine embryonic stem (ES) cells show sensitivity to hypoxia and glucose deprivation and altered FA homeostasis. Our results indicate that cells can use a novel mechanism involving CPT1C and FA metabolism to protect against metabolic stress. CPT1C may thus be a new therapeutic target for the treatment of hypoxic tumors.

Targeting the CXCL12/CXCR4 pathway and myeloid cells to improve radiation treatment of locally advanced cervical cancer.

Cervical cancer is the fourth most commonly diagnosed cancer and the fourth leading cause of cancer death in women worldwide. Approximately half of cervical cancer patients present with locally advanced disease, for which surgery is not an option. These cases are nonetheless potentially curable with radiotherapy and cisplatin chemotherapy. Unfortunately, some tumours are resistant to treatment, and lymph node and distant recurrences are major problems in patients with advanced disease at diagnosis. New targeted treatments that can overcome treatment resistance and reduce metastases are urgently needed. The CXCL12/CXCR4 chemokine pathway is ubiquitously expressed in many normal tissues and cancers, including cervical cancer. Emerging evidence indicates that it plays a central role in cervical cancer pathogenesis, malignant progression, the development of metastases and radiation treatment response. Pre-clinical studies of standard-of-care fractionated radiotherapy and concurrent weekly cisplatin plus the CXCR4 inhibitor Plerixafor (AMD3100) in patient-derived orthotopic cervical cancer xenografts have shown improved primary tumour response and reduced lymph node metastases with no increase in early or late side effects. These studies have pointed the way forward to future clinical trials of radiotherapy/cisplatin plus Plerixafor or other newly emerging CXCL12 or CXCR4 inhibitors in women with cervical cancer.

Nucleon axial radius and muonic hydrogen-a new analysis and review.

Weak capture in muonic hydrogen (µH) as a probe of the chiral properties and nucleon structure predictions of quantum chromodynamics (QCD) is reviewed. A recent determination of the axial-vector charge radius squared, [Formula: see text], from a model independent z expansion analysis of neutrino-nucleon scattering data is employed in conjunction with the MuCap measurement of the singlet muonic hydrogen capture rate, [Formula: see text], to update the induced pseudoscalar nucleon coupling [Formula: see text] derived from experiment, and [Formula: see text] predicted by chiral perturbation theory. Accounting for correlated errors this implies [Formula: see text], confirming theory at the 8% level. If instead, the predicted expression for [Formula: see text] is employed as input, then the capture rate alone determines [Formula: see text], or together with the independent z expansion neutrino scattering result, a weighted average [Formula: see text]. Sources of theoretical uncertainty are critically examined and potential experimental improvements are described that can reduce the capture rate error by about a factor of 3. Muonic hydrogen can thus provide a precise and independent [Formula: see text] value which may be compared with other determinations, such as ongoing lattice gauge theory calculations. The importance of an improved [Formula: see text] determination for phenomenology is illustrated by considering the impact on critical neutrino-nucleus cross sections at neutrino oscillation experiments.

Acid secretion by the boring organ of the burrowing giant clam, Tridacna crocea.

The giant clam Tridacna crocea, native to Indo-Pacific coral reefs, is noted for its unique ability to bore fully into coral rock and is a major agent of reef bioerosion. However, T. crocea's mechanism of boring has remained a mystery despite decades of research. By exploiting a new, two-dimensional pH-sensing technology and manipulating clams to press their presumptive boring tissue (the pedal mantle) against pH-sensing foils, we show that this tissue lowers the pH of surfaces it contacts by greater than or equal to 2 pH units below seawater pH day and night. Acid secretion is likely mediated by vacuolar-type H+-ATPase, which we demonstrate (by immunofluorescence) is abundant in the pedal mantle outer epithelium. Our discovery of acid secretion solves this decades-old mystery and reveals that, during bioerosion, T. crocea can liberate reef constituents directly to the soluble phase, rather than producing sediment alone as earlier assumed.

Hedgehog inhibition enhances efficacy of radiation and cisplatin in orthotopic cervical cancer xenografts.

BACKGROUND: The Hedgehog (Hh) pathway is upregulated in cervical cancer and associated with poor outcome. We explored the effects of Hh pathway inhibition in combination with RTCT in a patient derived orthotopic cervical cancer xenograft model (OCICx). METHODS: 5E1, a monoclonal antibody for SHH, or Sonidegib (LDE225), a clinical SMO inhibitor (Novartis) were added to RTCT. We investigated tumour growth delay, metastasis and GI toxicity using orthotopic cervical cancer xenografts models. The xenografts were treated with radiotherapy (15 × 2 Gy daily fractions over 3 weeks) and weekly cisplatin 4 mg kg-1 concurrently, with or without 5E1 or Sonidegib (LDE225). The Hh inhibitors were administered by subcutaneous injection (5E1; 20 mg kg-1 weekly for 3 weeks), or by oral gavage (Sonidegib; 60 mg kg-1 daily for 3 weeks). RESULTS: We observed that both Hh inhibitors administered with RTCT were well tolerated and showed increased tumour growth delay, and reduced metastasis, with no increase in acute GI-toxicity relative to RTCT alone. CONCLUSIONS: Our data suggest Hh can be a valid therapeutic target in cervical cancer and supports data suggesting a potential therapeutic role for targeting Hh in patients undergoing RTCT. This warrants further investigation in clinical trials.

Metabolic targeting of HIF-dependent glycolysis reduces lactate, increases oxygen consumption and enhances response to high-dose single-fraction radiotherapy in hypoxic solid tumors.

BACKGROUND: A high rate of glycolysis leading to elevated lactate content has been linked to poor clinical outcomes in patients with head and neck and cervical cancer treated with radiotherapy. Although the biological explanation for this relationship between lactate and treatment response remains unclear, there is a continued interest in evaluating strategies of targeting metabolism to enhance the effectiveness of radiotherapy. The goal of this study was to investigate the effect of metabolic-targeting through HIF-1α inhibition and the associated changes in glycolysis, oxygen consumption and response on the efficacy of high-dose single-fraction radiotherapy (HD-SFRT). METHODS: HIF-1α wild-type and HIF-1α knockdown FaDu and ME180 xenograft tumors were grown in the hind leg of mice that were placed in an environmental chamber and exposed to different oxygen conditions (air-breathing and hypoxia). Ex vivo bioluminescence microscopy was used to measure lactate and ATP levels and the hypoxic fraction was measured using EF5 immunohistochemical staining. The oxygen consumption rate (OCR) in each cell line in response to in vitro hypoxia was measured using an extracellular flux analyzer. Tumor growth delay in vivo was measured following HD-SFRT irradiation of 20 Gy. RESULTS: Targeting HIF-1α reduced lactate content, and increased both oxygen consumption and hypoxic fraction in these tumors after exposure to short-term continuous hypoxia. Tumors with intact HIF-1α subjected to HD-SFRT immediately following hypoxia exposure were less responsive to treatment than tumors without functional HIF-1α, and tumors irradiated under air breathing conditions regardless of HIF-1α status. CONCLUSIONS: Blocking the HIF1 response during transient hypoxic stress increased hypoxia, reduced lactate levels and enhanced response to HD-SFRT. This strategy of combining hypofractionated radiotherapy with metabolic reprogramming to inhibit anaerobic metabolism may increase the efficacy of HD-SFRT through increased oxygen consumption and complementary killing of radiosensitive and hypoxic, radioresistant cells.

Risk of Surgical Site Infection in Elective Hip and Knee Replacements After Confirmed Eradication of MRSA in Chronic Carriers.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is globally endemic and is a leading cause of surgical site infection (SSI). The purpose of this study was to evaluate the incidence of SSI in MRSA carriers undergoing elective hip or knee arthroplasty, who had confirmed eradication and to compare it with incidence of SSI in non-MRSA carriers. METHODS: This is a retrospective analysis of 6613 patients who underwent elective total hip arthroplasty (THA; n = 3347) and total knee arthroplasty (TKA; n = 3266) at our institution. A cohort of patients who were preoperatively colonized with MRSA was identified. We compared the infection rates with non-MRSA carriers. RESULTS: We had a colonization rate of 1.3% (83 patients). A total of 79 patients had confirmed eradication of carrier status before surgical intervention. Of these, 38 were THAs and 41 were TKAs. Five of 79 patients (6.32%; 95% confidence interval [CI]: 2.35%-14.79%) had "deep SSI" within 1 year of surgery. There were 2 MRSA infections in THAs (relative risk 4.46; 95% CI: 1.12-17.82). There were 2 MRSA and 1 methicillin-sensitive Staphylococcus aureus infections in TKAs (relative risk 5.61; 95% CI: 1.81-17.38). A significant statistical difference in infection rates from MRSA negative control group was noted, which had a deep sepsis rate of 1.17% in THAs and 1.3% in TKAs over the same period. CONCLUSION: In spite of a selective treatment program for carriers and confirmed eradication, there is still a significantly increased risk of SSI in MRSA-colonized patients undergoing hip or knee arthroplasties.