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Metastatic disease is the leading cause of death among cancer patients and involves a complex and inefficient process. Every step of the metastatic process can be rate limiting and is influenced by non-malignant host cells interacting with the tumor cell. Over a century ago, experiments first indicated a link between the immune system and metastasis. This phenomenon, called concomitant immunity, indicates that the primary tumor induces an immune response, which may not be sufficient to destroy the primary tumor, but prevents the growth of a secondary tumor or metastases. Since that time, many different immune cells have been shown to play a role in both inhibiting and promoting metastatic disease. Here we review classic and new observations, describing the links between the immune system and metastasis that inform the development of cancer therapies.

This paper introduces the concept of an operational reference glass database, specifically designed for broken glass fragments from ATM attacks, jewelry store robberies, and ramraids on high-end clothing stores. The database, initiated in 2014, is used to compare glass traces from organized crews involved said criminal activities. Utilizing LA-ICPMS, this study establishes a methodology for collecting reference glass samples from the scenes of the aforementioned crimes, thus creating a comprehensive database containing over 3500 reference glass samples from crime scenes. The operational database is employed to match trace elemental profiles of glass fragments from suspected items to known reference samples, offering specificity and accuracy. Analysis of results, while ongoing due to the nature of active cases, find matches of trace materials in over 50 % of case requests since 2019. Challenges such as database scalability and continuous updating are acknowledged, and future directions include technological advancements to enhance precision and the application into other areas of forensic material analysis. The paper emphasizes the efficacy of this specialized approach in chemical profiling, providing a potent tool for linking glass traces to specific criminal contexts and providing intelligence and investigative leads into individuals involved in ATM-related crimes. [Display omitted] •Introduction of the concept of an operational glass database by means of chemical profiling.•Glass fragments can be matched to reference glass that was received months prior.•Over 50 % of case requests since 2019 yield matches with earlier stored reference glass.

High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rβ). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in mice. NKTR-214 shows superior anti-tumor activity over native IL-2 and systemically expands anti-tumor CD8 + T cells while inducing Treg depletion in tumor tissue but not in the periphery. Similar trends of intratumoral Treg dynamics are observed in a small cohort of patients treated with NKTR-214. Mechanistically, intratumoral Treg depletion is mediated by CD8 + Teff-associated cytokines IFN-γ and TNF-α. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies. Interleukin-2 can induce an anti-tumour response, but is associated with toxicity. Here, the authors demonstrate that an engineered interleukin-2 promotes intratumoral T regulatory cell depletion while enhancing effective anti-tumour CD8 +  T cell responses that result in potent tumor suppression.

CD40 agonists bind the CD40 molecule on antigen-presenting cells and activate them to prime tumor-specific CD8 + T cell responses. Here, we study the antitumor activity and mechanism of action of a nonreplicating adenovirus encoding a chimeric, membrane-bound CD40 ligand (ISF35). Intratumoral administration of ISF35 in subcutaneous B16 melanomas generates tumor-specific, CD8 + T cells that express PD-1 and suppress tumor growth. Combination therapy of ISF35 with systemic anti-PD-1 generates greater antitumor activity than each respective monotherapy. Triple combination of ISF35, anti-PD-1, and anti-CTLA-4 results in complete eradication of injected and noninjected subcutaneous tumors, as well as melanoma tumors in the brain. Therapeutic efficacy is associated with increases in the systemic level of tumor-specific CD8 + T cells, and an increased ratio of intratumoral CD8 + T cells to CD4 + Tregs. These results provide a proof of concept of systemic antitumor activity after intratumoral CD40 triggering with ISF35 in combination with checkpoint blockade for multifocal cancer, including the brain. Treatment options for metastatic melanoma are limited. Here the authors show that combining an immunostimulant adenovirus, currently in clinical trials for leukemia, with immune checkpoints blockade (ICB) results in systemic eradication of ICB resistant melanoma tumours from both skin and brain of mice.

ObjectivesIn the intensive care unit (ICU), antibiotics are often given longer than recommended in guidelines. A better understanding of the factors influencing antibiotic therapy duration is needed to develop improvement strategies to effectively address these drivers of excessive duration. This study aimed to explore the determinants of adherence to recommended antibiotic therapy durations among healthcare professionals involved in antibiotic decision-making within the ICU, focusing on multidisciplinary meetings (MDMs).MethodsSemistructured interviews were held with healthcare professionals involved in antibiotic decision-making during MDMs in four Dutch ICUs. Participants included intensivists, clinical microbiologists and ICU residents. Transcripts were analysed using deductive and inductive content analysis methods.ResultsA total of 20 participants were interviewed. The interviews revealed that decision-making regarding antibiotic therapy duration is a complex process, primarily centred around professional interactions during MDMs and involving a broad range of determinants. These determinants were categorised into the following four steps: (1) the introduction of duration as a topic for discussion in the MDM (eg, lack of priority to discuss antibiotic therapy duration); (2) the discussion of antibiotic therapy duration itself (eg, lack of core members during MDM); (3) the establishment of a concrete decision (eg, lack of documentation of the decisions made); (4) the execution of the decision (eg, forgetting to stop antibiotics).ConclusionsOur study identified numerous factors that influence decisions about the duration of antibiotic therapy during MDMs in the ICU. By describing these factors throughout the decision-making process, we provided valuable insights into barriers that commonly arise in specific steps, highlighting critical areas for improvement. Daily MDMs were deemed essential for informed decision-making regarding antibiotic therapy duration by the interviewees. Strategies to improve appropriate duration in the ICU should prioritise strengthening interdisciplinary communication between healthcare professionals and adding structure to these meetings.

Antibiotic therapy is commonly prescribed longer than recommended in intensive care patients (ICU). We aimed to provide insight into the decision-making process on antibiotic therapy duration in the ICU. A qualitative study was conducted, involving direct observations of antibiotic decision-making during multidisciplinary meetings in four Dutch ICUs. The study used an observation guide, audio recordings, and detailed field notes to gather information about the discussions on antibiotic therapy duration. We described the participants' roles in the decision-making process and focused on arguments contributing to decision-making. We observed 121 discussions on antibiotic therapy duration in sixty multidisciplinary meetings. 24.8% of discussions led to a decision to stop antibiotics immediately. In 37.2%, a prospective stop date was determined. Arguments for decisions were most often brought forward by intensivists (35.5%) and clinical microbiologists (22.3%). In 28.9% of discussions, multiple healthcare professionals participated equally in the decision. We identified 13 main argument categories. While intensivists mostly used arguments based on clinical status, clinical microbiologists used diagnostic results in the discussion. Multidisciplinary decision-making regarding the duration of antibiotic therapy is a complex but valuable process, involving different healthcare professionals, using a variety of argument-types to determine the duration of antibiotic therapy. To optimize the decision-making process, structured discussions, involvement of relevant specialties, and clear communication and documentation of the antibiotic plan are recommended. •Antibiotic therapy duration in the ICU is commonly longer than recommended.•ICU multidisciplinary meetings are central to determine antibiotic therapy duration.•Intensivist and clinical microbiologist play an important role.•Structured discussions, specialty involvement and clear documentation are recommended.

Extended abstract of a paper presented at Microscopy and Microanalysis 2013 in Indianapolis, Indiana, USA, August 4 – August 8, 2013.

The production of jets is studied in deep-inelastic ep scattering at large negative four momentum transfer squared 150

The production of jets is studied in deep-inelastic e+p scattering at low negative four momentum transfer squared 5

Events with high energy isolated electrons, muons or tau leptons and missing transverse momentum are studied using the full eᵖ data sample collected by the H1 experiment at HERA, corresponding to an integrated luminosity of 474 pb⁻1. Within the Standard Model, events with isolated leptons and missing transverse momentum mainly originate from the production of single W bosons. The total single W boson production cross section is measured as 1.14 0.25 (stat.) 0.14 (sys.) pb, in agreement with the Standard Model expectation. The data are also used to establish limits on the WW gauge couplings and for a measurement of the W boson polarisation.