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Bispecific antibodies (biAbs) used in cancer immunotherapies rely on functional autologous T cells, which are often damaged and depleted in patients with haematological malignancies and in other immunocompromised patients. The adoptive transfer of allogeneic T cells from healthy donors can enhance the efficacy of biAbs, but donor T cells binding to host-cell antigens cause an unwanted alloreactive response. Here we show that allogeneic T cells engineered with a T-cell receptor that does not convert antigen binding into cluster of differentiation 3 (CD3) signalling decouples antigen-mediated T-cell activation from T-cell cytotoxicity while preserving the surface expression of the T-cell-receptor-CD3 signalling complex as well as biAb-mediated CD3 signalling and T-cell activation. In mice with CD19 + tumour xenografts, treatment with the engineered human cells in combination with blinatumomab (a clinically approved biAb) led to the recognition and clearance of tumour cells in the absence of detectable alloreactivity. Our findings support the development of immunotherapies combining biAbs and 'off-the-shelf' allogeneic T cells., (© 2024. The Author(s).)

Meiotic recombination is a prominent force shaping genome evolution, and understanding the causes for varying recombination landscapes within and between species has remained a central, though challenging, question. Recombination rates are widely observed to negatively associate with the abundance of transposable elements (TEs), selfish genetic elements that move between genomic locations. While such associations are usually interpreted as recombination influencing the efficacy of selection at removing TEs, accumulating findings suggest that TEs could instead be the cause rather than the consequence. To test this prediction, we formally investigated the influence of polymorphic, putatively active TEs on recombination rates. We developed and benchmarked a novel approach that uses PacBio long-read sequencing to efficiently, accurately, and cost-effectively identify crossovers (COs), a key recombination product, among large numbers of pooled recombinant individuals. By applying this approach to Drosophila strains with distinct TE insertion profiles, we found that polymorphic TEs, especially RNA-based TEs and TEs with local enrichment of repressive marks, reduce the occurrence of COs. Such an effect leads to different CO frequencies between homologous sequences with and without TEs, contributing to varying CO maps between individuals. The suppressive effect of TEs on CO is further supported by two orthogonal approaches-analyzing the distributions of COs in panels of recombinant inbred lines in relation to TE polymorphism and applying marker-assisted estimations of CO frequencies to isogenic strains with and without transgenically inserted TEs. Our investigations reveal how the constantly changing mobilome can actively modify recombination landscapes, shaping genome evolution within and between species.

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enhancing anti-tumour immune responses, demonstrating significant efficacy in various malignancies, including melanoma. However, over 50% of patients experience limited or no response to ICI therapy. Resistance to ICIs is influenced by a complex interplay of tumour intrinsic and extrinsic factors. This review summarizes current ICIs for melanoma and the factors involved in resistance to the treatment. We also discuss emerging evidence that the microbiota can impact ICI treatment outcomes by modulating tumour biology and anti-tumour immune function. Furthermore, microbiota profiles may offer a non-invasive method for predicting ICI response. Therefore, future research into microbiota manipulation could provide cost-effective strategies to enhance ICI efficacy and improve outcomes for melanoma patients.

Background: Compared to the general population, Veterans Health Administration (VHA) patients have higher rates of mental illness, chronic pain, and substance use disorders (SUD), conditions that increase risk for opioid-related adverse events. VHA developed the Stratification Tool for Opioid Risk Mitigation (STORM) and mandated case reviews by an interdisciplinary team (IDT) for patients identified as very high risk, a process implemented and led by clinical pharmacist practitioners at the Orlando Veterans Affairs Healthcare System (OVAHCS) in 2018., Objective: To evaluate and describe the implementation and process for IDT reviews of patients identified as very high risk by the STORM clinical decision support tool at OVAHCS., Methods: A single center, retrospective, observational chart review was conducted. Veterans reviewed by the STORM IDT between January to September 2018 were reviewed for change in Morphine Equivalent Daily Dose (MEDD), naloxone, non-opioid analgesics, medications for SUD, benzodiazepines, engagement with clinical services (e.g., mental health, SUD, pain clinic), and overdose or suicide attempts in the year prior versus the year after IDT review. The frequency of follow-up IDT reviews was evaluated., Results: Seventeen patients were identified. Four were excluded due to non-opioid related death within 12 months after review. The average baseline MEDD was 82.2mg (range 10 - 496mg) and average 12 months after review was 7.5mg (range 0 - 67.5mg), a decrease of 74.7mg, or 90.9% reduction. An increase in medications for SUD (3 patients; 23%), SUD engagement (3 to 6 patients), and urine drug tests was observed (79% increase). Benzodiazepine use decreased by 50%., Conclusion: This report provides insight on the IDT case review process at OVAHCS, a process that may vary widely across facilities. A reduction in MEDD, increase in SUD treatment, and improved risk mitigation was observed. The central role of clinical pharmacy and expanded process for continued follow-up warrants further study., (Copyright © 2024. Published by Elsevier Inc.)

Background: The interleukin-1 receptor accessory protein (IL1RAP) is highly expressed on acute myeloid leukemia (AML) bulk blasts and leukemic stem cells (LSCs), but not on normal hematopoietic stem cells (HSCs), providing an opportunity to target and eliminate the disease, while sparing normal hematopoiesis. Herein, we report the activity of BIF002, a novel anti-IL1RAP/CD3 T cell engager (TCE) in AML., Methods: Antibodies to IL1RAP were isolated from CD138+ B cells collected from the immunized mice by optoelectric positioning and single cell sequencing. Individual mouse monoclonal antibodies (mAbs) were produced and characterized, from which we generated BIF002, an anti-human IL1RAP/CD3 TCE using Fab arm exchange. Mutations in human IgG1 Fc were introduced to reduce FcγR binding. The antileukemic activity of BIF002 was characterized in vitro and in vivo using multiple cell lines and patient derived AML samples., Results: IL1RAP was found to be highly expressed on most human AML cell lines and primary blasts, including CD34+ LSC-enriched subpopulation from patients with both de novo and relapsed/refractory (R/R) leukemia, but not on normal HSCs. In co-culture of T cells from healthy donors and IL1RAP high AML cell lines and primary blasts, BIF002 induced dose- and effector-to-target (E:T) ratio-dependent T cell activation and leukemic cell lysis at subnanomolar concentrations. BIF002 administered intravenously along with human T cells led to depletion of leukemic cells, and significantly prolonged survival of IL1RAP high MOLM13 or AML patient-derived xenografts with no off-target side effects, compared to controls. Of note, BiF002 effectively redirects T cells to eliminate LSCs, as evidenced by the absence of disease initiation in secondary recipients of bone marrow (BM) from BIF002+T cells-treated donors (median survival not reached; all survived > 200 days) compared with recipients of BM from vehicle- (median survival: 26 days; p = 0.0004) or isotype control antibody+T cells-treated donors (26 days; p = 0.0002)., Conclusions: The novel anti-IL1RAP/CD3 TCE, BIF002, eradicates LSCs and significantly prolongs survival of AML xenografts, representing a promising, novel treatment for AML., (© 2024. The Author(s).)

Phosphoinositides are essential signaling molecules. The PI5P4K family of phosphoinositide kinases and their substrates and products, PI5P and PI4,5P 2 , respectively, are emerging as intracellular metabolic and stress sensors. We performed an unbiased screen to investigate the signals that these kinases relay and the specific upstream regulators controlling this signaling node. We found that the core Hippo pathway kinases MST1/2 phosphorylated PI5P4Ks and inhibited their signaling in vitro and in cells. We further showed that PI5P4K activity regulated several Hippo- and YAP-related phenotypes, specifically decreasing the interaction between the key Hippo proteins MOB1 and LATS and stimulating the YAP-mediated genetic program governing epithelial-to-mesenchymal transition. Mechanistically, we showed that PI5P interacted with MOB1 and enhanced its interaction with LATS, thereby providing a signaling connection between the Hippo pathway and PI5P4Ks. These findings reveal how these two important evolutionarily conserved signaling pathways are integrated to regulate metazoan development and human disease.

Background: Recurrent FUO (fever of unknown origin) is a rare subtype of FUO for which diagnostic procedures are ill-defined and outcome data are lacking., Methods: We performed a retrospective multicentre study of patients with recurrent FUO between 1995 and 2018. By multivariate analysis, we identified epidemiological, clinical and prognostic variables independently associated with final diagnosis and mortality., Results: Of 170 patients, 74 (44%) had a final diagnosis. Being ≥ 65 years of age (OR = 5.2; p < 0.001), contributory history (OR = 10.4; p < 0.001), and abnormal clinical examination (OR = 4.0; p = 0.015) independently increased the likelihood of reaching a diagnosis, whereas lymph node and/or spleen enlargement decreased it (OR = 0.2; p = 0.004). The overall prognosis was good; 58% of patients recovered (70% of those with a diagnosis). Twelve (7%) patients died; patients without a diagnosis had a fatality rate of 2%. Being ≥ 65 years of age (OR = 41.3; p < 0.001) and presence of skin signs (OR = 9.5; p = 0.005) significantly increased the risk of death., Conclusion: This study extends the known yield of recurrent FUO and highlights the importance of repeated complete clinical examinations to discover potential diagnostic clues during follow-up. Moreover, their overall prognosis is excellent., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Sex differences in kidney stone formation are well known. Females generally have slightly acidic blood and higher urine pH when compared with males, which makes them more vulnerable to calcium stone formation, yet the mechanism is still unclear. We aimed to examine the role of sex in stone formation during hypercalciuria and urine alkalinization through acetazolamide and calcium gluconate supplementation, respectively, for 4 weeks in wild-type (WT) and moderately hypercalciuric [TRPC3 knockout [KO](-/-)] male and female mice. Our goal was to develop calcium phosphate (CaP) and CaP+ calcium oxalate mixed stones in our animal model to understand the underlying sex-based mechanism of calcium nephrolithiasis. Our results from the analyses of mice urine, serum, and kidney tissues show that female mice (WT and KO) produce more urinary CaP crystals, higher [Ca 2+ ], and pH in urine compared to their male counterparts. We identified a sex-based relationship of stone-forming phenotypes (types of stones) in our mice model following urine alkalization/calcium supplementation, and our findings suggest that female mice are more susceptible to CaP stones under those conditions. Calcification and fibrotic and inflammatory markers were elevated in treated female mice compared with their male counterparts, and more so in TRPC3 KO mice compared with their WT counterparts. Together these findings contribute to a mechanistic understanding of sex-influenced CaP and mixed stone formation that can be used as a basis for determining the factors in sex-related clinical studies., (Published by Elsevier Inc.)

Abstract: Treatment resistance of leukemia stem cells (LSCs) and suppression of the autologous immune system represent major challenges to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38pos), LSCs are frequently enriched in the CD34posCD38neg blast fraction. Here, we report that interferon gamma (IFN-γ) reduces LSCs clonogenic activity and induces CD38 upregulation in both CD38pos and CD38neg LSC-enriched blasts. IFN-γ-induced CD38 upregulation depends on interferon regulatory factor 1 transcriptional activation of the CD38 promoter. To leverage this observation, we created a novel compact, single-chain CD38-CD3 T-cell engager (BN-CD38) designed to promote an effective immunological synapse between CD38pos AML cells and both CD8pos and CD4pos T cells. We demonstrate that BN-CD38 engages autologous CD4pos and CD8pos T cells and CD38pos AML blasts, leading to T-cell activation and expansion and to the elimination of leukemia cells in an autologous setting. Importantly, BN-CD38 engagement induces the release of high levels of IFN-γ, driving the expression of CD38 on CD34posCD38neg LSC-enriched blasts and their subsequent elimination. Critically, although BN-CD38 showed significant in vivo efficacy across multiple disseminated AML cell lines and patient-derived xenograft models, it did not affect normal hematopoietic stem cell clonogenicity and the development of multilineage human immune cells in CD34pos humanized mice. Taken together, this study provides important insights to target and eliminate AML LSCs., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: The COVID-19 pandemic has drastically altered the medical landscape. Various strategies have been employed to preserve hospital beds, personal protective equipment, and other resources to accommodate the surges of COVID-19 positive patients, hospital overcapacities, and staffing shortages. This has had a dramatic effect on vascular surgical practice. The objective of this study is to analyze the impact of the COVID-19 pandemic on surgical delays and adverse outcomes for patients with chronic venous disease scheduled to undergo elective operations., Methods: The Vascular Surgery COVID-19 Collaborative (VASCC) was founded in March 2020 to evaluate the outcomes of patients with vascular disease whose operations were delayed. Modules were developed by vascular surgeon working groups and tested before implementation. A data analysis of outcomes of patients with chronic venous disease whose surgeries were postponed during the COVID-19 pandemic from March 2020 through February 2021 was performed for this study., Results: A total of 150 patients from 12 institutions in the United States were included in the study. Indications for venous intervention were: 85.3% varicose veins, 10.7% varicose veins with venous ulceration, and 4.0% lipodermatosclerosis. One hundred two surgeries had successfully been completed at the time of data entry. The average length of the delay was 91 days, with a median of 78 days. Delays for venous ulceration procedures ranged from 38 to 208 days. No patients required an emergent intervention due to their venous disease, and no patients experienced major adverse events following their delayed surgeries., Conclusions: Interventions may be safely delayed for patients with venous disease requiring elective surgical intervention during the COVID-19 pandemic. This finding supports the American College of Surgeons' recommendations for the management of elective vascular surgical procedures. Office-based labs may be safe locations for continued treatment when resources are limited. Although the interventions can be safely postponed, the negative impact on quality of life warrants further investigation., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Rotavirus group A (RVA) is the most common cause of severe childhood diarrhea worldwide. The introduction of rotavirus vaccination programs has contributed to a reduction in hospitalizations and mortality caused by RVA. From 2016 to 2021, we conducted surveillance to monitor RVA prevalence and genotype distribution in Nam Dinh and Thua Thien Hue (TT Hue) provinces where a pilot Rotavin-M1 vaccine (Vietnam) implementation took place from 2017 to 2020. Out of 6626 stool samples, RVA was detected in 2164 (32.6%) by ELISA. RT-PCR using type-specific primers were used to determine the G and P genotypes of RVA-positive specimens. Whole genome sequences of a subset of 52 specimens randomly selected from 2016 to 2021 were mapped using next-generation sequencing. From 2016 to 2021, the G9, G3 and G8 strains dominated, with detected frequencies of 39%, 23%, and 19%, respectively; of which, the most common genotypes identified were G9P[8], G3P[8] and G8P[8]. G1 strains re-emerged in Nam Dinh and TT Hue (29.5% and 11.9%, respectively) from 2020 to 2021. G3 prevalence decreased from 74% to 20% in TT Hue and from 21% to 13% in Nam Dinh province between 2017 and 2021. The G3 strains consisted of 52% human typical G3 (hG3) and 47% equine-like G3 (eG3). Full genome analysis showed substantial diversity among the circulating G3 strains with different backgrounds relating to equine and feline viruses. G9 prevalence decreased sharply from 2016 to 2021 in both provinces. G8 strains peaked during 2019-2020 in Nam Dinh and TT Hue provinces (68% and 46%, respectively). Most G8 and G9 strains had no genetic differences over the surveillance period with very high nucleotide similarities of 99.2-99.9% and 99.1-99.7%, respectively. The G1 strains were not derived from the RVA vaccine. Changes in the genotype distribution and substantial diversity among circulating strains were detected throughout the surveillance period and differed between the two provinces. Determining vaccine effectiveness against circulating strains over time will be important to ensure that observed changes are due to natural secular variation and not from vaccine pressure., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention – USA. Trang Nguyen reports financial support for this project was provided byBill & Melinda Gates Foundation - USA. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Twitter is rich in data for text and data analytics research, with the ability to capture trends., Objectives: This study examines Canadian tweets on marijuana legalization and terminology used. Presented as a case study, Twitter analytics will demonstrate the varied applications of how this kind of research method may be used to inform library practice., Methods: Twitter API was used to extract a subset of tweets using seven relevant hashtags. Using open-source programming tools, the sampled tweets were analysed between September to November 2018, identifying themes, frequently used terms, sentiment, and co-occurring hashtags., Results: More than 1,176,000 tweets were collected. The most popular hashtag co-occurrence, two hashtags appearing together, was #cannabis and #CdnPoli. There was a high variance in the sentiment analysis of all collected tweets but most scores had neutral sentiment., Discussion: The case study presents text-mining applications relevant to help make informed decisions in library practice through service analysis, quality analysis, and collection analysis., Conclusions: Findings from sentiment analysis may determine usage patterns from users. There are several ways in which libraries may use text mining to make evidence-informed decisions such as examining all possible terminologies used by the public to help inform comprehensive evidence synthesis projects and build taxonomies for digital libraries and repositories., (© 2023 Health Libraries Group.)

Influenza viruses escape immunity owing to rapid antigenic evolution, which requires vaccination strategies that allow for broadly protective antibody responses. We found that the lipid globotriaosylceramide (Gb3) expressed on germinal center (GC) B cells is essential for the production of high-affinity antibodies. Mechanistically, Gb3 bound and disengaged CD19 from its chaperone CD81, permitting CD19 to translocate to the B cell receptor complex to trigger signaling. Moreover, Gb3 regulated major histocompatibility complex class II expression to increase diversity of T follicular helper and GC B cells reactive with subdominant epitopes. In influenza infection, elevating Gb3, either endogenously or exogenously, promoted broadly reactive antibody responses and cross-protection. These data demonstrate that Gb3 determines the affinity and breadth of B cell immunity and has potential as a vaccine adjuvant.

Tumors develop strategies to evade immunity by suppressing antigen presentation. In this work, we show that prosaposin (pSAP) drives CD8 T cell-mediated tumor immunity and that its hyperglycosylation in tumor dendritic cells (DCs) leads to cancer immune escape. We found that lysosomal pSAP and its single-saposin cognates mediated disintegration of tumor cell-derived apoptotic bodies to facilitate presentation of membrane-associated antigen and T cell activation. In the tumor microenvironment, transforming growth factor-β (TGF-β) induced hyperglycosylation of pSAP and its subsequent secretion, which ultimately caused depletion of lysosomal saposins. pSAP hyperglycosylation was also observed in tumor-associated DCs from melanoma patients, and reconstitution with pSAP rescued activation of tumor-infiltrating T cells. Targeting DCs with recombinant pSAP triggered tumor protection and enhanced immune checkpoint therapy. Our studies demonstrate a critical function of pSAP in tumor immunity and may support its role in immunotherapy.

Introduction: This study aimed to provide an updated analysis of the different prognostic trajectories of patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibodies., Methods: Among a cohort of 70 patients, baseline characteristics and phenotypes, treatments and outcomes were analyzed. A Cox proportional hazards model was used to identify factors associated with poor outcomes, i.e., death or progressive disease at the last follow-up., Results: Among the 70 patients, 45 were women, and 54 were Caucasian. A dermatologic involvement was observed in 58 (83%) patients, including 40 with MDA5 vasculopathy-related skin lesions. Muscular involvement was observed in 39 (56%) patients. Interstitial lung disease (ILD) was observed at baseline in 52 (74%) patients, including 23 (44%) who developed rapidly progressive (RP) ILD. Seven (10%) patients showed thromboembolic complications within the first weeks of diagnosis, and eight (11%) other patients developed a malignancy (4 before the diagnosis of anti-MDA5 disease). Poor outcomes were observed in 28 (40%) patients, including 13 (19%) deaths. Among the 23 patients with RP-ILD, 19 (79%) showed poor outcomes, including 12 (63%) who died. In multivariate analyses, RP-ILD (hazard ratio (HR), 95% CI: 8.24 [3.21-22], p<0.0001), the occurrence of thromboembolic events (HR: 5.22 [1.61-14.77], p=0.008) and the presence of any malignancy (HR: 19.73 [6.67-60], p<0.0001) were the three factors independently associated with poor outcomes., Discussion: This new independent cohort confirms the presence of different clinical phenotypes of anti-MDA5 diseases at baseline and the poor prognosis associated with RP-ILD. Thromboembolic events and malignancies were also identified as prognostic factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer CB declared a shared parent affiliation with the author CC to the handling editor at the time of review., (Copyright © 2024 de Boysson, Cuchet, Cassius, Cuchet, Agard, Audemard-Verger, Marchand-Adam, Cohen-Sors, Gallay, Graveleau, Lesort, Ly, Meyer, Monseau, Néel, Bonnotte, Pérard, Schleinitz, Mariotte, Le Mauff, Bourdenet, Masmoudi, Deshayes, Dumont, Dompmartin, Kottler and Aouba.)

Purpose To present results from a literature survey on practices in deep learning segmentation algorithm evaluation and perform a study on expert quality perception of brain tumor segmentation. Materials and Methods A total of 180 articles reporting on brain tumor segmentation algorithms were surveyed for the reported quality evaluation. Additionally, ratings of segmentation quality on a four-point scale were collected from medical professionals for 60 brain tumor segmentation cases. Results Of the surveyed articles, Dice score, sensitivity, and Hausdorff distance were the most popular metrics to report segmentation performance. Notably, only 2.8% of the articles included clinical experts' evaluation of segmentation quality. The experimental results revealed a low interrater agreement (Krippendorff α, 0.34) in experts' segmentation quality perception. Furthermore, the correlations between the ratings and commonly used quantitative quality metrics were low (Kendall tau between Dice score and mean rating, 0.23; Kendall tau between Hausdorff distance and mean rating, 0.51), with large variability among the experts. Conclusion The results demonstrate that quality ratings are prone to variability due to the ambiguity of tumor boundaries and individual perceptual differences, and existing metrics do not capture the clinical perception of segmentation quality. Keywords: Brain Tumor Segmentation, Deep Learning Algorithms, Glioblastoma, Cancer, Machine Learning Clinical trial registration nos. NCT00756106 and NCT00662506 Supplemental material is available for this article. © RSNA, 2023.