M1 Polarization Markers Are Upregulated in Basal-Like Breast Cancer Molecular Subtype and Associated With Favorable Patient Outcome

Background: Breast cancer heterogeneity is an essential element that plays a role in the therapy response variability and the patient’s outcome. This highlights the need for more precise subtyping methods that focus not only on tumor cells but also investigate the profile of stromal cells as well as immune cells. Objectives: To mine publicly available transcriptomic breast cancer datasets and reanalyze their transcriptomic profiling using unsupervised clustering in order to identify novel subsets in molecular subtypes of breast cancer, then explore the stromal and immune cells profile in each subset using bioinformatics and systems immunology approaches. Materials and Methods: Transcriptomic data from 1,084 breast cancer patients obtained from The Cancer Genome Atlas (TCGA) database were extracted and subjected to unsupervised clustering using a recently described, multi-step algorithm called Iterative Clustering and Guide-gene Selection (ICGS). For each cluster, the stromal and immune profile was investigated using ESTIMATE and CIBERSORT analytical tool. Clinical outcomes and differentially expressed genes of the characterized clusters were identified and validated in silico and in vitro in a cohort of 80 breast cancer samples by immunohistochemistry. Results: Seven unique sub-clusters showed distinct molecular and clinical profiles between the well-known breast cancer subtypes. Those unsupervised clusters identified more homogenous subgroups in each of the classical subtypes with a different prognostic profile. Immune profiling of the identified clusters showed that while the classically activated macrophages (M1) are correlated with the more aggressive basal-like breast cancer subtype, the alternatively activated macrophages (M2) showed a higher level of infiltration in luminal A and luminal B subtypes. Indeed, patients with higher levels of M1 expression showed less advanced disease and better patient outcomes presented as prolonged overall survival. Moreover, the M1 high basal-like breast cancer group showed a higher expression of interferon-gamma induced chemokines and guanylate-binding proteins (GBPs) involved in immunity against microbes. Conclusion: Adding immune profiling using transcriptomic data can add precision for diagnosis and prognosis and can cluster patients according to the available modalities of therapy in a more personalized approach

Subaxial Cervical Spine Injuries: WFNS Spine Committee Recommendations

To formulate specific guidelines for the recommendation of subaxial cervical spine injuries concerning classification, management, posttraumatic locked facets and vertebral artery injury. Computerized literature was searched on PubMed and google scholar database from 2009 to 2020. For classification, keywords "Sub Axial Cervical Spine Classification," resulting in 22 articles related to subaxial cervical spine injury classification system (SLICS) system and 11 articles related to AO (Arbeitsgemeinschaft für Osteosynthesefragen, German for "Association for the Study of Internal Fixation") Spine system. The literature search yielded 210 and 78 articles on "management of subaxial cervical spine injuries" and the role of "SLICS" and "AO Spine" respectively. Keywords "management of traumatic facet locks" were searched and closed reduction, traction, approaches and techniques were studied. "Vertebral artery injury and cervical fracture" exhibited 2,328 references from the last 15 years. The objective was to identify the appropriate diagnostic tests and optimal treatment. Up-to-date information was reviewed, and statements were produced to reach a consensus in 2 separate consensus meetings of World Federation of Neurosurgical Societies (WFNS) Spine Committee. The statements were voted and reached a positive or negative consensus using Delphi method. Based on the most relevant literature, panelists in Moscow consensus meeting conducted in May 2019 drafted the statements, and after a preliminary voting session, the consensus was identified on various statements. Another meeting was conducted at Peshawar in November 2019, where in addition to previous statements, few other statements were discussed and voted. Specific recommendations were then formulated guiding classification, management, locked facets and vertebral artery injuries. This review summarizes the WFNS Spine Committee recommendations on subaxial cervical spine injuries.info:eu-repo/semantics/publishedVersio

DKK3’s protective role in prostate cancer is partly due to the modulation of immune-related pathways

While it is considered one of the most common cancers and the leading cause of death in men worldwide, prognostic stratification and treatment modalities are still limited for patients with prostate cancer (PCa). Recently, the introduction of genomic profiling and the use of new techniques like next-generation sequencing (NGS) in many cancers provide novel tools for the discovery of new molecular targets that might improve our understanding of the genomic aberrations in PCa and the discovery of novel prognostic and therapeutic targets. In this study, we investigated the possible mechanisms through which Dickkopf-3 (DKK3) produces its possible protective role in PCa using NGS in both the DKK3 overexpression PCa cell line (PC3) model and our patient cohort consisting of nine PCa and five benign prostatic hyperplasia. Interestingly, our results have shown that DKK3 transfection-modulated genes are involved in the regulation of cell motility, senescence-associated secretory phenotype (SASP), and cytokine signaling in the immune system, as well as in the regulation of adaptive immune response. Further analysis of our NGS using our in vitro model revealed the presence of 36 differentially expressed genes (DEGs) between DKK3 transfected cells and PC3 empty vector. In addition, both CP and ACE2 genes were differentially expressed not only between the transfected and empty groups but also between the transfected and Mock cells. The top common DEGs between the DKK3 overexpression cell line and our patient cohort are the following: IL32, IRAK1, RIOK1, HIST1H2BB, SNORA31, AKR1B1, ACE2, and CP. The upregulated genes including IL32, HIST1H2BB, and SNORA31 showed tumor suppressor functions in various cancers including PCa. On the other hand, both IRAK1 and RIOK1 were downregulated and involved in tumor initiation, tumor progression, poor outcome, and radiotherapy resistance. Together, our results highlighted the possible role of the DKK3-related genes in protecting against PCa initiation and progression

Field Response of Magnetic Vortices in Dusty Olivine From the Semarkona Chondrite

Recent paleomagnetic studies have constrained the strength and longevity of the magnetic field generated by the solar nebula, which has broad implications for the early evolution of the solar system. Paleomagnetic evidence was recorded by nanoscale iron inclusions in olivine crystals in the Semarkona LL 3.0 chondrite. These dusty olivines, have been shown to be credible carriers of ancient magnetic remanence. The small scale of the iron inclusions presents several challenges for defining their fundamental magnetic properties. Here we present the first correlative study of the response of these magnetic structures under applied laboratory fields. Results show that the majority of particles are in a single‐vortex state and exhibit stable magnetic behavior in applied fields up to 200 mT. Experimental observations using Lorentz microscopy and magnetic transmission X‐ray microscopy are shown to compare well with the results of finite‐element micromagnetic simulations derived from 3D models of the particles obtained using electron tomography. This correlative approach may be used to characterize the fundamental magnetic behavior of many terrestrial and extraterrestrial paleomagnetic carriers in the single‐ to multi‐vortex size range, which represent the vast majority of stable magnetic carriers in rocks and meteorites.ERC Grant Agreement No. 32075

Intra-anal imiquimod cream against human papillomavirus infection in men who have sex with men living with hiv: A single-arm, open-label pilot study

Men who have sex with men (MSM) living with HIV have a high prevalence and incidence of anal high-risk human papillomavirus (hrHPV) and anal cancer. We conducted an open-label, single-arm pilot study to examine the tolerability of imiquimod cream among MSM aged ≥18 years, living with HIV, who tested positive for anal hrHPV at Melbourne Sexual Health Centre between April 2018 and June 2020. We instructed men to apply 6.25 mg imiquimod intra-anally and peri-anally 3 doses per week for 16 weeks (period 1) and then one dose per week for a further 48 weeks (period 2). Twenty-seven MSM enrolled in period 1 and 24 (86%) applied at least 50% of doses. All men reported adverse events (AEs), including 39.5% grade 1, 39.5% grade 2, and 21% grade 3 AEs on at least one occasion. Eighteen MSM (67%) temporarily stopped using imiquimod during period 1, most commonly due to local AEs (n = 11) such as irritation and itching. Eighteen MSM continued in period 2 and all applied at least 50% of doses with no treatment-limiting AEs reported. Imiquimod 3 doses per week caused local AEs in most men and was not well tolerated. In contrast, once-a-week application was well tolerated over 48-weeks with no treatment-limiting AEs

Substrate stabilisation and small structures in coral restoration: State of knowledge, and considerations for management and implementation.

Coral reef ecosystems are under increasing pressure from local and regional stressors and a changing climate. Current management focuses on reducing stressors to allow for natural recovery, but in many areas where coral reefs are damaged, natural recovery can be restricted, delayed or interrupted because of unstable, unconsolidated coral fragments, or rubble. Rubble fields are a natural component of coral reefs, but repeated or high-magnitude disturbances can prevent natural cementation and consolidation processes, so that coral recruits fail to survive. A suite of interventions have been used to target this issue globally, such as using mesh to stabilise rubble, removing the rubble to reveal hard substrate and deploying rocks or other hard substrates over the rubble to facilitate recruit survival. Small, modular structures can be used at multiple scales, with or without attached coral fragments, to create structural complexity and settlement surfaces. However, these can introduce foreign materials to the reef, and a limited understanding of natural recovery processes exists for the potential of this type of active intervention to successfully restore local coral reef structure. This review synthesises available knowledge about the ecological role of coral rubble, natural coral recolonisation and recovery rates and the potential benefits and risks associated with active interventions in this rapidly evolving field. Fundamental knowledge gaps include baseline levels of rubble, the structural complexity of reef habitats in space and time, natural rubble consolidation processes and the risks associated with each intervention method. Any restoration intervention needs to be underpinned by risk assessment, and the decision to repair rubble fields must arise from an understanding of when and where unconsolidated substrate and lack of structure impair natural reef recovery and ecological function. Monitoring is necessary to ascertain the success or failure of the intervention and impacts of potential risks, but there is a strong need to specify desired outcomes, the spatial and temporal context and indicators to be measured. With a focus on the Great Barrier Reef, we synthesise the techniques, successes and failures associated with rubble stabilisation and the use of small structures, review monitoring methods and indicators, and provide recommendations to ensure that we learn from past projects

Asymmetric WIMP dark matter

In existing dark matter models with global symmetries the relic abundance of dark matter is either equal to that of anti-dark matter (thermal WIMP), or vastly larger, with essentially no remaining anti-dark matter (asymmetric dark matter). By exploring the consequences of a primordial asymmetry on the coupled dark matter and anti-dark matter Boltzmann equations we find large regions of parameter space that interpolate between these two extremes. Interestingly, this new asymmetric WIMP framework can accommodate a wide range of dark matter masses and annihilation cross sections. The present-day dark matter population is typically asymmetric, but only weakly so, such that indirect signals of dark matter annihilation are not completely suppressed. We apply our results to existing models, noting that upcoming direct detection experiments will constrain a large region of the relevant parameter space.Comment: 32 pages, 6 figures, updated references, updated XENON100 bounds, typo in figure caption correcte

Allergic reaction related to ramipril use: a case report

<p>Abstract</p> <p>Background</p> <p>Angiotensin-converting enzyme (ACE) inhibitors are widely prescribed for patients with diabetes as a nephroprotector drug or to treat hypertension. Generally they are safe for clinical practice, but the relationship between these drugs and angioedema is known. The exact mechanism for ACE inhibitors-induced angioedema is not clear and it is still a matter of discussion.</p> <p>Case Report</p> <p>We reported a case of a 23-year-old black female with an 11 year history of type 1 diabetes, regularly monitored in the department of diabetes, in use of 0,98 UI/kg/day of human insulin, which presented an allergic reaction 24 h after ramipril use. The drug had been prescribed to treat diabetic nephropathy. There was no previous history of drug induced or alimentary allergy. The patient was instructed to discontinue the use of ramipril and oral antihistaminic drug and topical corticosteroid were prescribed. Skin biopsies were performed and confirmed the clinical hypothesis of pharmacodermy. The evaluation of ACE polymorphism identified <it>DD </it>genotype. Six months after the withdrawal of ramipril the patient was prescribed the angiotensin-II receptor blocker (ARB) losartan as nephroprotector. She remained well without adverse reactions.</p> <p>Conclusions</p> <p>ACE inhibitors-induced angioedema is uncommon and the clinical presentation is variable with lips, tongue, oropharinge, and larynge as the most common locations. The presence of angioedema during treatment requires the immediate cessation of treatment due to the risk of possible severe complications. The case reported presented moderate symptoms, with the development of early onset edema in uncommon regions. ACE <it>DD </it>genotype had been associated with angioedema-ACE inhibitors induced. In patients who have experienced ACE inhibitor-related angioedema, ARB should be used cautiously used. However in the case of our patient, the prescription of losartan as nefroprotector did not result in any recurrent adverse effect.</p

Fractal Dimension Analysis of Transient Visual Evoked Potentials: Optimisation and Applications

Purpose The visual evoked potential (VEP) provides a time series signal response to an external visual stimulus at the location of the visual cortex. The major VEP signal components, peak latency and amplitude, may be affected by disease processes. Additionally, the VEP contains fine detailed and non-periodic structure, of presently unclear relevance to normal function, which may be quantified using the fractal dimension. The purpose of this study is to provide a systematic investigation of the key parameters in the measurement of the fractal dimension of VEPs, to develop an optimal analysis protocol for application. Methods VEP time series were mathematically transformed using delay time, τ, and embedding dimension, m, parameters. The fractal dimension of the transformed data was obtained from a scaling analysis based on straight line fits to the numbers of pairs of points with separation less than r versus log(r) in the transformed space. Optimal τ, m, and scaling analysis were obtained by comparing the consistency of results using different sampling frequencies. The optimised method was then piloted on samples of normal and abnormal VEPs. Results Consistent fractal dimension estimates were obtained using τ = 4 ms, designating the fractal dimension = D2 of the time series based on embedding dimension m = 7 (for 3606 Hz and 5000 Hz), m = 6 (for 1803 Hz) and m = 5 (for 1000Hz), and estimating D2 for each embedding dimension as the steepest slope of the linear scaling region in the plot of log(C(r)) vs log(r) provided the scaling region occurred within the middle third of the plot. Piloting revealed that fractal dimensions were higher from the sampled abnormal than normal achromatic VEPs in adults (p = 0.02). Variances of fractal dimension were higher from the abnormal than normal chromatic VEPs in children (p = 0.01). Conclusions A useful analysis protocol to assess the fractal dimension of transformed VEPs has been developed