Search

Immunotherapy is the “fourth pillar” of cancer treatment (Nobel Prize in 2018 by Drs. Allison and Honjo).The gut microbiome has been shown to impact immunotherapy outcomes in cancer. In human-to-mouse experiments involving fecal transplantation (FMT), the effect of the gut microbiome on immunotherapy outcomes was observed to be transferable.Cancer patients who receive antibiotics prior to initiation of immunotherapy may have worse outcomes, which is hypothesized to be due to the negative impact of antibiotics on the gut microbiome.Microbiota have also been identified in solid tumors of the pancreas and breast—organs that communicate with the outside world.In a murine model of pancreatic cancer, the intra-tumoral microbiome was shown to promote inhibitory immune pathways, and antibiotic reversed this effect.

Abstract Background Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is established as the preferred method of mediastinal lymph node (LN) staging in non-small cell lung cancer (NSCLC). Selective (targeted) LN sampling is most commonly performed however studies in early stage NSCLC and locally advanced NSCLC confirm systematic EBUS-TBNA evaluation improves accuracy of mediastinal staging. This study aims to establish the rate of detection of positron emission tomography (PET)-occult LN metastases following systematic LN staging by EBUS-TBNA, and to determine the utility of systematic mediastinal staging for accurate delineation of radiation treatment fields in patients with locally advanced NSCLC. Methods Consecutive patients undergoing EBUS-TBNA for diagnosis/staging of locally advanced NSCLC will be enrolled in this international multi-centre single arm study. Systematic mediastinal LN evaluation will be performed, with all LN exceeding 6 mm to be sampled by TBNA. Where feasible, endoscopic ultrasound staging (EUS-B) may also be performed. Results of minimally invasive staging will be compared to FDG-PET. The primary end-point is proportion of patients in whom systematic LN staging identified PET-occult NSCLC metastases. Secondary outcome measures include (i) rate of nodal upstaging, (ii) false positive rate of PET for mediastinal LN assessment, (iii) analysis of clinicoradiologic risk factors for presence of PET-occult LN metastases, (iv) impact of systematic LN staging in patients with discrepant findings on PET and EBUS-TBNA on target coverage and dose to organs at risk (OAR) in patients undergoing radiotherapy. Discussion With specificity of PET of 90%, guidelines recommend tissue confirmation of positive mediastinal LN to ensure potentially early stage patients are not erroneously denied potentially curative resection. However, while confirmation of pathologic LN is routinely sought, the exact extent of mediastinal LN involvement in NSCLC in patient with Stage III NSCLC is rarely established. Studies examining systematic LN staging in early stage NSCLC report a significant discordance between PET and EBUS-TBNA. In patients with locally advanced disease this has significant implications for radiation field planning, with risk of geographic miss in the event of PET-occult mediastinal LN metastases. The SEISMIC study will examine both diagnostic outcomes following systematic LN staging with EBUS-TBNA, and impact on radiation treatment planning. Trial registration ACTRN12617000333314, ANZCTR, Registered on 3 March 2017.

The COVID-19 pandemic highlights the importance of materials that block airborne virus transmission. Here, a nanostructured membrane is shown to filter coronavirus-sized particles, while the membrane surface incorporates enzymes that denature the SARS-CoV-2 spike protein within 30 s.

Immune literacy garnered significant attention in recent years due to the threat posed by emerging infectious diseases. The pace of immunological discoveries and their relevance to society are substantial yet coordinated educational efforts have been rare. This motivated us to create a task force of educators to reflect on pedagogical approaches to teaching immunology and to draft, develop, and evaluate key competencies for undergraduate immunology education. The research questions addressed include: 1) Which competencies are considered important by educators? 2) Are the illustrative skills clear, accurate and well aligned with the core competencies listed in the Vision and Change report?; 3) What are the concerns of immunology educators about competencies and skills? We collected data on the draft competencies using surveys, focus groups, and interviews. The iterative revision phase followed the community review phase before finalizing the framework. Here, we report a hierarchical learning framework, with six core competencies, twenty illustrative skills, and companion immunology-specific example learning outcomes. Predominant themes from interviews and focus groups, which informed revisions of this framework are shared. With the growing need for immunology education across the sciences, the ImmunoSkills Guide and accompanying discussion can be used as a resource for educators, administrators and policymakers. [ABSTRACT FROM AUTHOR]

Objective: To determine the impact of persistent symptoms after coronavirus disease 2019 (COVID‐19) in an Australian population. Design, setting, participants: We conducted a statewide health survey of a stratified random sample of adults who had had a confirmed acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection (COVID‐19‐positive group) and their close contacts (control group). The sample was drawn from Victoria's COVID‐19 database between January 2020 and October 2022. Data were collected from 12 688 survey respondents between September 2022 and April 2023 (11 174 in the COVID‐19‐positive group and 1514 in the control group). Main outcome measures: Persistent new symptoms, recovery, and daily function using validated questionnaires for fatigue, neurocognitive symptoms, anxiety, depression and quality of life. Results: At a mean of 12.6 months after infection, 4560 respondents in the COVID‐19‐positive group (39.1%; 95% CI, 37.9–40.3%) reported at least one persistent new symptom, compared with 216 respondents in the control group (20.8%; 95% CI, 18.5–23.1%). A total of 1656 respondents (14.2%; 95% CI, 13.4–15.0%) were classified as having clinical long COVID using the criteria of at least one persistent new symptom and less than 80% recovery three months after the infection. Of the respondents with clinical long COVID, 535 (3.2%; 95% CI, 2.6–3.8%) reported at least moderate problems with usual activities at 12 months after their infection. The proportion of respondents with clinical long COVID was lower for those with more recent infections. The risk factors for clinical long COVID were female sex, age 40–49 years, infection severity, chronic illness, and past anxiety or depression. Factors associated with a decreased risk of having clinical long COVID included infection when the Omicron strain was dominant and infection when the Delta strain was dominant, as compared with when the ancestral strain of the virus was dominant. Conclusion: Persistent symptoms after COVID‐19 are common, though with a lower incidence following infection from less virulent strains. Although long COVID can be largely managed in primary care, a minority of people who have persistent symptoms and impaired function may require specialist care pathways, the effectiveness of which should be a focus of future research. [ABSTRACT FROM AUTHOR]

ABSTRACT Immune literacy—the ability to hear, learn, read, write, explain, and discuss immunological content with varied audiences—has become critically important in recent years. Yet, with its complex terminology and discipline-specific concepts, educating individuals about the immune system and its role in health and disease may seem daunting. Here, we reflect on how to demystify the discipline and increase its accessibility for a broader audience. To address this, a working group of immunology educators from diverse institutions associated with the research coordination network, ImmunoReach, convened virtually. As a result of these discussions, we request a call to action for a system-level change and present a set of practical recommendations that novice and experienced educators from diverse institutions, professional societies, and policymakers may adopt to foster immune literacy in their classrooms and communities.

Background COPD patients are more susceptible to viral respiratory infections and their sequelae, and have intrinsically weaker immune responses to vaccinations against influenza and other pathogens. Prime-boost, double-dose immunisation has been suggested as a general strategy to overcome weak humoral response to vaccines, such as seasonal influenza vaccination, in susceptible populations with weak immunity. However, this strategy, which may also provide fundamental insights into the nature of weakened immunity, has not been formally studied in COPD. Methods We conducted an open-label study of seasonal influenza vaccination in 33 vaccine-experienced COPD patients recruited from established cohorts (mean age 70 (95% CI 66.9–73.2) years; mean forced expiratory volume in 1 s/forced vital capacity ratio 53.4% (95% CI 48.0–58.8%)). Patients received two sequential standard doses of the 2018 quadrivalent influenza vaccine (15 μg haemagglutinin per strain) in a prime-boost schedule 28 days apart. We measured strain-specific antibody titres, an accepted surrogate of likely efficacy, and induction of strain-specific B-cell responses following the prime and boost immunisations. Results Whereas priming immunisation induced the expected increase in strain-specific antibody titres, a second booster dose was strikingly ineffective at further increasing antibody titres. Similarly, priming immunisation induced strain-specific B-cells, but a second booster dose did not further enhance the B-cell response. Poor antibody responses were associated with male gender and cumulative cigarette exposure. Conclusions Prime-boost, double-dose immunisation does not further improve influenza vaccine immunogenicity in previously vaccinated COPD patients. These findings underscore the need to design more effective vaccine strategies for COPD patients for influenza.

Radiotherapy efficacy is the result of radiation-mediated cytotoxicity coupled with stimulation of antitumor immune responses. We develop an in silico 3-dimensional agent-based model of diverse tumor-immune ecosystems (TIES) represented as anti- or pro-tumor immune phenotypes. We validate the model in 10,469 patients across 31 tumor types by demonstrating that clinically detected tumors have pro-tumor TIES. We then quantify the likelihood radiation induces antitumor TIES shifts toward immune-mediated tumor elimination by developing the individual Radiation Immune Score (iRIS). We show iRIS distribution across 31 tumor types is consistent with the clinical effectiveness of radiotherapy, and in combination with a molecular radiosensitivity index (RSI) combines to predict pan-cancer radiocurability. We show that iRIS correlates with local control and survival in a separate cohort of 59 lung cancer patients treated with radiation. In combination, iRIS and RSI predict radiation-induced TIES shifts in individual patients and identify candidates for radiation de-escalation and treatment escalation. This is the first clinically and biologically validated computational model to simulate and predict pan-cancer response and outcomes via the perturbation of the TIES by radiotherapy.

Phosphatase of Regenerating Liver-3 (PRL-3) is associated with cancer progression and metastasis. The mechanisms that drive PRL-3’s oncogenic functions are not well understood, partly due to a lack of research tools available to study this protein. We have begun to address these issues by developing alpaca-derived single domain antibodies, or nanobodies, targeting PRL-3 with a KD of 30–300 nM and no activity towards highly homologous family members PRL-1 and PRL-2. We found that longer and charged N-terminal tags on PRL-3, such as GFP and FLAG, changed PRL-3 localization compared to untagged protein, indicating that the nanobodies may provide new insights into PRL-3 trafficking and function. The nanobodies perform equally, if not better, than commercially available antibodies in immunofluorescence and immunoprecipitation. Finally, hydrogen-deuterium exchange mass spectrometry (HDX-MS) showed that the nanobodies bind partially within the PRL-3 active site and can interfere with PRL-3 phosphatase activity. Co-immunoprecipitation with a known PRL-3 active site binding partner, the CBS domain of metal transporter CNNM3, showed that the nanobodies reduced the amount of PRL-3:CBS inter-action. The potential of blocking this interaction is highly relevant in cancer, as multiple research groups have shown that PRL-3 binding to CNNM proteins is sufficient to promote metastatic growth in mouse models. The anti-PRL-3 nanobodies represent an important expansion of the research tools available to study PRL-3 function and can be used to define the role of PRL-3 in cancer progression.

Background Groundbreaking studies have linked the gut microbiome with immune homeostasis and antitumor immune responses. Mounting evidence has also demonstrated an intratumoral microbiome, including in soft tissue sarcomas (STS), although detailed characterization of the STS intratumoral microbiome is limited. We sought to characterize the intratumoral microbiome in patients with STS undergoing preoperative radiotherapy and surgery, hypothesizing the presence of a distinct intratumoral microbiome with potentially clinically significant microbial signatures.Methods We prospectively obtained tumor and stool samples from adult patients with non-metastatic STS using a strict sterile collection protocol to minimize contamination. Metagenomic classification was used to estimate abundance using genus and species taxonomic levels across all classified organisms, and data were analyzed with respect to clinicopathologic factors.Results Fifteen patients were enrolled. Most tumors were located at an extremity (67%) and were histologic grade 3 (87%). 40% were well-differentiated/dedifferentiated liposarcoma histology. With a median follow-up of 24 months, 4 (27%) patients developed metastases, and 3 (20%) died. Despite overwhelming human DNA (>99%) intratumorally, we detected a small but consistent proportion of bacterial DNA (0.02–0.03%) in all tumors, including Proteobacteria, Bacteroidetes, and Firmicutes, as well as viral species. In the tumor microenvironment, we observed a strong positive correlation between viral relative abundance and natural killer (NK) infiltration, and higher NK infiltration was associated with superior metastasis-free and overall survival by immunohistochemical, flow cytometry, and multiplex immunofluorescence analyses.Conclusions We prospectively demonstrate the presence of a distinct and measurable intratumoral microbiome in patients with STS at multiple time points. Our data suggest that the STS tumor microbiome has prognostic significance with viral relative abundance associated with NK infiltration and oncologic outcome. Additional studies are warranted to further assess the clinical impact of these findings.

Puromycin-sensitive aminopeptidase (E.C. 3.4.11.14, UniProt P55786), a zinc metallopeptidase belonging to the M1 family, degrades a number of bioactive peptides as well as peptides released from the proteasome, including polyglutamine. We report the crystal structure of PSA at 2.3 Ǻ. Overall, the enzyme adopts a V-shaped architecture with four domains characteristic of the M1 family aminopeptidases, but it is in a less compact conformation compared to most M1 enzymes of known structure. A microtubule binding sequence is present in a C-terminal HEAT repeat domain of the enzyme in a position where it might serve to mediate interaction with tubulin. In the catalytic metallopeptidase domain, an elongated active site groove lined with aromatic and hydrophobic residues and a large S1 subsite may play a role in broad substrate recognition. The structure with bound polyglutamine shows a possible interacting mode of this peptide, which is supported by mutation.

Glioblastoma (GBM) is the most common malignant adult brain and has a poor prognosis. Routine post-treatment MRI evaluations are required to assess treatment response and disease progression. We present a case of an 83-year-old female who underwent MRI assessment of post-treatment GBM after intravenous iron replacement therapy, ferumoxytol. The brain MRI revealed unintended alteration of MRI signal characteristics from the iron containing agent which confounded diagnostic interpretation and subsequently, the treatment planning. Ferumoxytol injection prior to contrast enhanced MRI must be screened in post-treatment GBM patients to accurately evaluate tumor activity.

This article presents the results of a three-year study of graduate and undergraduate students' level of satisfaction with online instruction at one university. The study expands on earlier research into student satisfaction with e-learning. Researchers conducted a series of surveys over eight academic terms. Five hundred and fifty-three students participated in the study. Responses were consistent throughout, although there were some differences noted in the level of student satisfaction with their experience. There were no statistically significant differences in the level of satisfaction based on gender, age, or level of study. Overall, students rated their online instruction as moderately satisfactory, with hybrid or partially online courses rated as somewhat more satisfactory than fully online courses. "Convenience" was the most cited reason for satisfaction. "Lack of interaction" was the most cited reason for dissatisfaction. Preferences for hybrid courses surfaced in the responses to an open-ended question asking what made the experience with online or partially online courses satisfactory or unsatisfactory. This study's findings support the literature to date and reinforce the significance of student satisfaction to student retention.

This article presents the results of two studies that focus on the role that threaded discussion plays in student learning. Over a period of three and one-half years, researchers conducted a series of surveys of graduate and undergraduate students at a private, nonprofit university in Southwestern Pennsylvania to determine how students viewed the value of threaded discussions in enhancing their ability to learn course material. Students were asked which types of threaded discussions they preferred; whether they found the threaded discussion to be a better tool for learning than a written assignment; and, which learning environment they felt was more conducive to learning, classroom or online. Results from the combined studies revealed some statistically significant differences based on enrollment status and gender. Upon comparing study results, researchers found statistically significant differences with regard to a preference for classroom versus online instruction and the usefulness of threaded discussions to learning.

Over the last few decades, there has been a shift in the classroom from lecture-based to active learning settings with the argument that students retain more information when they are involved in the learning process. This correlation is even stronger when the active learning setting incorporates a real-world or personal connection. Using active learning activities that develop students' ability to comprehend primary scientific literature is particularly important in the field of immunology, due to the rapid expansion of information in the field, which has been further accelerated due to the COVID-19 pandemic. By nature, immunology is interdisciplinary, requiring an integrated knowledge of concepts from several scientific disciplines to understand complex immune processes. Engaging undergraduate students through the use of primary literature can improve scientific literacy, develop critical thinking, and enhance understanding of complex topics. To explore this, we utilized a group learning activity in an introductory immunology course that incorporated both a coronavirus-related review and COVID-19 clinical research article. We found that this learning activity significantly enhanced student confidence in key scientific literacy skills: reading scientific literature, clearly explaining relevant points, and describing conclusions generated from the data. Moreover, all students reported that they enjoyed the activity and that it helped them understand more about the current COVID-19 pandemic in the context of the immune response.