A Viral-Encoded Homologue of IPS-1 Modulates Innate Immune Signaling During KSHV Lytic Replication.

Modulation of innate immunity is critical for virus persistence in a host. In particular, viral-encoded disruption of type I interferon, a major antiviral cytokine induced to fight viral infection, is a key component in the repertoire of viral pathogenicity genes. We have identified a previously undescribed open reading frame within the Kaposi's sarcoma-associated herpesvirus (KSHV) genome that encodes a homologue of the human IPS-1 (also referred to as MAVS) protein that we have termed viral-IPS-1 (v-IPS-1). This protein is expressed during the lytic replication program of KSHV, and expression of v-IPS-1 blocks induction of type I interferon upstream of the TRAF3 signaling node including signaling initiated via both the RLR and TLR3/4 signaling axes. This disruption of signaling coincides with destabilization of the cellular innate signaling adaptors IPS-1 and TRIF along with a concatenate stabilization of the TRAF3 protein. Additionally, expression of v-IPS-1 leads to decreased antiviral responses indicating a blot to type I interferon induction during viral infection. Taken together, v-IPS-1 is the first described viral homologue of IPS-1 and this viral protein leads to reprogramming of innate immunity through modulation of type I interferon signaling during KSHV lytic replication.

Clinical impact of CEUS on non-characterizable observations and observations with intermediate probability of malignancy on CT/MRI in patients at risk for HCC.

BACKGROUND: Hepatocellular carcinoma (HCC) is a unique cancer allowing tumor diagnosis with identification of definitive patterns of enhancement on contrast-enhanced imaging, avoiding invasive biopsy. However, it is still unclear to what extent Contrast-Enhanced Ultrasound (CEUS) is a clinically useful additional step when Computed tomography (CT) or Magnetic resonance imaging (MRI) are inconclusive. METHODS: A prospective international multicenter validation study for CEUS Liver Imaging Reporting and Data System (LI-RADS) was conducted between January 2018 and August 2021. 646 patients at risk for HCC with focal liver lesions were enrolled. CEUS was performed using an intravenous ultrasound contrast agent within 4 weeks of CT/MRI. Liver nodules were categorized based on LI-RADS (LR) criteria. Histology or one-year follow-up CT/MRI imaging results were used as the reference standard. The diagnostic performance of CEUS was evaluated for inconclusive CT/MRI scan in two scenarios for which the AASLD recommends repeat imaging or imaging follow-up: observations deemed non-characterizable (LR-NC) or with indeterminate probability of malignancy (LR-3). RESULTS: 75 observations on CT or MRI were categorized as LR-3 (n = 54) or LR-NC (n = 21) CEUS recategorization of such observations into a different LR category (namely, into one among LR-1, LR-2, LR-5, LR-M, or LR-TIV) resulted in management recommendation changes in 33.3% (25/75) and in all but one (96.0%, 24/25) observation, the new management recommendations were correct. CONCLUSION: CEUS LI-RADS resulted in management recommendations change in substantial number of liver observations with initial indeterminate CT/MRI characterization, identifying both non-malignant lesions and HCC, potentially accelerating the diagnostic process and alleviating the need for biopsy or follow-up imaging. CLINICALTRIALS: gov number, NCT03318380.

Fibril-Guided Three-Dimensional Assembly of Human Fibroblastic Reticular Cells.

Fibroblastic reticular cells (FRCs) are stromal cells (SCs) that can be isolated from lymph node (LN) biopsies. Studies have shown that these nonhematopoietic cells have the capacity to shape and regulate adaptive immunity and can become a form of personalized cell therapy. Successful translational efforts, however, require the cells to be formulated as injectable units, with their native architecture preserved. The intrinsic reticular organization of FRCs, however, is lost in the monolayer cultures. Organizing FRCs into three-dimensional (3D) clusters would recapitulate their structural and functional attributes. Herein, we report a scaffolding method based on the self-assembling peptide (SAP) EAKII biotinylated at the N-terminus (EAKbt). Cross-linking with avidin transformed the EAKbt fibrils into a dense network of coacervates. The combined forces of fibrillization and bioaffinity interactions in the cross-linked EAKbt likely drove the cells into a cohesive 3D reticula. This facile method of generating clustered FRCs (clFRCs) can be completed within 10 days. In vitro clFRCs attracted the infiltration of T cells and rendered an immunosuppressive milieu in the cocultures. These results demonstrate the potential of clFRCs as a method for stromal cell delivery.

Continuing benefits of the Montreal Protocol and protection of the stratospheric ozone layer for human health and the environment.

The protection of Earth's stratospheric ozone (O3) is an ongoing process under the auspices of the universally ratified Montreal Protocol and its Amendments and adjustments. A critical part of this process is the assessment of the environmental issues related to changes in O3. The United Nations Environment Programme's Environmental Effects Assessment Panel provides annual scientific evaluations of some of the key issues arising in the recent collective knowledge base. This current update includes a comprehensive assessment of the incidence rates of skin cancer, cataract and other skin and eye diseases observed worldwide; the effects of UV radiation on tropospheric oxidants, and air and water quality; trends in breakdown products of fluorinated chemicals and recent information of their toxicity; and recent technological innovations of building materials for greater resistance to UV radiation. These issues span a wide range of topics, including both harmful and beneficial effects of exposure to UV radiation, and complex interactions with climate change. While the Montreal Protocol has succeeded in preventing large reductions in stratospheric O3, future changes may occur due to a number of natural and anthropogenic factors. Thus, frequent assessments of potential environmental impacts are essential to ensure that policies remain based on the best available scientific knowledge.

A miniaturized additive-manufactured carbon black/PLA electrochemical sensor for pharmaceuticals detection.

Additive manufacturing is a technique that allows the construction of prototypes and has evolved a lot in the last 20 years, innovating industrial fabrication processes in several areas. In chemistry, additive manufacturing has been used in several functionalities, such as microfluidic analytical devices, energy storage devices, and electrochemical sensors. Theophylline and paracetamol are important pharmaceutical drugs where overdosing can cause adverse effects, such as tachycardia, seizures, and even renal failure. Therefore, this paper aims at the development of miniaturized electrochemical sensors using 3D printing and polylactic acid-based conductive carbon black commercial filament for theophylline and paracetamol detection. Electrochemical characterizations of the proposed sensor were performed to prove the functionality of the device. Morphological characterizations were carried out, in which chemical treatment could change the surface structure, causing the improvement of the analytical signal. Thus, the detection of theophylline at a linear range of 5.00-150 µmol L-1 with a limit of detection of 1.2 µmol L-1 was attained, and the detection of paracetamol at a linear range of 1.00-200 µmol L-1 with a limit of detection of 0.370 µmol L-1 was obtained, demonstrating the proposed sensor effectively detected pharmaceutical drugs.

Antimony release and volatilization from organic-rich and iron-rich submerged soils.

Antimony (Sb) is an poorly understood, increasingly common pollutant, especially in soils susceptible to waterlogging. We investigated the impact of waterlogging on Sb release, methylation, and volatilization from an organic-rich wetland soil and an iron (Fe)-rich floodplain soil in a 27-day microcosm experiment. The release of Sb into the porewaters of the organic-rich soil was environmentally relevant and immediate with waterlogging (3.2 to 3.5 mg L-1), and likely associated with a complex interplay of sulfide precipitation, sorption with organic matter and manganese (Mn) (oxyhydr)oxides in the soil. The release of Sb from the Fe-rich soil was likely associated with Fe-(oxyhydr)oxide reduction and immobilized due to co-precipitation with Fe-sulfides or as Sb-sulfides. Volatile Sb was produced from the soils after waterlogging. The organic-rich soil produced more volatile Sb (409 to 835 ng kgsoil-1), but the Fe-rich soil volatilized Sb more efficiently. The negligible association of Sb volatilization with soil parameters indicates a more complex underlying, potentially microbial, mechanism and that antimony volatilization could be ubiquitous and not dependent on specific soil properties. Future works should investigate the microbial and physiochemical drivers of Sb volatilization in soils as it may be an environmentally relevant part of the biogeochemical cycle.

Spodoptera cosmioides (Lepidoptera: Noctuidae) in Brazil: spatial distribution and relationship in the S. latifascia species group

ABSTRACT Spodoptera cosmioides (Walker, 1858) is an economically relevant polyphagous moth, widely distributed in the Neotropics and part of the Spodoptera latifascia (Walker, 1856) species group. In this study, we used extensive sampling from different regions to describe the spatial distribution of S. cosmioides in Brazil and evaluate its variability both from morphological and molecular perspectives. Variable coloration and several morphological similarities were found among S. cosmioides and congeners of the S. latifascia complex, diverging from each 0.5 to 3.5% of mitochondrial DNA. The genetic divergence at the species level of S. cosmioides was 0.5% throughout Brazil, and a geographic structure was absent, including shared haplotypes with S. descoinsi Lalanne-Cassou & Silvain, 1994. Spodoptera cosmioides was found in all six biomes of Brazil, with the highest abundance recorded in the Cerrado, followed by the Amazon, Atlantic Rainforest, Caatinga, Pantanal, and Pampa.

Mechanisms of systemic resistance to pathogen infection in plants and their potential application in forestry.

BACKGROUND: The complex systemic responses of tree species to fight pathogen infection necessitate attention due to the potential for yield protection in forestry. RESULTS: In this paper, both the localized and systemic responses of model plants, such as Arabidopsis and tobacco, are reviewed. These responses were compared to information available that investigates similar responses in woody plant species and their key differences were highlighted. In addition, tree-specific responses that have been documented were summarised, with the critical responses still relying on certain systemic acquired resistance pathways. Importantly, coniferous species have been shown to utilise phenolic compounds in their immune responses. Here we also highlight the lack of focus on systemic induced susceptibility in trees, which can be important to forest health. CONCLUSIONS: This review highlights the possible mechanisms of systemic response to infection in woody plant species, their potential applications, and where research may be best focused in future.

Value of prolonged scrotal drainage after penile prosthesis implantation: a multicenter prospective nonrandomized pilot study.

We aimed to understand the risks and benefits of post-inflatable penile prosthesis (IPP) implantation drainage and optimal duration. Our patients were divided into 3 groups: Group 1 (n = 114) had no drain placed, Group 2 had a drain placed for 24 h (n = 114) and Group 3 had a drain placed for 72 h (n = 117). Postoperative scrotal hematoma and prosthesis infection rates were compared between the groups. The patients from Group 3 demonstrated a statistically significant lower incidence of hematoma on the 10th postoperative day: (n = 1, 0.9%) compared to Group 2: (n = 11, 9.6%) and Group 1: (n = 8, 7%), (p = 0.013). However, on the 3rd postoperative day, there was a statistically significant lower incidence of hematoma in both Groups 3 and 2: (0.9% and 6.1%, respectively) vs. Group 1: (11.4%), (p = 0.004). Hematoma rates followed the same group order after the first day of surgery: 1.7% (n = 2), 5.3% (n = 6), and 8.8% (n = 10), respectively, (p = 0.05). Five patients (4.4%) in Group 1 and four patients (3.5%) in Group 2 developed an IPP associated infection, opposed to only a single patient (0.85%) in Group 3, (p = 0.210). We concluded that prolonged scrotal drainage for 72 h after virgin IPP implantation significantly reduces hematoma and infection rates.

Integrating the patients' voice in designing and delivering a research study: The Yorkshire Cancer Research funded PREHABS study's experience.

INTRODUCTION: Engaging with patients when designing a clinical or research project is beneficial; feedback from the intended audience provides invaluable insight form the patients' perspective. Working with patients can result in developing successful research grants and interventions. The benefit of including the voice of the patient in the Yorkshire Cancer Research funded PREHABS study is described in this article. METHODS: Patients were included in the PREHABS study from inception to completion. The Theory of Change methodology was used to provide a framework to implement patient feedback to refine the study intervention. RESULTS: In total, 69 patients engaged with the PREHABS project. Two patients were recruited as co-applicants on the grant and were members on the Trial Management Group. Six patients attended the pre application workshop and provided feedback on their lived experiences of being a lung cancer patient. Commentary from the patients influenced the interventions selected and the design of the prehabs study. Following ethical approval (21/EE/0048) and informed written consent, 61 patients were recruited into the PREHABS study between October 2021 and November 2022. The breakdown of recruited patients was 19 males: mean age 69.1 years (SD 8.91) and 41 females; mean age 74.9 years (SD 8.9). CONCLUSION: It is practicable and beneficial to include patients at all stages of designing and delivering a research study. Patient feedback can help refine the study interventions to allow for maximum acceptance, recruitment and retention. IMPLICATIONS FOR PRACTICE: Including patients in the design of radiotherapy research studies can provide invaluable insight that can support the selection and delivery of interventions that are acceptable to the patient cohort.

SGLT2 inhibitor ertugliflozin decreases elevated intracellular sodium, and improves energetics and contractile function in diabetic cardiomyopathy.

BACKGROUND: Elevated myocardial intracellular sodium ([Na+]i) was shown to decrease mitochondrial calcium ([Ca2+]MITO) via mitochondrial sodium/calcium exchanger (NCXMITO), resulting in decreased mitochondrial ATP synthesis. The sodium-glucose co-transporter 2 inhibitor (SGLT2i) ertugliflozin (ERTU) improved energetic deficit and contractile dysfunction in a mouse model of high fat, high sucrose (HFHS) diet-induced diabetic cardiomyopathy (DCMP). As SGLT2is were shown to lower [Na+]i in isolated cardiomyocytes, we hypothesized that energetic improvement in DCMP is at least partially mediated by a decrease in abnormally elevated myocardial [Na+]i. METHODS: Forty-two eight-week-old male C57BL/6J mice were fed a control or HFHS diet for six months. In the last month, a subgroup of HFHS-fed mice was treated with ERTU. At the end of the study, left ventricular contractile function and energetics were measured simultaneously in isolated beating hearts by 31P NMR (Nuclear Magnetic Resonance) spectroscopy. A subset of untreated HFHS hearts was perfused with vehicle vs. CGP 37157, an NCXMITO inhibitor. Myocardial [Na+]i was measured by 23Na NMR spectroscopy. RESULTS: HFHS hearts showed diastolic dysfunction, decreased contractile reserve, and impaired energetics as reflected by decreased phosphocreatine (PCr) and PCr/ATP ratio. Myocardial [Na+]i was elevated > 2-fold in HFHS (vs. control diet). ERTU reversed the impairments in HFHS hearts to levels similar to or better than control diet and decreased myocardial [Na+]i to control levels. CGP 37157 normalized the PCr/ATP ratio in HFHS hearts. CONCLUSIONS: Elevated myocardial [Na+]i contributes to mitochondrial and contractile dysfunction in DCMP. Targeting myocardial [Na+]i and/or NCXMITO may be an effective strategy in DCMP and other forms of heart disease associated with elevated myocardial [Na+]i.

Novel approaches utilizing robotic navigational bronchoscopy: a single institution experience.

The effective biopsy of pulmonary nodules is crucial to early diagnosis and consequent effective treatment for patients. As a relatively new procedure, few studies look at the effectiveness of the Monarch system in achieving this goal. The aim of this study is to describe the validity of the Monarch-guided robotic navigational bronchoscopy as an effective diagnostic method for pulmonary disease. A secondary aim is to describe the validity of dye localization using the robotic platform to improve the diagnostic accuracy of surgical biopsies in suspicious subcentimeter nodules. This observational cohort study includes patients who underwent robotic navigational bronchoscopy at John Muir Health between July 8, 2020 and October 11, 2021. Some underwent the navigational bronchoscopy in conjugation with a dye localization procedure. Patient data were collected from the institutional database. We measured specificity, sensitivity, and likelihood ratios. A total of 69 patients underwent robotic navigational bronchoscopy. The procedure had a specificity and sensitivity of 100% and 91.3%, respectively. Additionally, 28 patients underwent robotic navigational bronchoscopy in conjugation with dye localization. The specificity and sensitivity for the combined procedures was 100% and 100%, respectively. Robotic Navigational Bronchoscopy can be a successful diagnostic technique to diagnose pulmonary disease quickly and accurately. The technique allowed for the effective biopsy of traditionally difficult to access nodules. Additionally, by combining dye localization techniques, surgical biopsy of the nodules significantly improved the diagnostic accuracy. This single anesthetic event can potentially lead to earlier diagnosis, staging, and treatment of early stage lung cancers.

Targeting STAT3 in tumor-associated antigen-presenting cells as a strategy for kidney and bladder cancer immunotherapy.

Introduction: Immune checkpoint blockade (ICB) improved clinical outcomes in renal and bladder cancer patients, but the response rates remain limited especially in metastatic disease. While STAT3 transcription factor is well-known master regulator of tumor immune evasion, little is known about the role of STAT3 in the resistance of renal or bladder cancers to immunotherapy. Methods: To better understand immune alterations associated with ICB resistance, we assessed blood biomarkers in renal cancer patients classified as responders or non-responders to first line nivolumab/ipilimumab immunotherapy. Results: We observed that non-responders showed elevated levels of proinflammatory mediators, such as IL-1RA, IL-6, IL-8 and to lesser extent IL-10, which are associated with STAT3 activation and tumor immunosuppression. In addition, we found STAT3 activation primarily in circulating myeloid immune cells such as tolerogenic MDSCs. To assess whether STAT3 inhibition within these cell subsets can promote antitumor immune responses and/or enhance sensitivity to ICB in vivo, we used an original antisense oligonucleotide (ASO) strategy for myeloid-cell selective STAT3 knockdown (CpG-STAT3ASO). Our results in syngeneic models of renal and bladder cancers in mice demonstrated potent antitumor activity of CpG-STAT3ASO alone in contrast to PD1 blockade alone in both models. The CpG-STAT3ASO/anti-PD1 combination improved therapeutic efficacy especially against bladder tumors. Therapeutic efficacy correlated with activation of dendritic cells (DCs) and M1 macrophages in the tumor microenvironment, reduced percentages of regulatory T cells (Tregs) and the expansion of CD8 T cells in both tumor models. Discussion/Conclusion: Our study underscores the potential of using myeloid-cell targeted CpG-STAT3 inhibitors for genitourinary cancer therapy to disrupt tolerogenic signaling, restore immune cell activity and sensitivity to immune checkpoint inhibitors and/or T cell-based immunotherapies.

Prehabilitation and Rehabilitation for Patients with Lung Cancer: A Review of Where we are Today.

Lung cancer is the third most common type of cancer in the UK, with nearly 50 000 new cases diagnosed a year. Treatments for lung cancer have improved in recent years with the advent of new surgical and radiotherapy techniques and the increased use of immunotherapies. These advances have resulted in increasing numbers of patients surviving beyond the completion of their treatment. Lung cancer patients are now not dying from their cancer diagnosis, but from other co-existing pathologies. Lung cancer patients commonly present with multiple comorbidities. Mitigating the effects of poor lifestyles and changing behaviours may improve the efficacy of treatments, reduce side-effects and improve the quality of life for lung cancer patients. Published evidence supports the use of interventions to manage behavioural habits, to optimise the health of patients. There is no consensus as to what, when or how to embed these into the patient pathway. Supporting patients before, during and after their cancer treatments to increase activity, eat well and stop smoking have been seen to decrease side-effects and improve patient outcomes and wellbeing. The challenge is to provide a package of interventions that is acceptable to patients and fits within the patient pathway so as not to conflict with diagnostic and therapeutic activities. This article reviews where we are today with providing behavioural support to optimise the health of lung cancer patients undergoing treatment.

Development of New Simple Compositions of Silver Inks for the Preparation of Pseudo-Reference Electrodes.

Silver materials are known to present excellent properties, such as high electrical and thermal conductivity as well as chemical stability. Silver-based inks have drawn a lot of attention for being compatible with various substrates, which can be used in the production uniform and stable pseudo-reference electrodes with low curing temperatures. Furthermore, the interest in the use of disposable electrodes has been increasing due to the low cost and the possibility of their use in point-of-care and point-of-need situations. Thus, in this work, two new inks were developed using Ag as conductive material and colorless polymers (nail polish (NP) and shellac (SL)), and applied to different substrates (screen-printed electrodes, acetate sheets, and 3D-printed electrodes) to verify the performance of the proposed inks. Measurements attained with open circuit potential (OCP) attested to the stability of the potential of the pseudo-reference proposed for 1 h. Analytical curves for ß-estradiol were also obtained using the devices prepared with the proposed inks as pseudo-references electrodes, which presented satisfactory results concerning the potential stability (RSD < 2.6%). These inks are simple to prepare and present great alternatives for the development of pseudo-reference electrodes useful in the construction of disposable electrochemical systems.

Localized PD-1 Blockade in a Mouse Model of Renal Cell Carcinoma.

Herein we report the impact of localized delivery of an anti-mouse PD-1-specific monoclonal antibody (aPD1) on Renca tumors in the resulting T cell responses and changes in broader immune gene expression profiles. Renca is a BALB/c mice syngeneic tumor that has been used to model human renal cell carcinoma In this study, T cell subsets were examined in tumors and draining lymph nodes of mice treated with localized PD-1 with and without the addition of adenosine deaminase (ADA), an enzyme that catabolizes adenosine (ADO), identified as an immune checkpoint in several types of human cancers. The biologics, aPD1, or aPD1 with adenosine deaminase (aPD1/ADA), were formulated with the self-assembling peptides Z15_EAK to enhance retention near the tumor inoculation site. We found that both aPD1 and aPD1/ADA skewed the local immune milieu towards an immune stimulatory phenotype by reducing Tregs, increasing CD8 T cell infiltration, and upregulating IFNÉ£. Analysis of tumor specimens using bulk RNA-Seq confirmed the impact of the localized aPD1 treatment and revealed differential gene expressions elicited by the loco-regional treatment. The effects of ADA and Z15_EAK were limited to tumor growth delay and lymph node enlargement. These results support the notion of expanding the use of locoregional PD-1 blockade in solid tumors.

Recrystallization of Adenosine for Localized Drug Delivery.

Adenosine (ADO) is an endogenous metabolite with immense potential to be repurposed as an immunomodulatory therapeutic, as preclinical studies have demonstrated in models of epilepsy, acute respiratory distress syndrome, and traumatic brain injury, among others. The currently licensed products Adenocard and Adenoscan are formulated at 3 mg/mL of ADO for rapid bolus intravenous injection, but the systemic administration of the saline formulations for anti-inflammatory purposes is limited by the nucleoside's profound hemodynamic effects. Moreover, concentrations that can be attained in the airway or the brain through direct instillation or injection are limited by the volumes that can be accommodated in the anatomical space (<5 mL in humans) and the rapid elimination by enzymatic and transport mechanisms in the interstitium (half-life <5 s). As such, highly concentrated formulations of ADO are needed to attain pharmacologically relevant concentrations at sites of tissue injury. Herein, we report a previously uncharacterized crystalline form of ADO (rcADO) in which 6.7 mg/mL of the nucleoside is suspended in water. Importantly, the crystallinity is not diminished in a protein-rich environment, as evidenced by resuspending the crystals in albumin (15% w/v). To the best of our knowledge, this is the first report of crystalline ADO generated using a facile and organic solvent-free method aimed at localized drug delivery. The crystalline suspension may be suitable for developing ADO into injectable formulations for attaining high concentrations of the endogenous nucleoside in inflammatory locales.

Environmental effects of stratospheric ozone depletion, UV radiation, and interactions with climate change: UNEP Environmental Effects Assessment Panel, Update 2021.

The Environmental Effects Assessment Panel of the Montreal Protocol under the United Nations Environment Programme evaluates effects on the environment and human health that arise from changes in the stratospheric ozone layer and concomitant variations in ultraviolet (UV) radiation at the Earth's surface. The current update is based on scientific advances that have accumulated since our last assessment (Photochem and Photobiol Sci 20(1):1-67, 2021). We also discuss how climate change affects stratospheric ozone depletion and ultraviolet radiation, and how stratospheric ozone depletion affects climate change. The resulting interlinking effects of stratospheric ozone depletion, UV radiation, and climate change are assessed in terms of air quality, carbon sinks, ecosystems, human health, and natural and synthetic materials. We further highlight potential impacts on the biosphere from extreme climate events that are occurring with increasing frequency as a consequence of climate change. These and other interactive effects are examined with respect to the benefits that the Montreal Protocol and its Amendments are providing to life on Earth by controlling the production of various substances that contribute to both stratospheric ozone depletion and climate change.