bluuebunny/crossref_metadata_2025 huggingface dataset:
A Linear Relationship between the Number of Cancers among First-Degree Relatives and the Risk of Multiple Primary Cancers
Authors: He Shisi , Barry Kathryn H. , Mitchell Braxton D. , Chen Shuo , Zhang Yuji , Beane Freeman Laura E. , Berndt Sonja I.
Published: June 2024

With advances in the early detection and treatment of cancer, the incidence of multiple primary cancers (MPC) or second primary cancers has increased over time. Characterization of etiologic risk factors, including family history of cancer, within the general population is critical for assessing MPC risk in patients. We examined the association between family history of cancer among first-degree relatives and MPC risk in a prospective study of 139,958 participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cox proportional hazard models were used to calculate HRs and 95% confidence intervals (95% CI), adjusting for potential confounders. Over a median follow-up of 16 years (IQR: 11–19 years), 6,170 participants were diagnosed with MPC. Having a family history of cancer increased the risk of MPC by 18% (HR, 1.18; 95% CI, 1.12–1.24). A positive linear trend was observed between the reported number of cancers in the family history and MPC risk with HRs (95% CI) of 1.13 (1.07–1.20), 1.23 (1.14–1.33), 1.29 (1.15–1.45), and 1.42 (1.20–1.70) for one, two, three, and four or more cancers among first-degree relatives, respectively (Ptrend = 2.36 × 10−13). No significant differences were observed by cancer histology or specific cancer types reported in the family history. Our study demonstrates that the family history of cancer is an important risk factor for the development of MPCs and that a comprehensive assessment of the number of cancers reported among first-degree relatives may identify those at higher risk who may benefit from targeted cancer prevention and screening strategies.

Prevention Relevance: Our study makes a substantial contribution to the understanding of risk factors for MPCs in the general population. It demonstrates that individuals with a strong family history of cancer are at higher risk for MPCs and may benefit from more targeted cancer prevention and screening interventions.
Tumor Promoters and Opportunities for Molecular Cancer Prevention
Authors: Hill William , Weeden Clare E. , Swanton Charles
Published: June 2024

Environmental carcinogens increase cancer incidence via both mutagenic and non-mutagenic mechanisms. There are over 500 known or suspected carcinogens classified by the International Agency for Research on Cancer. Sequencing of both cancerous and histologically non-cancerous tissue has been instrumental in improving our understanding of how environmental carcinogens cause cancer. Understanding how and defining which environmental or lifestyle exposures drive cancer will support cancer prevention. Recent research is revisiting the mechanisms of early tumorigenesis, paving the way for an era of molecular cancer prevention.

Significance: Recent data have improved our understanding of how carcinogens cause cancer, which may reveal novel opportunities for molecular cancer prevention.
Cancer Core Europe: Leveraging Institutional Synergies to Advance Oncology Research and Care Globally
Authors: Carmona Javier , Chavarria Elena , Donoghue Kate , von Gertten Christina , Oberrauch Petra , Pailler Emma , Scoazec Giovanni , Weijer Ruud , Balmaña Judith , Brana Irene , Brunelli Cinzia , Delaloge Suzette , Deloger Marc , Delpy Pierre , Ernberg Ingemar , Fitzgerald Rebecca C. , Garralda Elena , Lablans Martin , Lëhtio Janne , Lopez Carlos , Fernández Maialen , Miceli Rosalba , Nuciforo Paolo , Perez-Lopez Raquel , Provenzano Elena , Schmidt Marjanka K. , Serrano Cesar , Steeghs Neeltje , Tamborero David , Wirta Valtteri , Baird Richard D. , Barker Karen , Barlesi Fabrice , Baumann Michael , Bergh Jonas , de Braud Filippo , Fizazi Karim , Fröhling Stefan , Piris-Giménez Alejandro , Seamon Kenneth , Van der Heijden Michiel S. , Zwart Wilbert , Tabernero Josep
Published: June 2024

Cancer Core Europe brings together the expertise, resources, and interests of seven leading cancer institutes committed to leveraging collective innovation and collaboration in precision oncology. Through targeted efforts addressing key medical challenges in cancer and partnerships with multiple stakeholders, the consortium seeks to advance cancer research and enhance equitable patient care.
Identification of Core Techniques That Enhance Genome Editing of Human T Cells Expressing Synthetic Antigen Receptors
Authors: Chang Ju-Fang , Wellhausen Nils , Engel Nils W. , Landmann Jack H. , Hopkins Caitlin R. , Salas-McKee January , Bear Adham S. , Selli Mehmet E. , Agarwal Sangya , Jadlowsky Julie K. , Linette Gerald P. , Gill Saar , June Carl H. , Fraietta Joseph A. , Singh Nathan
Published: June 2024

Genome editing technologies have seen remarkable progress in recent years, enabling precise regulation of exogenous and endogenous genes. These advances have been extensively applied to the engineering of human T lymphocytes, leading to the development of practice changing therapies for patients with cancer and the promise of synthetic immune cell therapies for a variety of nonmalignant diseases. Many distinct conceptual and technical approaches have been used to edit T-cell genomes, however targeted assessments of which techniques are most effective for manufacturing, gene editing, and transgene expression are rarely reported. Through extensive comparative evaluation, we identified methods that most effectively enhance engineering of research-scale and preclinical T-cell products at critical stages of manufacturing.
CD8
+
T Cells Drive Plaque Smooth Muscle Cell Dedifferentiation in Experimental Atherosclerosis
Authors: Schäfer Sarah , Gogiraju Rajinikanth , Rösch Melanie , Kerstan Yvonne , Beck Lina , Garbisch Janine , Saliba Antoine-Emmanuel , Gisterå Anton , Hermanns Heike M. , Boon Louis , Kastenmüller Wolfgang , Schäfer Katrin , Cochain Clément , Zernecke Alma
Published: June 2024

BACKGROUND:

Atherosclerosis is driven by the infiltration of the arterial intima by diverse immune cells and smooth muscle cells (SMCs). CD8
+
T cells promote lesion growth during atherosclerotic lesion development, but their role in advanced atherosclerosis is less clear. Here, we studied the role of CD8
+
T cells and their effects on SMCs in established atherosclerosis.

METHODS:

CD8
+
T cells were depleted in (SMC reporter) low-density lipoprotein receptor-deficient (
Ldlr
−/−
) mice with established atherosclerotic lesions. Atherosclerotic lesion formation was examined, and single-cell RNA sequencing of aortic SMCs and their progeny was performed. Additionally, coculture experiments with primary aortic SMCs and CD8
+
T cells were conducted.

RESULTS:

Although we could not detect differences in atherosclerotic lesion size, an increased plaque SMC content was noted in mice after CD8
+
T-cell depletion. Single-cell RNA sequencing of aortic lineage-traced SMCs revealed contractile SMCs and a modulated SMC cluster, expressing macrophage- and osteoblast-related genes. CD8
+
T-cell depletion was associated with an increased contractile but decreased macrophage and osteoblast-like gene signature in this modulated aortic SMC cluster. Conversely, exposure of isolated aortic SMCs to activated CD8
+
T cells decreased the expression of genes indicative of a contractile SMC phenotype and induced a macrophage and osteoblast-like cell state. Notably, CD8
+
T cells triggered calcium deposits in SMCs under osteogenic conditions. Mechanistically, we identified transcription factors highly expressed in modulated SMCs, including
Runx1
, to be induced by CD8
+
T cells in cultured SMCs in an IFNγ (interferon-γ)-dependent manner.

CONCLUSIONS:

We here uncovered CD8
+
T cells to control the SMC phenotype in atherosclerosis. CD8
+
T cells promote SMC dedifferentiation and drive SMCs to adopt features of macrophage-like and osteoblast-like, procalcifying cell phenotypes. Given the critical role of SMCs in atherosclerotic plaque stability, CD8
+
T cells could thus be explored as therapeutic target cells during lesion progression.
PAI-1 Regulates the Cytoskeleton and Intrinsic Stiffness of Vascular Smooth Muscle Cells
Authors: Khoukaz Hekmat B. , Vadali Manisha , Schoenherr Alex , Ramirez-Perez Francisco I. , Morales-Quinones Mariana , Sun Zhe , Fujie Shumpei , Foote Christopher A. , Lyu Zhen , Zeng Shuai , Augenreich Marc A. , Cai Dunpeng , Chen Shi-You , Joshi Trupti , Ji Yan , Hill Michael A. , Martinez-Lemus Luis A. , Fay William P.
Published: June 2024

BACKGROUND:

Plasma concentration of PAI-1 (plasminogen activator inhibitor-1) correlates with arterial stiffness. Vascular smooth muscle cells (SMCs) express PAI-1, and the intrinsic stiffness of SMCs is a major determinant of total arterial stiffness. We hypothesized that PAI-1 promotes SMC stiffness by regulating the cytoskeleton and that pharmacological inhibition of PAI-1 decreases SMC and aortic stiffness.

METHODS:

PAI-039, a specific inhibitor of PAI-1, and small interfering RNA were used to inhibit PAI-1 expression in cultured human SMCs. Effects of PAI-1 inhibition on SMC stiffness, F-actin (filamentous actin) content, and cytoskeleton-modulating enzymes were assessed. WT (wild-type) and PAI-1–deficient murine SMCs were used to determine PAI-039 specificity. RNA sequencing was performed to determine the effects of PAI-039 on SMC gene expression. In vivo effects of PAI-039 were assessed by aortic pulse wave velocity.

RESULTS:

PAI-039 significantly reduced intrinsic stiffness of human SMCs, which was accompanied by a significant decrease in cytoplasmic F-actin content. PAI-1 gene knockdown also decreased cytoplasmic F-actin. PAI-1 inhibition significantly increased the activity of cofilin, an F-actin depolymerase, in WT murine SMCs, but not in PAI-1–deficient SMCs. RNA-sequencing analysis suggested that PAI-039 upregulates AMPK (AMP-activated protein kinase) signaling in SMCs, which was confirmed by Western blotting. Inhibition of AMPK prevented activation of cofilin by PAI-039. In mice, PAI-039 significantly decreased aortic stiffness and tunica media F-actin content without altering the elastin or collagen content.

CONCLUSIONS:

PAI-039 decreases intrinsic SMC stiffness and cytoplasmic stress fiber content. These effects are mediated by AMPK-dependent activation of cofilin. PAI-039 also decreases aortic stiffness in vivo. These findings suggest that PAI-1 is an important regulator of the SMC cytoskeleton and that pharmacological inhibition of PAI-1 has the potential to prevent and treat cardiovascular diseases involving arterial stiffening.
Study on different isolation technology on the performance of blue micro-LEDs array applications
Authors: Lin Shao-Hua , Lo Yu-Yun , Hsu Yu-Hsuan , Lin Chien-Chung , Zan Hsiao-Wen , Lin Yi-Hsin , Wuu Dong-Sing , Hsiao Ching-Lien , Horng Ray-Hua
Published: June 2024

In this study, a 3 × 3 blue micro-LED array with a pixel size of 10 × 10 μm2 and a pitch of 15 μm was fabricated on an epilayer grown on a sapphire substrate using metalorganic chemical vapor deposition technology. The fabrication process involved photolithography, wet and dry etching, E-beam evaporation, and ion implantation technology. Arsenic multi-energy implantation was utilized to replace the mesa etching for electrical isolation, where the implantation depth increased with the average energy. Different ion depth profiles had varying effects on electrical properties, such as forward current and leakage currents, potentially causing damage to the n-GaN layer and increasing the series resistance of the LEDs. As the implantation depth increased, the light output power and peak external quantum efficiency of the LEDs also increased, improving from 5.33 to 9.82%. However, the efficiency droop also increased from 46.3 to 48.6%.
High heteroplasmy is associated with low mitochondrial copy number and selection against non-synonymous mutations in the snail Cepaea nemoralis
Authors: Davison Angus , Chowdhury Mehrab , Johansen Margrethe ,   Wellcome Sanger Institute Tree of Life programme, Uliano-Silva Marcela , Blaxter Mark
Published: June 2024

Molluscan mitochondrial genomes are unusual because they show wide variation in size, radical genome rearrangements and frequently show high variation (> 10%) within species. As progress in understanding this variation has been limited, we used whole genome sequencing of a six-generation matriline of the terrestrial snail Cepaea nemoralis, as well as whole genome sequences from wild-collected C. nemoralis, the sister species C. hortensis, and multiple other snail species to explore the origins of mitochondrial DNA (mtDNA) variation. The main finding is that a high rate of SNP heteroplasmy in somatic tissue was negatively correlated with mtDNA copy number in both Cepaea species. In individuals with under ten mtDNA copies per nuclear genome, more than 10% of all positions were heteroplasmic, with evidence for transmission of this heteroplasmy through the germline. Further analyses showed evidence for purifying selection acting on non-synonymous mutations, even at low frequency of the rare allele, especially in cytochrome oxidase subunit 1 and cytochrome b. The mtDNA of some individuals of Cepaea nemoralis contained a length heteroplasmy, including up to 12 direct repeat copies of tRNA-Val, with 24 copies in another snail, Candidula rugosiuscula, and repeats of tRNA-Thr in C. hortensis. These repeats likely arise due to error prone replication but are not correlated with mitochondrial copy number in C. nemoralis. Overall, the findings provide key insights into mechanisms of replication, mutation and evolution in molluscan mtDNA, and so will inform wider studies on the biology and evolution of mtDNA across animal phyla.
Identification of genetic variants controlling diosgenin content in Dioscorea zingiberensis tuber by genome-wide association study
Authors: Sun Shi xian , Li Yanmei , Jia Lu , Ye Shili , Luan Yunpeng
Published: June 2024

Background

Diosgenin is an important steroidal precursor renowned for its diverse medicinal uses. It is predominantly sourced from Dioscorea species, particularly Dioscorea zingiberensis. Dioscorea zingiberensis has an ability to accumulate 2–16% diosgenin in its rhizomes. In this study, a diverse population of 180 D. zingiberensis accessions was used to evaluate the genomic regions associated with diosgenin biosynthesis by the genome wide association study approach (GWAS).

Results

The whole population was characterized for diosgenin contents from tubers by gas chromatography mass spectrometry. The individuals were genotyped by the genotyping-by-sequencing approach and 10,000 high-quality SNP markers were extracted for the GWAS. The highest significant marker-trait-association was observed as an SNP transversion (G to T) on chromosome 10, with 64% phenotypic variance explained. The SNP was located in the promoter region of CYP94D144 which is a member of P450 gene family involved in the independent biosynthesis of diosgenin from cholesterol. The transcription factor (TF) binding site enrichment analysis of the promoter region of CYP94D144 revealed NAC TF as a potential regulator. The results were further validated through expression profiling by qRT-PCR, and the comparison of high and low diosgenin producing hybrids obtained from a bi-parental population.

Conclusions

This study not only enhanced the understanding of the genetic basis of diosgenin biosynthesis but also serves as a valuable reference for future genomic investigations on CYP94D144, with the aim of augmenting diosgenin production in yam tubers.
Compounding stress: A mixed-methods study on the psychological experience of miscarriage amid the COVID-19 pandemic
Authors: Fernandez-Pineda Madeline , Swift Alison , Dolbier Christyn , Banasiewicz Kaitlin Guard
Published: June 2024

Background

Experiencing a miscarriage can have profound psychological implications, and the added strain of the COVID-19 pandemic may have compounded these effects. This study aimed to explore the psychological experiences, assess the levels of psychological distress (depression, anxiety, and post-traumatic stress disorder), and examine the relationships of personal significance of miscarriage and perceived stress with psychological distress of women in North Carolina who suffered a miscarriage of a desired pregnancy between March 30, 2020, and February 24, 2021, of the COVID-19 pandemic, at 14 to 31 months after the loss.

Methods

We conducted a cross-sectional mixed-methods study using a convergent parallel design. A total of 71 participants from North Carolina completed the online survey and 18 completed in-depth interviews. The survey assessed demographics, mental health and reproductive history, personal significance of miscarriage, perceived stress, anxiety, depression, and PTSD. Interview questions asked about the psychological experience of the miscarriage and how the COVID-19 pandemic affected them and their experience.

Results

Findings indicated moderate to severe levels of depression, anxiety, and PTSD, which persisted 14 to 31 months post-miscarriage. After conducting hierarchical binary logistic regressions, we found that perceived stress and prior trauma increased the odds of depression, perceived stress increased the odds of anxiety, and personal significance and prior trauma increased the odds of PTSD symptoms 14–31 months post-miscarriage. Notably, a subsequent successful childbirth emerged as a protective factor against depression, anxiety, and PTSD. Qualitative findings depicted emotions such as profound isolation, guilt, and grief. Women noted that additional pandemic-specific stressors exacerbated their distress. The categories identified via conventional content analysis fell under five broader thematic groups: mental health disorders, negative emotions/feelings, positive emotions/feelings, thoughts, and other experiences.

Conclusions

Miscarriage during the COVID-19 pandemic intensified and added complexity to the psychological distress experienced by affected women. The study underscores the need for comprehensive mental health screenings, specialized support for vulnerable groups, and the necessity of trauma-informed care. Providers are strongly encouraged to adopt a multifaceted, individualized approach to patient care that is cognizant of the unique stressors introduced by the pandemic.
Genetic and clinical landscape of Chinese frontotemporal dementia: dominance of TBK1 and OPTN mutations
Authors: Nan Haitian , Kim Yeon-Jeong , Chu Min , Li Dan , Li Jieying , Jiang Deming , Wu Yiming , Ohtsuka Toshihisa , Wu Liyong
Published: June 2024

Background

Our study aims to evaluate the genetic and phenotypic spectrum of Frontotemporal dementia (FTD) gene variant carriers in Chinese populations, investigate mutation frequencies, and assess the functional properties of TBK1 and OPTN variants.

Methods

Clinically diagnosed FTD patients underwent genetic analysis through exome sequencing, repeat-primed polymerase chain reaction, and Sanger sequencing. TBK1 and OPTN variants were biologically characterized in vitro using immunofluorescence, immunoprecipitation, and immunoblotting analysis. The frequencies of genes implicated in FTD in China were analyzed through a literature review and meta-analysis.

Results

Of the 261 Chinese FTD patients, 61 (23.4%) carried potential causative variants in FTD-related genes, including MAPT (n = 17), TBK1 (n = 7), OPTN (n = 6), GRN (n = 6), ANXA11 (n = 4), CHMP2B (n = 3), C9orf72 GGGGCC repeats (n = 2), CYLD (n = 2), PRNP (n = 2), SQSTM1 (n = 2), TARDBP (n = 2), VCP (n = 1), CCNF (n = 1), CHCHD10 (n = 1), SIGMAR1 (n = 1), CHCHD2 (n = 1), FUS (n = 1), TMEM106B (n = 1), and UBQLN2 (n = 1). 29 variants can be considered novel, including the MAPT p.D54N, p.E342K, p.R221P, p.T263I, TBK1 p.E696G, p.I37T, p.E232Q, p.S398F, p.T78A, p.Q150P, p.W259fs, OPTN p.R144G, p.F475V, GRN p.V473fs, p.C307fs, p.R101fs, CHMP2B p.K6N, p.R186Q, ANXA11 p.Q155*, CYLD p.T157I, SQSTM1 p.S403A, UBQLN2 p.P509H, CCNF p.S160N, CHCHD10 p.A8T, SIGMAR1 p.S117L, CHCHD2 p.P53fs, FUS p.S235G & p.S236G, and TMEM106B p.L144V variants. Patients with TBK1 and OPTN variants presented with heterogeneous clinical phenotypes. Functional analysis demonstrated that TBK1 I37T and E232Q mutants showed decreased autophosphorylation, and the OPTN phosphorylation was reduced by the TBK1 I37T mutant. The OPTN-TBK1 complex formation was enhanced by the TBK1 E696G mutant, while OPTN R144G and F475V mutants exhibited reduced recruitment to autophagosomes compared to the wild-type. The overall frequency of TBK1 and OPTN in Chinese FTD patients was 2.0% and 0.3%, respectively.

Conclusions

Our study demonstrates the extensive genetic and phenotypic heterogeneity of Chinese FTD patients. TBK1 mutations are the second most frequent cause of clinical FTD after MAPT in the Chinese.
Giant complete hydatidiform mole: a case report and review of the literature
Authors: Bonomo Iris , Fopa Suzy , Van Vinckenroy Grégory , Maillard Charlotte
Published: June 2024

Background

This case describes the youngest patient documented in the literature who presented with a giant hydatidiform mole, effectively addressed through conservative treatment.

Case presentation

Our department received a 20-year-old Caucasian patient who was admitted due to significant metrorrhagia in an undisclosed pregnancy. During examination, we identified a massive, highly vascularized hydatidiform mole measuring 22 cm (cm). We performed a surgical dilatation and curettage. The anatomopathological findings confirmed the presence of a complete hydatidiform mole (CHM). Following the established guidelines, we conducted weekly monitoring of human chorionic gonadotropin (hCG). Unfortunately, the patient discontinued the follow-up and became pregnant again before achieving hCG negativation.

Conclusion

This case suggests that conservative treatment is a viable option regardless of the size of gestational trophoblastic disease (GTD), especially when the preservation of fertility is a crucial consideration, as effectively demonstrated in our case.
Utilization of maternal health facilities and rural women’s well-being: towards the attainment of sustainable development goals
Authors: Adejoorin Mobolaji Victoria , Salman Kabir Kayode , Adenegan Kemisola Omorinre , Obi-Egbedi Ogheneruemu , Dairo Magbagbeola David , Omotayo Abiodun Olusola
Published: June 2024

Background

The sustenance of any household is tied to the well-being of the mother's health before, during, and after pregnancy. Maternal health care has continued a downward slope, increasing maternal mortality in rural communities in Nigeria. Presently, few empirical findings connect maternal healthcare facilities' use to mothers' well-being in Nigeria. Using maternal health facilities and the well-being of rural women is crucial in achieving the United Nations’ Sustainable Development Goals 1, 2, and 3 (No poverty, zero hunger, good health, and well-being).

Objective

The objective of the study was to examine the level of maternal healthcare utilization and its effect on mothers’ well-being status among mothers in rural Nigeria.

Methods

In this study, secondary data extracted from the Nigeria’s 2018 National Demographic Health Survey was used. Data was analyzed with Multiple correspondence analysis, Fuzzy set analysis, and Extended ordered logit model.

Results

Women in rural Nigeria were moderate users of maternal health care services and had moderate well-being indices (0.54 ± 0.2, 0.424 ± 0.2, respectively). Mothers' moderate well-being status was increased by using maternal health care facilities, having a larger household, and having mothers who worked exclusively in agriculture.

Conclusion

We concluded that mothers in rural Nigeria use maternal healthcare facilities moderately, and their well-being level was improved using maternal healthcare facilities. Therefore, Nigeria’s Ministry of Health should raise awareness about the vitality of mothers using health care services before, during, and after pregnancy. In order to promote greater female participation in full-scale agricultural production, it is imperative for the Nigerian government to allocate substantial resources in the form of subsidies and incentives. The Nigerian government should source these resources from various channels, including expanded development cooperation. Additionally, policymakers should focus on designing developmental programmes specifically tailored for rural households and the health sector.
The optimal second-line therapy for older adults with type 2 diabetes mellitus: protocol for a systematic review and network meta-analysis using individual participant data (IPD)
Authors: Wang Jingya , Nirantharakumar Krishnarajah , Sainsbury Christopher , Moore David J. , Sinclair Alan , Thomas G. Neil , Hanif Wasim , Singh Megha , Tan Luyuan , Wang Zhaonan , Simms-Williams Nikita , Yao Mi , Gunathilaka M. Niluka , Singh Pushpa , Toulis Konstantinos , Tsapas Apostolos , Coomar Dyuti , Price Malcolm James
Published: June 2024

Background

Due to increasing life expectancy, almost half of people with type 2 diabetes are aged 65 years or over worldwide. When metformin alone does not control blood sugar, the choice of which second-line therapy to prescribe next is not clear from currently available evidence. The existence of frailty and comorbidities in older adults further increases the complexity of medical decision-making. As only a relatively small proportion of trials report results separately for older adults, the relative efficacy and safety of second-line therapies in older adults with type 2 diabetes mellitus are unknown and require further investigation. This individual participant data (IPD) network meta-analysis evaluates the relative efficacy and safety of second-line therapies on their own or in combination in older adults with type 2 diabetes mellitus.

Methods

All relevant published and unpublished trials will be identified. Studies published prior to 2015 will be identified from two previous comprehensive aggregate data network meta-analyses. Searches will be conducted in CENTRAL, MEDLINE, and EMBASE from 1st January 2015 onwards, and in clinicaltrials.gov from inception. Randomised controlled trials with at least 100 estimated older adults (≥ 65 years) receiving at least 24 weeks of intervention that assess the effects of glucose-lowering drugs on mortality, glycemia, vascular and other comorbidities outcomes, and quality of life will be eligible. The screening and data extraction process will be conducted independently by two researchers. The quality of studies will be assessed using the Cochrane risk of bias tool 2. Anonymised IPD of all eligible trials will be requested via clinical trial portals or by contacting the principal investigators or sponsors. Received data will be reanalysed where necessary to standardise outcome metrics. Network meta-analyses will be performed to determine the relative effectiveness of therapies.

Discussion

With the increasing number of older adults with type 2 diabetes worldwide, an IPD network meta-analysis using data from all eligible trials will provide new insights into the optimal choices of second-line antidiabetic drugs to improve patient management and reduce unnecessary adverse events and the subsequent risk of comorbidities in older adults.

Systematic review registration

PROSPERO CRD42021272686.
Tapping the alphabets of learning-oriented assessment: self-assessment, classroom climate, mindsets, trait emotional intelligence, and academic engagement are in focus
Authors: Namaziandost Ehsan , Kargar Behbahani Hossein , Heydarnejad Tahereh
Published: June 2024

This study investigates the role of self-assessment (SA), classroom climate (CC), and psychological variables in learning-oriented assessment (LOA) within English as a foreign language (EFL) education. Utilizing a mixed-methods approach, data was collected through surveys and semi-structured interviews from EFL learners and instructors. Findings reveal that SA plays a pivotal role in promoting learner autonomy, self-regulated learning, and academic engagement (AE). By actively involving students in the assessment process and providing opportunities for reflection and feedback, educators can empower learners to take ownership of their learning journey and enhance their overall learning outcomes. Moreover, the study underscores the importance of creating a supportive CC characterized by mutual respect, collaboration, and inclusivity. Positive teacher-student relationships and inclusive learning environments contribute significantly to students’ academic and socioemotional development. Additionally, the study highlights the influence of psychological variables such as growth mindset and emotional intelligence (EI) on student learning outcomes. Learners who adopt a growth-oriented mindset and possess high levels of EI are more likely to persevere in the face of challenges and actively engage in the learning process. The implications of this study suggest the importance of adopting a holistic approach to assessment and instruction in EFL education, with stakeholders urged to incorporate strategies to promote SA, create supportive CC, and foster psychological variables for enhanced student learning and well-being.
Protection of Guizhou Miao batik culture based on knowledge graph and deep learning
Authors: Quan Huafeng , Li Yiting , Liu Dashuai , Zhou Yue
Published: June 2024

In the globalization trend, China’s cultural heritage is in danger of gradually disappearing. The protection and inheritance of these precious cultural resources has become a critical task. This paper focuses on the Miao batik culture in Guizhou Province, China, and explores the application of knowledge graphs, natural language processing, and deep learning techniques in the promotion and protection of batik culture. We propose a dual-channel mechanism that integrates semantic and visual information, aiming to connect batik pattern features with cultural connotations. First, we use natural language processing techniques to automatically extract batik-related entities and relationships from the literature, and construct and visualize a structured batik pattern knowledge graph. Based on this knowledge graph, users can textually search and understand the images, meanings, taboos, and other cultural information of specific patterns. Second, for the batik pattern classification, we propose an improved ResNet34 model. By embedding average pooling and convolutional operations into the residual blocks and introducing long-range residual connections, the classification performance is enhanced. By inputting pattern images into this model, their categories can be accurately identified, and then the underlying cultural connotations can be understood. Experimental results show that our model outperforms other mainstream models in evaluation metrics such as accuracy, precision, recall, and F1-score, achieving 94.46%, 94.47%, 93.62%, and 93.8%, respectively. This research provides new ideas for the digital protection of batik culture and demonstrates the great potential of artificial intelligence technology in cultural heritage protection.
Correlation-based outlier detection for ships’ in-service datasets
Authors: Gupta Prateek , Rasheed Adil , Steen Sverre
Published: June 2024

With the advent of big data, it has become increasingly difficult to obtain high-quality data. Solutions are required to remove undesired outlier samples from massively large datasets. Ship operators rely on high-frequency in-service datasets recorded onboard the ships for monitoring the performance of their fleet. The large in-service datasets are known to be highly unbalanced, making it difficult to adopt ordinary outlier detection techniques, as they would also result in the removal of rare but quite valuable data samples. Thus, the current work proposes to establish a correlation-based outlier detection scheme for ships’ in-service datasets using two well-known dimensionality reduction methods, namely, Principal Component Analysis (PCA) and Autoencoders. The correlation-based approach detects samples which do not fit the prominent correlations present in the dataset and avoids misidentifying the rare but correlation-following samples in the sparse regions of data domain. The study also attempts to provide the physical meaning of the latent variables obtained using PCA. The effectiveness of the proposed methodology is proven using an actual dataset recorded onboard a ship.
Ambient air pollution and the risk of violence in primary and secondary school settings: a cross-sectional study
Authors: Rau Austin T. , Harding Alyson B. , Ryan Andy , Ramirez Marizen R. , Renner Lynette M. , Berman Jesse D.
Published: June 2024

Background

Individual and social characteristics are attributed to violent behavior in schools, yet environmental hazards may play an understudied role. Ambient air pollution has been linked to neurological dysfunction that inhibits decision-making and may result in violent behavior in adult populations. However, little is known on how air pollution may be associated with violent behaviors in children.

Methods

A cross-sectional ecologic study was designed to estimate the associations between air pollution (fine particulate matter, carbon monoxide, and nitrogen dioxide) with the occurrence of violent incidents and incidents involving a weapon among a cohort of children in Minnesota schools (2008–2012). Differences by urban and rural status of schools were also explored. Negative binomial regression models were developed to estimate incidence rate ratios (IRR) and incidence rate differences (IRD) to describe associations between air pollution and violent incidents in school settings.

Results

Our results indicate that the highest levels of carbon monoxide, nitrogen dioxide and fine particulate matter concentrations were associated with increased violent disciplinary incidents. Among the total student population, the 4th quartile of carbon monoxide exposure was associated with an IRD of 775.62 (95% CI 543.2, 1008.05) violent incidents per 100,000 students per school year compared to schools in the lowest quartile of exposure. Comparing the 4th to the 1st quartiles of exposure, nitrogen dioxide and fine particulate matter had an IRD of 629.16 (95% CI 384.87, 873.46), and 510.49 (95% CI 274.92, 746.05) violent incidents per 100,000 students per school year respectively. Schools in urban settings shared a larger burden of violent incidents associated with air pollution compared to rural schools.

Conclusions

Modifying environmental pollutants surrounding school environments, particularly for high exposure communities, may be a novel tool for reducing violence and subsequent injuries in schools.
Appendiceal neoplasms derived from appendiceal tip remnants following appendectomy: a report of two cases
Authors: Fujii Yusuke , Hida Koya , Sugimoto Akihiko , Nishijima Ryohei , Fujimoto Masakazu , Hoshino Nobuaki , Maekawa Hisatsugu , Okamura Ryosuke , Itatani Yoshiro , Obama Kazutaka
Published: June 2024

Background

Neoplasms derived from remnant appendix are rarely described, with most cases arising from the appendiceal “stump”. Here, we present two surgical cases of appendiceal neoplasms derived from appendiceal “tip” remnants.

Case presentation

The first patient was a 71-year-old man who had undergone laparoscopic appendectomy for acute appendicitis 12 years prior. During appendectomy, the appendiceal root was ligated, but the appendix was not completely removed due to severe inflammation. At the most recent presentation, computed tomography (CT) was performed to examine choledocholithiasis, which incidentally revealed a cystic lesion of approximately 90 mm adjacent to the cecum. A retrospective review revealed that the cystic lesion had increased in size over time, and laparoscopic ileocecal resection was performed. Pathology revealed no continuity from the appendiceal orifice to the cyst, and a diagnosis of low-grade appendiceal mucinous neoplasm (LAMN) was made from the appendiceal tip remnant. The patient was discharged without complications. The second patient was a 65-year-old man who had undergone surgery for peritonitis due to severe appendicitis 21 years prior. During this operation, the appendix could not be clearly identified due to severe inflammation; consequently, cecal resection was performed. He was referred to our department with a chief complaint of general fatigue and loss of appetite and a cystic lesion of approximately 85 mm close to the cecum that had increased over time. CT showed irregular wall thickening, and malignancy could not be ruled out; therefore, laparoscopic ileocecal resection with D3 lymph node dissection was performed. The pathological diagnosis revealed mucinous adenocarcinoma (TXN0M0) arising from the remnant appendiceal tip. The patient is undergoing follow-up without postoperative adjuvant chemotherapy, with no evidence of pseudomyxoma peritonei or cancer recurrence for 32 months postoperatively.

Conclusions

If appendicitis-associated inflammation is sufficiently severe that accurate identification of the appendix is difficult, it may remain on the apical side of the appendix, even if the root of the appendix is ligated and removed. If the appendectomy is terminated incompletely, it is necessary to check for the presence of a residual appendix postoperatively and provide appropriate follow-up.
Elevated IRF9 raised cell apoptosis and tissue damages through suppressing SIRT1 in hyperlipidemia acute pancreatitis with liver injury
Authors: Pan Jin-Ge , Qin Ru-Xue , Ma Xue-Ying , Han Zi-Yu , Lu Zhong-Hua , Sun Yun , Yu Wei-Li
Published: June 2024

Background

Hyperlipidemia is a vital etiology of acute pancreatitis (AP), 12 to 20% of which have a history of hyperlipidemia. Multiple organ failure is the major cause of the high mortality rate of AP. Liver injury has been discovered in 80% of AP patients. The relationship and role of IRF9 and SIRT1 have not been presented in AP and hyperlipidemia AP (HLAP) with liver injury. This investigation was designed to explore the function and relationship of IRF9 and SIRT1.

Methods

HLAP model in vivo was performed by feeding high-fat forage and induced by peritoneal injection with 20% L-arginine. The severity of pancreas and liver tissues was assessed. Cell apoptosis in the liver was determined by the TUNEL experiment. IRF9, SIRT1, p53, and acetylated p53 (Ac-p53) expression levels in liver tissues were detected by qRT-PCR and Western blot. The association of IRF9 expression with SIRT1 levels was evaluated. The relevance of triglyceride level to tissue damage was analyzed.

Results

Our observation exhibited more distinct liver damage, a large number of hepatic cell apoptosis, marked raised IRF9, Ac-p53, and sharply dropped SIRT1 in the AP and HLAP groups. Compared with other groups, HLAP showed the most significant changes in liver injury, hepatic cell apoptosis, protein, and mRNA levels. The declined expression of SIRT1 was correlated with the elevated expression of IRF9. The damage of the pancreas and liver exacerbated with the increase in triglyceride levels.

Conclusion

Elevated IRF9 in pancreatitis with liver injury raised cell apoptosis and tissue damage by decreasing SIRT1 expression.
Reshaping the tumor microenvironment of cold soft-tissue sarcomas with anti-VEGFR targeted therapy: A Phase 2 Trial of Regorafenib combined with avelumab.
Authors: Italiano Antoine , Guegan Jean-Philippe , Valentin Thibaud , Bahleda Rastilav , Metges Jean Philippe , Cassier Philippe Alexandre , Toulmonde Maud , spalato-Ceruso Mariella , Peyraud Florent , Palussière Jean , Kind Michèle , Cantarel Coralie , Bellera Carine A. , Bessede Alban
Published: June 2024

11516

Background: Vascular Endothelial Growth Factor (VEGF)-driven angiogenesis is a pivotal factor in creating an immunosuppressive tumor microenvironment. Approximately 80% of Soft Tissue Sarcomas (STS) are characterized by a 'cold' microenvironment, lacking tertiary lymphoid structures (TLS). While the efficacy of VEGF pathway and PD-1/PD-L1 axis blockade has been established in various tumor types, their impact on 'cold' STS remains unexplored. This study aims to evaluate the synergistic effect of anti-angiogenesis and PD-1 blockade in altering the microenvironment of cold STS, potentially enhancing immune response and therapeutic efficacy. Methods: In this phase II, single-arm, open-label, multicentric trial, we explored the efficacy and safety of combining regorafenib (R) and avelumab (A) in advanced TLS-negative STS patients. Patients were administered 160 mg of R daily for 3 weeks in a 4-week cycle, alongside 10 mg/kg of A biweekly. Endpoints included high-throughput analysis of tumor and plasma samples, response rate, progression-free survival (PFS), overall survival (OS), and safety, as per the NCI-CTCAE v5.0 guidelines. Results: From May 2019 to August 2021, 49 TLS-negative STS patients were enrolled, including leiomyosarcoma (45%), synovial sarcoma (18%), and other subtypes. The median age was 57.1 years, with patients having undergone an average of 2 prior treatment lines. High-throughput analysis of sequential plasma samples indicated an upregulation of immune-inducing protein biomarkers such as CXCL10 and soluble CD8 antigen. Multiplex immunofluorescence analysis of sequential tumor samples revealed significant increase in CD8 T cell infiltration on-treatment. The most common severe adverse events were grade 1 or 2 palmar-plantar erythrodysesthesia, fatigue, and diarrhea. The median follow-up was 7.1 months, with 32.6% of patients experiencing tumor shrinkage, and a clinical benefit rate of 48.8%. The 6-month PFS was 22.1%, with a median OS of 15.1 months. Conclusions: The combination of regorafenib and avelumab demonstrates a marked mobilization of antitumor immunity in patients with TLS-negative STS. The observed efficacy appears superior to that of single-agent immune checkpoint inhibition in 'cold' STS, and higher than the 6-month PFS benchmark of 14% set by EORTC. This indicates the potential effectiveness of this treatment combination in managing advanced cold STS, marking a significant stride in precision immunotherapy for this group of tumors. Clinical trial information: NCT03475953 .
Immune infiltrate analysis to reveal distinct immune classes for leiomyosarcomas.
Authors: Gingrich Alicia , Beird Hannah , Lazcano Segura Rossana , Denu Ryan , Nakazawa Michael , Ratan Ravin , Livingston J. Andrew , Zarzour Maria Alejandra , Conley Anthony Paul , Somaiah Neeta , Araujo Dejka M. , Patel S Shreyaskumar , Roland Christina Lynn , Futreal Andrew , Lazar Alexander J. , Keung Emily Zhi-Yun , Nassif Haddad Elise F ,   Rare Tumor Initiative Team, Patient Mosaic Team
Published: June 2024

11546

Background: Leiomyosarcomas (LMS) are aggressive malignancies of smooth-muscle origin. Few targeted molecular options exist and immunotherapy (IO) agents against T cells have been disappointing. In this study, we examine the immune infiltrate of LMS tumors by immunohistochemistry (IHC) and gene expression. Our objective was to identify actionable targets for immunotherapy in patients with LMS. Methods: Tumor samples from a series of LMS patients were prospectively collected and banked for DNA and RNA sequencing as part of the MD Anderson Patient Mosaic. Associated clinical data for the patients were collected and maintained. IHC was performed on available separate tissue microarrays. Differential gene expression (DGE) analysis was done using the DESeq2 package for R and the Benjamini-Hochberg procedure used to control for false discovery rate. Immune cell fractions were estimated using the MCPcounter package. All gene expression analyses were repeated on The Cancer Genome Atlas (TCGA) dataset as an independent dataset. Results: A total of 104 TCGA samples and 72 samples from Mosaic from 53 patients with uterine or soft tissue LMS were included in the analysis. Tumors in the TCGA group were treatment naive. Of the samples in the Mosaic group, 61 (85%) had been previously treated with chemotherapy, 8 (11%) had been radiated, and 5 (7.5%) had been previously treated with immunotherapy. Thirty-one (43%) tumors were metastatic. Fifty-one (70%) were soft tissue LMS and 21 (30%) were uterine LMS. Four distinct immune classes were seen in both the TGCA and Mosaic: a predominantly B-cell group, a monocyte/macrophage group, a mixed infiltrate group and a group with a neutrophil signature. DGE performed between the subgroups revealed a unique gene expression pattern for tumors in the B cell and monocyte/macrophage subgroups. Interrogation of specific immune-associated genes revealed low levels of expression in the neutrophil group, suggesting this may be the most immunologically “cold” subset. Some of these results were reproduced by IHC using a TMA: the presence of a cluster of samples with B-cells and higher expression of immune checkpoints, a macrophage driven cluster, and an immunologically cold cluster. Conclusions: Analyses of LMS samples across two large datasets demonstrate the existence of 4 distinct immune classes of tumors that persist despite variation in clinical and treatment conditions: B cell, monocytic/macrophage, mixed-infiltrate and neutrophil rich. The B cell and monocytic groups have increased expression of immune markers which may be amenable to targeted therapies.
Do patients with myxofibrosarcoma and undifferentiated pleomorphic sarcoma have different clinical outcomes to immune checkpoint blockade-based therapy?
Authors: Rosenbaum Evan , Seier Kenneth , Bradic Martina , Desir Rhoena , Kelly Ciara Marie , Movva Sujana , Avutu Viswatej , Banks Lauren Baker , Chan Jason Earl , Chi Ping , Dickson Mark Andrew , Keohan Mary Louise , Gounder Mrinal M. , Maki Robert G. , Singer Samuel , Qin Li-Xuan , Antonescu Cristina R. , Tap William D. , D'Angelo Sandra P.
Published: June 2024

11567

Background: Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) are distinct histologic subtypes of soft tissue sarcoma that exist on a spectrum of dedifferentiation. Molecular analyses have found MFS and UPS to be indistinguishable, except for a higher expression of matrix-associated genes in MFS. While immune checkpoint blockade (ICB) is a recognized treatment option for UPS patients according to the National Comprehensive Cancer Network guidelines, clinical outcomes to ICB-based therapy in MFS have not been well described. Methods: The objectives of this study were to compare the overall response rate (ORR), progression free survival (PFS), and overall survival (OS) of MFS and UPS patients treated with ICB-based therapy. We retrospectively searched our clinical trial database for MFS and UPS patients treated at our Center with ICB-based therapy. Given the low number of MFS patients identified, we included any MFS patient treated with ICB-based therapy off-label. To determine whether MFS patients treated off-label differed from those treated on a study, a sensitivity analysis was performed comparing PFS and OS between these two groups. Kaplan Meier methods were used to analyze OS and PFS and log rank test was used to compare between groups. ORR were compared using Fisher’s exact test. Results: A total of 70 patients were included, 43 (61%) with UPS and 27 (39%) with MFS. All UPS patients and 13 MFS patients were treated on one of 8 different clinical trials, two utilized ICB alone and 6 combined ICB with another agent. Eleven of 14 (79%) MFS patients treated off-label received ICB alone; 3 (21%) received ICB plus another agent. Fifty-five patients treated on trials were assessed by RECIST 1.1 (12 MFS and 43 UPS). The median age of MFS patients was higher than UPS (69.5 and 57.2, respectively). Both cohorts were predominantly male (55.6% in MFS and 60.5% in UPS) and had a median of 1 prior line of therapy (range: 0 – 6 in MFS and 0 - 7 in UPS). The median myxoid component of baseline MFS tumors was 30% (range: 10 – 90%). Median PFS and OS (in months) and ORR (%) are outlined (Table). A sensitivity analysis within MFS did not find a significant difference between MFS patients treated off or on a clinical trial. Conclusions: In this retrospective analysis, clinical outcomes to ICB-based therapy did not differ between MFS and UPS patients. Based on these data, it may be reasonable to (a) consider ICB as a treatment option for unresectable or metastatic MFS refractory to standard chemotherapy and (b) group UPS and MFS together onto a single cohort in clinical studies of ICB-based therapy. [Table: see text]