bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome Sequence of a Clinical Isolate of the Human Pathogenic Strain “
Candidatus
Borrelia fainii” Qtaro
Authors: Itokawa Kentaro , Sato Kozue , Qiu Yongjin , Yamagishi Jyunya , Changula Katendi , Kawai Naoko , Hayashida Kyoko , Ndebe Joseph , Hang’ombe Bernard Mudenda , Sawa Hirofumi , Kasai Shinji , Akeda Yukihiro , Kawabata Hiroki
Published: April 2023

We report sequences of the complete linear chromosome and five linear plasmids of the relapsing fever spirochete “
Candidatus
Borrelia fainii” Qtaro. The chromosome sequence of 951,861 bp and the 243,291 bp of plasmid sequences were predicted to contain 852 and 239 protein-coding genes, respectively. The predicted total GC content was 28.4%.
Vibrio cholerae Invasion Dynamics of the Chironomid Host Are Strongly Influenced by Aquatic Cell Density and Can Vary by Strain
Authors: Zhao Dianshu , Ali Afsar , Zuck Cameron , Uy Laurice , Morris J. Glenn , Wong Adam Chun-Nin
Published: April 2023

Vibrio cholerae
is the causative agent of cholera, a significant diarrheal disease affecting millions of people worldwide. Increasing evidence suggests that the environmental facets of the
V. cholerae
life cycle involve symbiotic associations with aquatic arthropods, which may facilitate its environmental persistence and dissemination.
Making sense of shear zone fabrics that record multiple episodes of deformation: Electron backscatter diffraction–derived and crystallographic vorticity axis–enhanced petrochronology
Authors: Miranda Elena A. , Brown Virginia , Schwartz Joshua J. , Klepeis Keith A.
Published: April 2023

We present a new method of linking microstructures, electron backscatter diffraction (EBSD)–derived crystallographic vorticity axis (CVA) analysis, and titanite petrochronology to directly link fabric development to specific deformation events in shear zone rocks with complex histories. This approach is particularly useful where overprinting is incomplete, such that it is unknown which fabric is being dated by the petrochronometer. Here, we compared single-phase CVA patterns of fabric-forming minerals with those of synkinematic petrochronometers (e.g., titanite) to associate the timing of fabric development with deformational events in the middle crust of the George Sound shear zone, Fiordland, New Zealand. The host rocks to the George Sound shear zone include the Carboniferous Large Pluton, where titanite petrochronology demonstrates an unequivocally Cretaceous age of metamorphic titanite growth within mylonitic foliation. However, the host rocks show two distinct CVA patterns: a transtensional deformation event recorded by quartz and plagioclase, and a pure-shear–dominated transpressional deformation event recorded by biotite and titanite. Therefore, the transpressional CVA pattern of the titanite, coupled with its Cretaceous age, shows that it cannot be used to date the quartz and plagioclase fabric developed in response to an older transtensional deformation event. These results demonstrate the necessity of combining EBSD and CVA analysis with petrochronology to demonstrate that synkinematic accessory phase petrochronometers show the same kinematic deformation geometry (i.e., CVA pattern) as the fabric being dated.
Supplemental Material: Three-dimensional mineral dendrites reveal a nonclassical crystallization pathway
Authors: Hou Zhaoliang , al. et
Published: April 2023

Supplemental methods, Figures S1–S4, and Movies S1 and S2.  
Ventilation failure with elective tracheostomy during oral cancer surgery: a case of tracheal diverticulum
Authors: Mitra Sandipta , Singh Anup , Vig Saurabh , Meena Sanjay Kumar
Published: April 2023

Tracheal diverticulum is usually detected incidentally. Rarely, it may lead to difficulty in securing the airway intraoperatively. Our patient underwent oncological resection under general anaesthesia for advanced oral cancer. Elective tracheostomy was performed at the end of the surgery, and a cuffed tracheostomy tube (T-tube) of 7.5 mm size was inserted through the tracheostoma. Despite repeated attempts at T-tube insertion, ventilation could not be established. However, on advancing the endotracheal tube beyond tracheostoma, ventilation was restored. The T-tube was inserted into the trachea under fibreoptic guidance achieving successful ventilation. A fibreoptic bronchoscopy through the tracheostoma performed after decannulation revealed a mucosalised diverticulum extending behind the posterior wall of the trachea. The bottom of the diverticulum showed mucosa-lined cartilaginous ridge with differentiation into smaller bronchiole-like structures. Tracheal diverticulum should be considered as a possible differential in case of failed ventilation following an otherwise uneventful tracheostomy.
Rapid reviews methods series: Guidance on literature search
Authors: Klerings Irma , Robalino Shannon , Booth Andrew , Escobar-Liquitay Camila Micaela , Sommer Isolde , Gartlehner Gerald , Devane Declan , Waffenschmidt Siw
Published: April 2023

This paper is part of a series of methodological guidance from the Cochrane Rapid Reviews Methods Group. Rapid reviews (RR) use modified systematic review methods to accelerate the review process while maintaining systematic, transparent and reproducible methods. In this paper, we address considerations for RR searches. We cover the main areas relevant to the search process: preparation and planning, information sources and search methods, search strategy development, quality assurance, reporting, and record management. Two options exist for abbreviating the search process: (1) reducing time spent on conducting searches and (2) reducing the size of the search result. Because screening search results is usually more resource-intensive than conducting the search, we suggest investing time upfront in planning and optimising the search to save time by reducing the literature screening workload. To achieve this goal, RR teams should work with an information specialist. They should select a small number of relevant information sources (eg, databases) and use search methods that are highly likely to identify relevant literature for their topic. Database search strategies should aim to optimise both precision and sensitivity, and quality assurance measures (peer review and validation of search strategies) should be applied to minimise errors.
Changing from face-to-face to virtual meetings due to the COVID-19 pandemic: protocol for a mixed-methods study exploring the impact on cancer multidisciplinary team (MDT) meetings
Authors: McInnerney Daisy , Chung Donna , Mughal Muntzer , Onifade Anjola , Holden David , Goodman Jacob , Birchall Martin , Peake Michael D , Quaife Samantha L
Published: April 2023

Introduction

In the UK, the National Cancer Plan (2000) requires every cancer patient’s care to be reviewed by a multidisciplinary team (MDT). Since the introduction of these guidelines, MDTs have faced escalating demands with increasing numbers and complexity of cases. The COVID-19 pandemic has presented MDTs with the challenge of running MDT meetings virtually rather than face-to-face.

This study aims to explore how the change from face-to-face to virtual MDT meetings during the COVID-19 pandemic may have impacted the effectiveness of decision-making in cancer MDT meetings and to make recommendations to improve future cancer MDT working based on the findings.

Methods and analysis

A mixed-methods study with three parallel phases:

Semistructured remote qualitative interviews with ≤40 cancer MDT members.

A national cross-sectional online survey of cancer MDT members in England, using a validated questionnaire with both multiple-choice and free-text questions.

Live observations of ≥6 virtual/hybrid cancer MDT meetings at four NHS Trusts.

Participants will be recruited from Cancer Alliances in England. Data collection tools have been developed in consultation with stakeholders, based on a conceptual framework devised from decision-making models and MDT guidelines. Quantitative data will be summarised descriptively, and χ2tests run to explore associations. Qualitative data will be analysed using applied thematic analysis. Using a convergent design, mixed-methods data will be triangulated guided by the conceptual framework.

The study has been approved by NHS Research Ethics Committee (London—Hampstead) (22/HRA/0177). The results will be shared through peer-reviewed journals and academic conferences. A report summarising key findings will be used to develop a resource pack for MDTs to translate learnings from this study into improved effectiveness of virtual MDT meetings.

The study has been registered on the Open Science Framework (https://doi.org/10.17605/OSF.IO/D2NHW).
Cross-sectional analysis of pharmaceutical payments to Japanese board-certified gastroenterologists between 2016 and 2019
Authors: Murayama Anju , Kamamoto Sae , Kawashima Moe , Saito Hiroaki , Yamashita Erika , Tanimoto Tetsuya , Ozaki Akihiko
Published: April 2023

Objectives

Limited evidence is available regarding the financial relationships between gastroenterologists and pharmaceutical companies in Japan. This study analysed the magnitude, prevalence and trends of personal payments made by major pharmaceutical companies to board-certified gastroenterologists in Japan in recent years.

Design

Cross-sectional analysis

Setting and participants

Using payment data publicly disclosed by 92 major pharmaceutical companies, this study examined the non-research payments made to all board-certified gastroenterologists by the Japanese Society of Gastroenterology.

Primary and secondary outcome measures

The primary outcomes were payment amounts, the prevalence of gastroenterologists receiving payments, yearly trends in per-gastroenterologist payment values and the number of gastroenterologists with payments. Additionally, we evaluated the differences in payments among influential gastroenterologists, including clinical practice guideline authors, society board member gastroenterologists and other general gastroenterologists.

Results

Approximately 52.8% of all board-certified gastroenterologists received a total of US$89 151 253, entailing 134 249 payment contracts as the reimbursement for lecturing, consulting and writing, from 84 pharmaceutical companies between 2016 and 2019. The average and median payments per gastroenterologist were US$7670 (SD: US$26 842) and US$1533 (IQR: US$582–US$4781), respectively. The payment value per gastroenterologist did not significantly change during the study period, while the number of gastroenterologists with payments decreased by −1.01% (95% CI: −1.61% to −0.40%, p<0.001) annually. Board member gastroenterologists (median: US$132 777) and the guideline authoring gastroenterologists (median: US$106 069) received 29.9 times and 17.3 times higher payments, respectively, than general gastroenterologists (median: US$284).

Conclusion

Most gastroenterologists received personal payments from pharmaceutical companies, but only very few influential gastroenterologists with authority accepted substantial amounts in Japan. There should be transparent and rigorous management strategies for financial conflicts of interest among gastroenterologists working in influential positions.
Dismantling cognitive–behavioural therapy components for attention-deficit hyperactivity disorder in adolescents and adults: protocol for a network meta-analysis
Authors: Hamatani Sayo , Matsumoto Kazuki , Kunisato Yoshihiko , Okawa Sho , Yamashita Masatoshi , Mizuno Yoshifumi
Published: April 2023

Introduction

Cognitive–behavioural therapy (CBT) consists of multiple treatment techniques for each treatment model and is tailored to the patient’s characteristics. Randomised controlled trials (RCTs) have reported that CBT is effective for attention-deficit/hyperactivity disorder (ADHD); however, which CBT components are effective is unknown. In order to provide the best treatment technique, it is important to know which therapeutic component or combination thereof is more effective and what the specific effect size is.

Methods and analysis

We will perform component network meta-analysis (cNMA). The search will include studies published from database inception up to 31 March 2022, in English. The electronic databases of MEDLINE (via PubMed), EMBASE, PsycINFO, ClinicalTrials.gov and Cochrane Library will be searched. We will systematically identify all RCTs in the treatment of ADHD between the ages of 10 and 60 years, comparing interventions composed of various CBT components with controlled interventions. We will perform pairwise and network meta-analysis with random effects to estimate summary ORs and standardised mean differences. We will assess the risk of bias in selected studies using the Cochrane risk of bias tool.

Ethics and dissemination

Since we will review published papers, ethical approval is not required. The results from this cNMA will provide a panorama of the CBT-based ADHD studies. The results of this study will be published in a peer-reviewed journal.

PROSPERO registration number

CRD42022323898.
Effect of school-based nutrition interventions among primary school children in sub-Saharan Africa: a systematic review protocol
Authors: Osei Angela Nyamekye , Djekic-Ivankovic Marija , Larson Charles P , Agbemafle Isaac , Jaeger-McEnroe Emily , Agbozo Faith
Published: April 2023

Introduction

Preadolescents are passing through an intensive growth and development period that will benefit from healthy eating practices. For those attending school, school environments offer several potential benefits and have been demonstrated to influence the quality of dietary intakes and consequentially, nutritional status of school-aged children (SAC). Considering the amount of time children spend in school and the enormous potential of evidence-based interventions, the purpose of this review is to critically appraise peer-reviewed literature addressing the impact of school-based interventions on the nutritional status of SAC aged 6–12 years in sub-Saharan Africa.

Methods and analysis

A systematic search will be conducted in the following databases and online search records: Medline, CINAHL, Web of Science, Embase, Global health, Global Index Medicus, Cochrane library, Hinari and Google Scholar using search terms and keywords codeveloped with two librarians. An additional search will also be conducted from the reference list of identified literature. Search results of titles and abstracts will be initially screened for eligibility criteria by two independent reviewers and where there is disagreement, a third reviewer will be consulted. Articles meeting these criteria will then undergo a full-text review for the eligibility and exclusion criteria. The Joanna Briggs Institute critical appraisal tool will be used to assess the risk of bias. Data from articles meeting all study criteria will be extracted, analysed and synthesised. A meta-analysis will also be conducted if sufficient data are available.

Ethics and dissemination

This systematic review is limited to publicly accessible data bases not requiring prior ethical approval to access. The results of the systematic review will be disseminated through publications in peer-reviewed journals as well as conference and stakeholder presentations.

PROSPERO registration number

CRD42022334829.
Experiences of Undergraduate Medical, Nursing Students and Faculty regarding Flipped Classroom: A Mixed Method Study at Private Medical University in Pakistan
Authors: Sultan Amber Shamim , Ali Rahila , Zahid Nida , Akbar Rozmeen , Ali Mehdia , Fatima Sadia , Ghias Kulsoom , Martins Russell , Tariq Muhammad , Ajani Khairulnissa
Published: April 2023

The ‘flipped classroom (FCR)’ is a teaching pedagogy where students are actively involved in the learning process. It reduces passivity, enables students to become active learners through reasoning and concept application and facilitates student interaction with their peers and instructors. This instructional approach enhances retention and decreases distraction by engaging students.

Objectives

The purpose of this study was to train the faculty of the medical college and school of nursing in developing FCRs as an innovative teaching and learning strategy, to facilitate them in conducting flipped sessions for their students and to explore the experiences of medical, nursing students along with faculty members regarding the FCR they had attended and conducted.

Setting

Private medical college.

Participants

A total of 442 students from medical college and school of nursing and midwifery participated in the evaluation survey with a female to male ratio of 339:103. Students who attended the flipped class sessions were included in the study sample. Students who did not complete the forms were excluded from the study. Nine faculty members who attended the workshop, agreed to facilitate the FCR session were invited to participate in the focus group discussion.

Results

Both medical and nursing students found FCR format stimulating. A significantly higher proportion of medical students (73%) found the FCR more engaging and interesting than a traditional lecture as compared with nursing students (59%) (p=0.009). Similarly, 73% of medical students believed the learning objectives of both the non-face-to-face and face-to-face sessions were shared with them as compared with the 62% of nursing students who believed the same (p=0.002). A significantly higher proportion of medical (76%) versus nursing (61%) students found the FCR format more useful for application of their theoretical knowledge into clinical practice (p=0.030).

Conclusion

Students found the FCR more engaging and interesting in terms of applying theoretical knowledge into practice. Similarly, faculty found this strategy as effective but challenging in terms of involving and engaging students in the learning process. It is recommended to conduct more FCR sessions for an interactive and student-centred learning, but proper planning of the session and using variety of technological tools to engage learners is a key to success.
Flash glucose monitoring in young people with type 1 diabetes—a qualitative study of young people, parents and health professionals: ‘It makes life much easier’
Authors: Beasant Lucy , Cullen Freyja , Thomas Elizabeth , Kandiyali Rebecca , Shield Julian P H , Mcgregor David , West Nicol , Ingram Jenny
Published: April 2023

Objectives

Flash glucose monitoring for patients with T1 diabetes avoids frequent painful finger-prick testing, thus potentially improving frequency of glucose self-monitoring. Our study aimed to explore experiences of young people using Freestyle Libre sensors and their parents, and to identify benefits and challenges to National Health Service (NHS) staff of its adoption in their care provision.

Participants

Young people with T1 diabetes, their parents and healthcare professionals were interviewed between February and December 2021. Participants were recruited via social media and through NHS diabetes clinic staff.

Design

Semistructured interviews were conducted online and analysed using thematic methods. Staff themes were mapped onto normalisation process theory (NPT) constructs.

Results

Thirty-four participants were interviewed: 10 young people, 14 parents and 10 healthcare professionals. Young people reported that life was much easier since changing to flash glucose monitoring, increasing confidence and independence to manage their condition. Parents’ quality of life improved and they appreciated access to real-time data. Using the NPT concepts to understand how technology was integrated into routine care proved useful; health professionals were very enthusiastic about flash glucose monitoring and coped with the extra data load to facilitate more tailored patient support within and between clinic visits.

Conclusion

This technology empowers young people and their parents to understand their diabetes adherence more completely; to feel more confident about adjusting their own care between clinic appointments; and provides an improved interactive experience in clinic. Healthcare teams appear committed to delivering improving technologies, acknowledging the challenge for them to assimilate new information required to provide expert advice.
Prediction models for the survival in patients with intestinal-type gastric adenocarcinoma: a retrospective cohort study based on the SEER database
Authors: Hong Jiawen , Cheng Yinfei , Gu Xiaodan , Xu Weibing
Published: April 2023

Objective

To explore the influencing factors of survival in intestinal-type gastric adenocarcinoma (IGA) and set up prediction model for the prediction of survival of patients diagnosed with IGA.

Design

A retrospective cohort study.

Setting and participants

A total of 2232 patients with IGA who came from the Surveillance, Epidemiology, and End Results database.

Primary and secondary outcome measures

Patients’ overall survival (OS) rate and cancer-specific survival (CSS) at the end of follow-up.

Results

Of the total population, 25.72% survived, 54.93% died of IGA and 19.35% died of other causes. The median survival time of patients was 25 months. The result showed that age, race, stage group, T stage, N stage, M stage, grade, tumour size, radiotherapy, number of lymph nodes removed and gastrectomy were independent prognostic factors of OS risk for patients with IGA; age, race, race, stage group, T stage, N stage, M stage, grade, radiotherapy and gastrectomy were associated with CSS risk for patients with IGA. In view of these prognostic factors, we developed two prediction models for predicting the OS and CSS risk for patients with IGA separately. For the developed OS-related prediction model, the C-index was 0.750 (95% CI: 0.740 to 0.760) in the training set, corresponding to 0.753 (95% CI: 0.736 to 0.770) in the testing set. Likewise, for the developed CSS-related prediction model, the C-index was 0.781 (95% CI: 0.770 to 0.793) in the training set, corresponding to 0.785 (95% CI: 0.766 to 0.803) in the testing set. The calibration curves of the training set and testing set revealed a good agreement between model predictions in the 1-year, 3-year and 5-year survival for patients with IGA and actual observations.

Conclusion

Combining demographic and clinicopathological features, two prediction models were developed to predict the risk of OS and CSS in patients with IGA, respectively. Both models have good predictive performance.
Signs and symptoms of acute pulmonary embolism and their predictive value for all-cause hospital death in respect of severity of the disease, age, sex and body mass index: retrospective analysis of the Regional PE Registry (REPER)
Authors: Ružičić Dušan Predrag , Dzudovic Boris , Matijasevic Jovan , Benic Marija , Salinger Sonja , Kos Ljiljana , Kovacevic-Preradovic Tamara , Mitevska Irena , Neskovic Aleksandar , Bozovic Bjanka , Bulatovic Nebojsa , Miloradovic Vladimir , Djuric Ivica , Obradovic Slobodan
Published: April 2023

Background

The incidence of the signs and symptoms of acute pulmonary embolism (PE) according to mortality risk, age and sex has been partly explored.

Patients and methods

A total of 1242 patients diagnosed with acute PE and included in the Regional Pulmonary Embolism Registry were enrolled in the study. Patients were classified as low risk, intermediate risk or high risk according to the European Society of Cardiology mortality risk model. The incidence of the signs and symptoms of acute PE at presentation with respect to sex, age, and PE severity was investigated.

Results

The incidence of haemoptysis was higher in younger men with intermediate-risk (11.7% vs 7.5% vs 5.9% vs 2.3%; p=0.01) and high-risk PE (13.8% vs 2.5% vs 0.0% vs 3.1%; p=0.031) than in older men and women. The frequency of symptomatic deep vein thrombosis was not significantly different between subgroups. Older women with low-risk PE presented with chest pain less commonly (35.8% vs 55.8% vs 48.8% vs 51.9%, respectively; p=0.023) than men and younger women. However, younger women had a higher incidence of chest pain in the lower-risk PE group than in the intermediate-risk and high-risk PE subgroups (51.9%, 31.4% and 27.8%, respectively; p=0.001). The incidence of dyspnoea (except in older men), syncope and tachycardia increased with the risk of PE in all subgroups (p<0.01). In the low-risk PE group, syncope was present more often in older men and women than in younger patients (15.5% vs 11.3% vs 4.5% vs 4.5%; p=0.009). The incidence of pneumonia was higher in younger men with low-risk PE (31.8% vs<16% in the other subgroups, p<0.001).

Conclusion

Haemoptysis and pneumonia are prominent features of acute PE in younger men, whereas older patients more frequently have syncope with low-risk PE. Dyspnoea, syncope and tachycardia are symptoms of high-risk PE irrespective of sex and age.
Impact of delayed screening invitations on screen-detected and interval cancers in the Dutch colorectal cancer screening programme: individual-level data analysis
Authors: Toes-Zoutendijk Esther , de Jonge Lucie , van Iersel Carola Adriana , Spaander Manon C W , van Vuuren Anneke J , van Kemenade Folkert , Ramakers Christian R , Dekker Evelien , Nagetaal Iris D , van Leerdam Monique E , Lansdorp-Vogelaar Iris
Published: April 2023

Objective

To assess the impact of delayed invitation on screen-detected and interval colorectal cancers (CRC) within a faecal immunochemical testing (FIT)-based CRC screening programme.

Design

All individuals that participated in 2017 and 2018 with a negative FIT and were eligible for CRC screening in 2019 and 2020 were included using individual-level data. Multivariable logistic regression analyses were used to assess the association between either the different time periods (ie, ‘before’, ‘during’ and ‘after’ the first COVID-19 wave) or the invitation interval on screen-detected and interval CRCs.

Results

Positive predictive value for advanced neoplasia (AN) was slightly lowerduring(OR=0.91) andafter(OR=0.95) the first COVID-19 wave, but no significant difference was observed for the different invitation intervals. Out of all individuals that previously tested negative, 84 (0.004%) had an interval CRC beyond the 24 months since their last invitation. The time period of invitation as well as the extended invitation interval was not associated with detection rates for AN and interval CRC rate.

Conclusion

The impact of the first COVID-19 wave on screening yield was modest. A very small proportion of the FIT negatives had an interval CRC possibly due to an extended interval, which potentially could have been prevented if they had received the invitation earlier. Nonetheless, no increase in interval CRC rate was observed, indicating that an extended invitation interval up to 30 months had no negative impact on the performance of the CRC screening programme and a modest extension of the invitation interval seems an appropriate intervention.
Incident cardiovascular events and imaging phenotypes in UK Biobank participants with past cancer
Authors: Raisi-Estabragh Zahra , Cooper Jackie , McCracken Celeste , Crosbie Emma J , Walter Fiona M , Manisty Charlotte H , Robson John , Mamas Mamas A , Harvey Nicholas C , Neubauer Stefan , Petersen Steffen E
Published: April 2023

Objectives

To evaluate incident cardiovascular outcomes and imaging phenotypes in UK Biobank participants with previous cancer.

Methods

Cancer and cardiovascular disease (CVD) diagnoses were ascertained using health record linkage. Participants with cancer history (breast, lung, prostate, colorectal, uterus, haematological) were propensity matched on vascular risk factors to non-cancer controls. Competing risk regression was used to calculate subdistribution HRs (SHRs) for associations of cancer history with incident CVD (ischaemic heart disease (IHD), non-ischaemic cardiomyopathy (NICM), heart failure (HF), atrial fibrillation/flutter, stroke, pericarditis, venous thromboembolism (VTE)) and mortality outcomes (any CVD, IHD, HF/NICM, stroke, hypertensive disease) over 11.8±1.7 years of prospective follow-up. Linear regression was used to assess associations of cancer history with left ventricular (LV) and left atrial metrics.

Results

We studied 18 714 participants (67% women, age: 62 (IQR: 57–66) years, 97% white ethnicities) with cancer history, including 1354 individuals with cardiovascular magnetic resonance. Participants with cancer had high burden of vascular risk factors and prevalent CVDs. Haematological cancer was associated with increased risk of all incident CVDs considered (SHRs: 1.92–3.56), larger chamber volumes, lower ejection fractions, and poorer LV strain. Breast cancer was associated with increased risk of selected CVDs (NICM, HF, pericarditis and VTE; SHRs: 1.34–2.03), HF/NICM death, hypertensive disease death, lower LV ejection fraction, and lower LV global function index. Lung cancer was associated with increased risk of pericarditis, HF, and CVD death. Prostate cancer was linked to increased VTE risk.

Conclusions

Cancer history is linked to increased risk of incident CVDs and adverse cardiac remodelling independent of shared vascular risk factors.
Intratumoral tertiary lymphoid structure (TLS) maturation is influenced by draining lymph nodes of lung cancer
Authors: He Miao , He Qihua , Cai Xiuyu , Liu Jun , Deng Hongshen , Li Feng , Zhong Ran , Lu Yi , Peng Haoxin , Wu Xiangrong , Chen Zisheng , Lao Shen , Li Caichen , Li Jianfu , He Jianxing , Liang Wenhua
Published: April 2023

Background

Tertiary lymphoid structure (TLS) is an organized infiltration of immune cells, showing features of germinal center (GC) commonly seen in secondary lymphoid organs. However, its relationship with tumor-draining lymph nodes (TDLNs) has not been studied and we hypothesized that TDLN may influence maturation of intratumoral TLS in non-small cell lung cancer (NSCLC).

Methods

Tissue slides of 616 patients that had undergone surgeries were examined. Cox proportional hazard regression model was used to assess risk factors of patients’ survival, and logistic regression model was used for their relationship with TLS. Single-cell RNA-sequencing (scRNA-seq) was employed to explore transcriptomic features of TDLNs. Immunohistochemistry, multiplex immunofluorescence and flow cytometry were performed to analyze cellular composition. Cellular components of NSCLC samples from The Cancer Genome Atlas database were inferred with Microenvironment Cell Populations-counter (MCP-counter) method. Murine NSCLC models were used to dissect underlying mechanisms for relationship between TDLN and TLS maturation.

Results

While GC+TLS was associated with better prognosis, GC−TLS was not. TDLN metastasis reduced the prognostic relevance of TLS, and was associated with less GC formation. Primary tumor sites showed reduced B cell infiltration in TDLN-positive patients, and scRNA-seq revealed diminished memory B cell formation in tumor-invaded TDLNs, together with an emphasis on weakened interferon (IFN)-γ response. Murine NSCLC models revealed that IFN-γ signaling is involved in memory B cell differentiation in TDLNs and GC formation in primary tumors.

Conclusions

Our research emphasizes the influence of TDLN on intratumoral TLS maturation and suggests a role of memory B cells and IFN-γ signaling in this communication.
Ectopic expression of cGAS inSalmonella typhimuriumenhances STING-mediated IFN-β response in human macrophages and dendritic cells
Authors: Waanders Lisette , van der Donk Lieve E H , Ates Louis S , Maaskant Janneke , van Hamme John L , Eldering Eric , van Bruggen Jaco A C , Rietveld Joanne M , Bitter Wilbert , Geijtenbeek Teunis B H , Kuijl Coenraad P
Published: April 2023

Background

Interferon (IFN)-β induction via activation of the stimulator of interferon genes (STING) pathway has shown promising results in tumor models. STING is activated by cyclic dinucleotides such as cyclic GMP–AMP dinucleotides with phosphodiester linkages 2′–5′ and 3′–5′ (cGAMPs), that are produced by cyclic GMP–AMP synthetase (cGAS). However, delivery of STING pathway agonists to the tumor site is a challenge. Bacterial vaccine strains have the ability to specifically colonize hypoxic tumor tissues and could therefore be modified to overcome this challenge. Combining high STING-mediated IFN-β levels with the immunostimulatory properties ofSalmonella typhimuriumcould have potential to overcome the immune suppressive tumor microenvironment.

Methods

We have engineeredS. typhimuriumto produce cGAMP by expression of cGAS. The ability of cGAMP to induce IFN-β and its IFN-stimulating genes was addressed in infection assays of THP-I macrophages and human primary dendritic cells (DCs). Expression of catalytically inactive cGAS is used as a control. DC maturation and cytotoxic T-cell cytokine and cytotoxicity assays were conducted to assess the potential antitumor response in vitro. Finally, by making use of differentS. typhimuriumtype III secretion (T3S) mutants, the mode of cGAMP transport was elucidated.

Results

Expression of cGAS inS. typhimuriumresults in a 87-fold stronger IFN-β response in THP-I macrophages. This effect was mediated by cGAMP production and is STING dependent. Interestingly, the needle-like structure of the T3S system was necessary for IFN-β induction in epithelial cells. DC activation included upregulation of maturation markers and induction of type I IFN response. Coculture of challenged DCs with cytotoxic T cells revealed an improved cGAMP-mediated IFN-γ response. In addition, coculture of cytotoxic T cells with challenged DCs led to improved immune-mediated tumor B-cell killing.

Conclusion

S. typhimuriumcan be engineered to produce cGAMPs that activate the STING pathway in vitro. Furthermore, they enhanced the cytotoxic T-cell response by improving IFN-γ release and tumor cell killing. Thus, the immune response triggered byS. typhimuriumcan be enhanced by ectopic cGAS expression. These data show the potential ofS. typhimurium–cGAS in vitro and provides rationale for further research in vivo.
BRD4 inhibition impairs DNA mismatch repair, induces mismatch repair mutation signatures and creates therapeutic vulnerability to immune checkpoint blockade in MMR-proficient tumors
Authors: Fu Yu , Yang Bin , Cui Yaoyuan , Hu Xingyuan , Li Xi , Lu Funian , Qin Tianyu , Zhang Li , Hu Zhe , Guo Ensong , Fan Junpeng , Xiao Rourou , Li Wenting , Qin Xu , Hu Dianxing , Peng Wenju , Liu Jingbo , Wang Beibei , Mills Gordon B , Chen Gang , Sun Chaoyang
Published: April 2023

Background

Mismatch repair deficiency (dMMR) is a well-recognized biomarker for response to immune checkpoint blockade (ICB). Strategies to convert MMR-proficient (pMMR) to dMMR phenotype with the goal of sensitizing tumors to ICB are highly sought. The combination of bromodomain containing 4 (BRD4) inhibition and ICB provides a promising antitumor effect. However, the mechanisms underlying remain unknown. Here, we identify that BRD4 inhibition induces a persistent dMMR phenotype in cancers.

Methods

We confirmed the correlation between BRD4 and mismatch repair (MMR) by the bioinformatic analysis on The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium data, and the statistical analysis on immunohistochemistry (IHC) scores of ovarian cancer specimens. The MMR genes (MLH1,MSH2,MSH6,PMS2) were measured by quantitative reverse transcription PCR, western blot, and IHC. The MMR status was confirmed by whole exome sequencing, RNA sequencing, MMR assay and hypoxanthine-guanine phosphoribosyl transferase gene mutation assay. The BRD4i AZD5153 resistant models were induced both in vitro and in vivo. The transcriptional effects of BRD4 on MMR genes were investigated by chromatin immunoprecipitation among cell lines and data from the Cistrome Data Browser. The therapeutic response to ICB was testified in vivo. The tumor immune microenvironment markers, such as CD4, CD8, TIM-3, FOXP3, were measured by flow cytometry.

Results

We identified the positive correlation betweenBRD4and MMR genes in transcriptional and translational aspects. Also, the inhibition of BRD4 transcriptionally reduced MMR genes expression, resulting in dMMR status and elevated mutation loads. Furthermore, prolonged exposure to AZD5153 promoted a persistent dMMR signature both in vitro and in vivo, enhancing tumor immunogenicity, and increased sensitivity to α-programmed death ligand-1 therapy despite the acquired drug resistance.

Conclusions

We demonstrated that BRD4 inhibition suppressed expression of genes critical to MMR, dampened MMR, and increased dMMR mutation signatures both in vitro and in vivo, sensitizing pMMR tumors to ICB. Importantly, even in BRD4 inhibitors (BRD4i)-resistant tumor models, the effects of BRD4i on MMR function were maintained rendering tumors sensitive to ICB. Together, these data identified a strategy to induce dMMR in pMMR tumors and further, indicated that BRD4i sensitive and resistant tumors could benefit from immunotherapy.
Irreversible electroporation augments β-glucan induced trained innate immunity for the treatment of pancreatic ductal adenocarcinoma
Authors: Woeste Matthew R , Shrestha Rejeena , Geller Anne E , Li Shu , Montoya-Durango Diego , Ding Chuanlin , Hu Xiaoling , Li Hong , Puckett Aaron , Mitchell Robert A , Hayat Traci , Tan Min , Li Yan , McMasters Kelly M , Martin Robert C G , Yan Jun
Published: April 2023

Background

Pancreatic cancer (PC) is a challenging diagnosis that is yet to benefit from the advancements in immuno-oncologic treatments. Irreversible electroporation (IRE), a non-thermal method of tumor ablation, is used in treatment of select patients with locally-advanced unresectable PC and has potentiated the effect of certain immunotherapies. Yeast-derived particulate β-glucan induces trained innate immunity and successfully reduces murine PC tumor burden. This study tests the hypothesis that IRE may augment β-glucan induced trained immunity in the treatment of PC.

Methods

β-Glucan-trained pancreatic myeloid cells were evaluated ex vivo for trained responses and antitumor function after exposure to ablated and unablated tumor-conditioned media. β-Glucan and IRE combination therapy was tested in an orthotopic murine PC model in wild-type and Rag−/−mice. Tumor immune phenotypes were assessed by flow cytometry. Effect of oral β-glucan in the murine pancreas was evaluated and used in combination with IRE to treat PC. The peripheral blood of patients with PC taking oral β-glucan after IRE was evaluated by mass cytometry.

Results

IRE-ablated tumor cells elicited a potent trained response ex vivo and augmented antitumor functionality. In vivo, β-glucan in combination with IRE reduced local and distant tumor burden prolonging survival in a murine orthotopic PC model. This combination augmented immune cell infiltration to the PC tumor microenvironment and potentiated the trained response from tumor-infiltrating myeloid cells. The antitumor effect of this dual therapy occurred independent of the adaptive immune response. Further, orally administered β-glucan was identified as an alternative route to induce trained immunity in the murine pancreas and prolonged PC survival in combination with IRE. β-Glucan in vitro treatment also induced trained immunity in peripheral blood monocytes obtained from patients with treatment-naïve PC. Finally, orally administered β-glucan was found to significantly alter the innate cell landscape within the peripheral blood of five patients with stage III locally-advanced PC who had undergone IRE.

Conclusions

These data highlight a relevant and novel application of trained immunity within the setting of surgical ablation that may stand to benefit patients with PC.
Naive T cells inhibit the outgrowth of intractable antigen-activated memory T cells: implications for T-cell immunotherapy
Authors: Sharma Sandhya , Woods Mae , Mehta Naren U , Sauer Tim , Parikh Kathan S , Schmueck-Henneresse Michael , Zhang Huimin , Mehta Birju , Brenner Malcolm K , Heslop Helen E , Rooney Cliona M
Published: April 2023

Background

The wider application of T cells targeting viral tumor-antigens via their native receptors is hampered by the failure to expand potent tumor-specific T cells from patients. Here, we examine reasons for and solutions to this failure, taking as our model the preparation of Epstein-Barr virus (EBV)-specific T cells (EBVSTs) for the treatment of EBV-positive lymphoma. EBVSTs could not be manufactured from almost one-third of patients, either because they failed to expand, or they expanded, but lacked EBV specificity. We identified an underlying cause of this problem and established a clinically feasible approach to overcome it.

Methods

CD45RO+CD45RA− memory compartment residing antigen-specific T cells were enriched by depleting CD45RA positive (+) peripheral blood mononuclear cells (PBMCs) that include naïve T cells, among other subsets, prior to EBV antigen stimulation. We then compared the phenotype, specificity, function and T-cell receptor (TCR) Vβ repertoire of EBVSTs expanded from unfractionated whole (W)-PBMCs and CD45RA-depleted (RAD)-PBMCs on day 16. To identify the CD45RA component that inhibited EBVST outgrowth, isolated CD45RA+ subsets were added back to RAD-PBMCs followed by expansion and characterization. The in vivo potency of W-EBVSTs and RAD-EBVSTs was compared in a murine xenograft model of autologous EBV+ lymphoma.

Results

Depletion of CD45RA+ PBMCs before antigen stimulation increased EBVST expansion, antigen-specificity and potency in vitro and in vivo. TCR sequencing revealed a selective outgrowth in RAD-EBVSTs of clonotypes that expanded poorly in W-EBVSTs. Inhibition of antigen-stimulated T cells by CD45RA+ PBMCs could be reproduced only by the naïve T-cell fraction, while CD45RA+ regulatory T cells, natural killer cells, stem cell memory and effector memory subsets lacked inhibitory activity. Crucially, CD45RA depletion of PBMCs from patients with lymphoma enabled the outgrowth of EBVSTs that failed to expand from W-PBMCs. This enhanced specificity extended to T cells specific for other viruses.

Conclusion

Our findings suggest that naïve T cells inhibit the outgrowth of antigen-stimulated memory T cells, highlighting the profound effects of intra-T-cell subset interactions. Having overcome our inability to generate EBVSTs from many patients with lymphoma, we have introduced CD45RA depletion into three clinical trials:NCT01555892andNCT04288726using autologous and allogeneic EBVSTs to treat lymphoma andNCT04013802using multivirus-specific T cells to treat viral infections after hematopoietic stem cell transplantation.
Severe cytopenia after CD19 CAR T-cell therapy: a retrospective study from the EBMT Transplant Complications Working Party
Authors: Penack Olaf , Peczynski Christophe , Koenecke Christian , Polge Emmanuelle , Kuhnl Andrea , Fegueux Nathalie , Daskalakis Michael , Kröger Nicolaus , Dreger Peter , Besley Caroline , Schanz Urs , Bloor Adrian , Ganser Arnold , Forcade Edouard , Corral Lucia López , Passweg Jakob R , Novak Urban , Moiseev Ivan , Schoemans Hélène , Basak Grzegorz W , Chabannon Christian , Sureda Anna , Averbuch Dina , Glass Bertram , de la Camara Rafael , Peric Zinaida
Published: April 2023

We investigated the incidence and outcome of anti-CD19 chimeric antigen receptor (CAR) T-cells-associated Common Terminology Criteria for Adverse Events (CTCAE) ≥grade 3 cytopenia. In the EBMT CAR-T registry, we identified 398 adult patients with large B-cell lymphoma who had been treated with CAR-T-cells with axicel (62%) or tisacel (38%) before August 2021 and had cytopenia status documented for the first 100 days. Most patients had received two or three previous lines of therapy, however, 22.3% had received four or more. Disease status was progressive in 80.4%, stable in 5.0% and partial/complete remission in 14.6%. 25.9% of the patients had received a transplantation before. Median age was 61.4 years (min–max; IQR=18.7–81; (52.9–69.5)).

The cumulative incidence of ≥grade 3 cytopenia was 9.0% at 30 days (95% CI (6.5 to 12.1)) and 12.1% at 100 days after CAR T-cell infusion (95% CI (9.1 to 15.5)). The median time from CAR-T infusion to cytopenia onset was 16.5 days (min–max; IQR=1–90; (4–29.8)). Grade 3 and grade 4 CTCAE cytopenia occurred in 15.2% and 84.8%, respectively. In 47.6% there was no resolution.

Severe cytopenia had no significant impact on overall survival (OS) (HR 1.13 (95% CI 0.74 to 1.73), p=0.57). However, patients with severe cytopenia had a poorer progression-free survival (PFS) (HR 1.54 (95% CI 1.07 to 2.22), p=0.02) and a higher relapse incidence (HR 1.52 (95% CI 1.04 to 2.23), p=0.03). In those patients who developed severe cytopenia during the first 100 days (n=47), OS, PFS, relapse incidence and non-relapse mortality at 12 months after diagnosis of severe cytopenia were 53.6% (95% CI (40.3 to 71.2)), 20% (95% CI (10.4 to 38.6)), 73.5% (95% CI (55.2 to 85.2)) and 6.5% (95% CI (1.7 to 16.2)), respectively.

In multivariate analysis of severe cytopenia risk factors, only year of CAR-T infusion (HR=0.61, 95% CI (0.39 to 0.95), p=0.028) and total number of treatment lines before CAR-T infusion (one or two lines vs three or more, HR=0.41, 95% CI (0.21 to 0.83), p=0.013) had a significant positive association with the incidence of cytopenia. Other factors, such as previous transplantation, disease status at time of CAR-T, patient age and patient sex, had no significant association.

Our data provide insight on frequency and clinical relevance of severe cytopenia after CAR T-cell therapy in the European real-world setting.
TP53c.455C>T p.(Pro152Leu) pathogenic variant is a lower risk allele with attenuated risks of breast cancer and sarcoma
Authors: Evans D Gareth , Harkness Elaine F , Woodward Emma R
Published: April 2023

Germline (likely) pathogenicTP53variants cause Li-Fraumeni syndrome (LFS), typically associated with sarcoma, brain, breast and adrenal tumours. Although classical LFS is highly penetrant, the p.R337H variant, common in Brazil, is typically associated with childhood adrenal tumours and an older onset age of other LFS tumours. Previously, we reported the finding of p.P152L in 6 children from 5 families with adrenal tumours. We have now assessed cancer risks over the subsequent 23 years, and in one further family with p.P152L. Cancer risks were compared with those in the 11 families known to our service with classical dominant negative mutations affecting neighbouring codons 245 and 248 (codon 245/248).

Compared with codon 245/248 families, we found lower age-related risks for all non-adrenal tumours in codon 152 families (p<0.0001) with an absence of breast cancer as compared with 100% penetrance by age 36 years in codon 245/248 families (p<0.0001), and lower rates of sarcoma in non-irradiated individuals (p=0.0001). Although there were more adrenal tumours in codon 152 families (6/26 individuals, 1/27 for codon 245/248), this was not significant (p=0.05).

Understanding codon-specific cancer risks in LFS is important for accurate personalised cancer risk assessment, and subsequent prevention and early detection strategies.