bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dawn of CAR-T cell therapy in autoimmune diseases
Authors: Liu Yuxin , Dong Minghao , Chu Yunhui , Zhou Luoqi , You Yunfan , Pang Xiaowei , Yang Sheng , Zhang Luyang , Chen Lian , Zhu Lifang , Xiao Jun , Wang Wei , Qin Chuan , Tian Daishi 
Published: April 2024

AbstractChimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in the treatment of hematological malignancies. Based on the immunomodulatory capability of CAR-T cells, efforts have turned toward exploring their potential in treating autoimmune diseases. Bibliometric analysis of 210 records from 128 academic journals published by 372 institutions in 40 countries/regions indicates a growing number of publications on CAR-T therapy for autoimmune diseases, covering a range of subtypes such as systemic lupus erythematosus, multiple sclerosis, among others. CAR-T therapy holds promise in mitigating several shortcomings, including the indiscriminate suppression of the immune system by traditional immunosuppressants, and non-sustaining therapeutic levels of monoclonal antibodies due to inherent pharmacokinetic constraints. By persisting and proliferatingin vivo, CAR-T cells can offer a tailored and precise therapeutics. This paper reviewed preclinical experiments and clinical trials involving CAR-T and CAR-related therapies in various autoimmune diseases, incorporating innovations well-studied in the field of hematological tumors, aiming to explore a safe and effective therapeutic option for relapsed/refractory autoimmune diseases.
Integrated analysis of single-cell and bulk RNA sequencing to construct a CD8 + T cell-related immune gene signature in pancreatic cancer
Authors: Liu Yuzhi , Xu Fei , Jiang Anyi , Ding Jie , Li Chungao , Quan Ming 
Published: April 2024

Background:
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor that responds poorly to immunotherapy. The pivotal influence of CD8 + T-cell infiltration on immunotherapy has been documented in various solid tumors. However, the specific contribution of CD8 + T cell-associated immune genes (TIGs) to the tumor immune microenvironment remains unclear.

Methods:
We obtained CD8 + T cell-related immune genes from the INNATE and IMMPORT databases. Univariate analysis and lasso regression analysis were utilized to screen hub TIGs and develop a prognostic signature, the TIGs score. This score was used to evaluate prognosis, immunocyte infiltration, cancer-associated signaling pathways, and the potential responsiveness of immunotherapy. The transcriptomic data and single-cell data from the GSE183795 and GE212966 datasets are employed to validate the reliability of the findings.

Results:
Our findings suggest that patients with low TIGs scores have stronger immune effector functions and immune checkpoint activation, resulting in a more favorable response to PD-L1 inhibitors. TIGs scores were significantly correlated with various molecular characteristics and clinical outcomes, such as tumor mutation burden, multiple tumor-associated pathways, and chemotherapeutic drug sensitivity. PSME2 was identified as a potential prognostic biomarker for predicting survival in patients with PDAC.

Conclusions:
This study elucidates the intricate regulatory mechanisms of TIGs within the tumor immune microenvironment of pancreatic cancer. Our findings strongly suggest that the TIGs score is a robust prognostic marker for prognosis and immunotherapy responsiveness. Additionally, targeting PSME2 may offer a novel avenue for enhancing the effectiveness of immunotherapy in pancreatic cancer.
Potentially Modifiable Dementia Risk Factors in Canada: An Analysis of Canadian Longitudinal Study on Aging with a Multi-Country Comparison
Authors: Son Surim , Speechley Mark , Zou Guangyong , Kivipelto Miia , Mangialasche Francesca , Feldman Howard , Chertkow Howard , Belleville Sylvie , Nygaard Haakon , Hachinski Vladimir , Pieruccini-Faria F , Montero-Odasso Manuel 
Published: April 2024

AbstractBACKGROUNDPrevious estimates suggested that up to 40% of dementia cases worldwide are associated with modifiable risk factors, however, these estimates are not known in Canada. Furthermore, sleep disturbance, an emerging factor, has not been incorporated into the life-course model of dementia prevention.ObjectiveTo estimate the population impact of 12 modifiable risk factors in Canadian adults including sleep disturbance, by sex and age groups, and to compare with other countries.DesignCross-sectional analysis of Canadian Longitudinal Study on Aging Baseline dataSettingCommunityParticipants30,097 adults aged 45 years and older.MeasurementsPrevalence and Population Attributable Fraction (PAF) of less education, hearing loss, traumatic brain injury, hypertension, excessive alcohol, obesity, smoking, depression, social isolation, physical inactivity, diabetes, and sleep disturbance.ResultsThe risk factors with the largest PAF were later life physical inactivity (10.2%; 95% CI, 6.8% to 13%), midlife hearing loss (6.5%; 3.7% to 9.3%), midlife obesity (6.4; 4.1% to 7.7%), and midlife hypertension (6.2%; 2.7% to 9.3%). The PAF of later life sleep disturbance was 3.0% (95% CI, 1.8% to 3.8%). The 12 risk factors accounted for 51.9% (32.2% to 68.0%) of dementia among men and 52.4% (32.5% to 68.7%) among women. Overall, the combined PAF of all risk factors was 49.2% (31.1% to 64.9%), and it increased with age.ConclusionNearly up to 50% of dementia cases in Canada could be prevented by modifying the 12 risk factors across the lifespan. Canadian risk reduction strategies should prioritize targeting physical inactivity, hearing loss, obesity, and hypertension.
Personalized CZA-ATM dosing against an XDRE. coliin liver transplant patients; the application of thein vitrohollow fibre infection model (HFIM)
Authors: Sadouki Zahra , Wey Emmanuel Q. , Iype Sateesh , Nasralla David , Potts Jonathan , Spiro Mike , Williams Alan , McHugh Timothy D. , Kloprogge Frank 
Published: April 2024

AbstractBackground & aimsAn extensively-drug resistant (XDR) NDM and OXA-48 producingE. colicontributing to repeat episodes of biliary sepsis was isolated from the blood stream of a 45-55 year-old male with a background of IgG4 related sclerosing cholangitis. The patient was awaiting orthotopic liver transplant (OLT). There is no standardized antibiotic prophylaxis regimen however in line with the Infectious Diseases Society of America (IDSA) guidance an antibiotic prophylactic regimen of Ceftazidime-Avibactam (CZA) 2.5g TDS with Aztreonam (ATM) 2g TDS IV was proposed.MethodsTo inform the individualised pharmacodynamic outcome likelihood prior to prophylaxis dosing the hollow fibre infection model (HFIM) was applied to simulate thein vivoantibiotic exposures of the CZA-ATM regimen. The HFIM was inoculated with ∼10 x 105bacterial CFU/mL of the XDRE. colistrain and CFUs/mL were measured for a total of 120 hours to determine thein vitroPK/PD killing dynamics.ResultsA 4-log reduction in CFU/mL in the first ten hours of the regimen exposure was observed however the killing dynamics were slow and six eight-hourly infusions were required to reduce bacterial cells to below the limit of quantification. Thus, the HFIM supported the use of the regimen for infection clearance however highlighted the need for several infusions. Standard local practise is to administer prophylaxis antibiotics at induction of OLT however the HFIM provided data to rationalise earlier dosing therefore the patient was dosed at 24 hours prior to their OLT induction. The patient was subsequently discharged 8 days after surgery.ConclusionsThe HFIM provides a dynamic culture solution for informing individualised medicine by testing antibiotic combinations and exposures against the bacterial isolates cultured from the patient’s infection.
Partnering for Progress: Lessons Learned from a Mental Health Assessment for Youth Living with HIV in India through Community-Based Participatory Research
Authors: Sannigrahi Siddhaparna , Seenappa Babu , Laxmikanth Prashant , Reddy Suhas , Filian Kacie , Raj Michael Babu , Ganapathi Lakshmi , Shet Anita 
Published: April 2024

ABSTRACTYLHIV face diverse mental health challenges necessitating interventions informed by their lived experiences. Failure to do so can perpetuate a self-reinforcing cycle of misaligned and ineffective support, further exacerbating existing vulnerabilities. This study directly addresses this gap by using a community-based participatory research (CBPR) approach to empower Youth Living with HIV (YLHIV) in India to address their mental health challenges. YLHIV actively participated in adapting and implementing a culturally responsive mental health screening program. The study, incorporating CBPR principles at every step aimed to identify practical methods for integrating YLHIV voices in research, and showcase the value of YLHIV participation in co-creating and implementing impactful interventions. Six youth investigators aged 18-24, born with HIV and residing in southern Indian states underwent certification in human subjects’ protection and training in mental health screening and survey administration techniques. They actively shaped the research process by culturally adapting standardized mental health screening tools (PHQ-9, GAD-7) through iterative discussions with experts, drawing on their own perspectives. Following field assessments of the mental health screening tools among their peers, they documented their reflections in surveys and written essays. Youth investigators’ involvement improved the research process by optimizing tools, combating stigma, and facilitating reliable data collection. Beyond data collection, the youth investigators’ participation significantly boosted their own knowledge, self-confidence, and research skills. This study serves as an illustrative model of CBPR in mental health research among YLHIV, highlighting the importance of interactive training, continuous feedback mechanisms, and respectful youth engagement in fostering impactful research that can inform tailored sustainable interventions.
Deep generative AI models analyzing circulating orphan non-coding RNAs enable accurate detection of early-stage non-small cell lung cancer
Authors: Karimzadeh Mehran , Momen-Roknabadi Amir , Cavazos Taylor B. , Fang Yuqi , Chen Nae-Chyun , Multhaup Michael , Yen Jennifer , Ku Jeremy , Wang Jieyang , Zhao Xuan , Murzynowski Philip , Wang Kathleen , Hanna Rose , Huang Alice , Corti Diana , Nguyen Dang , Lam Ti , Kilinc Seda , Arensdorf Patrick , Chau Kimberly H. , Hartwig Anna , Fish Lisa , Li Helen , Behsaz Babak , Elemento Olivier , Zou James , Hormozdiari Fereydoun , Alipanahi Babak , Goodarzi Hani 
Published: April 2024

AbstractLiquid biopsies have the potential to revolutionize cancer care through non-invasive early detection of tumors, when the disease can be more effectively managed and cured. Developing a robust liquid biopsy test requires collecting high-dimensional data from a large number of blood samples across heterogeneous groups of patients. We propose that the generative capability of variational auto-encoders enables learning a robust and generalizable signature of blood-based biomarkers that capture true biological signals while removing spurious confounders (e.g., library size, zero-inflation, and batch effects). In this study, we analyzed orphan non-coding RNAs (oncRNAs) from serum samples of 1,050 individuals diagnosed with non-small cell lung cancer (NSCLC) at various stages, as well as sex-, age-, and BMI-matched controls to evaluate the potential use of deep generative models. We demonstrated that our multi-task generative AI model, Orion, surpassed commonly used methods in both overall performance and generalizability to held-out datasets. Orion achieved an overall sensitivity of 92% (95% CI: 85%–97%) at 90% specificity for cancer detection across all stages, outperforming the sensitivity of other methods such as support vector machine (SVM) classifier, ElasticNet, or XGBoost on held-out validation datasets by more than ∼30%.
Discovering mechanisms underlying medical AI prediction of protected attributes
Authors: Gadgil Soham , DeGrave Alex J. , Daneshjou Roxana , Lee Su-In 
Published: April 2024

AbstractRecent advances in Artificial Intelligence (AI) have started disrupting the healthcare industry, especially medical imaging, and AI devices are increasingly being deployed into clinical practice. Such classifiers have previously demonstrated the ability to discern a range of protected demographic attributes (like race, age, sex) from medical images with unexpectedly high performance, a sensitive task which is difficult even for trained physicians. Focusing on the task of predicting sex from dermoscopic images of skin lesions, we are successfully able to train high-performing classifiers achieving a ROC-AUC score of ∼0.78. We highlight how incorrect use of these demographic shortcuts can have a detrimental effect on the performance of a clinically relevant downstream task like disease diagnosis under a domain shift. Further, we employ various explainable AI (XAI) techniques to identify specific signals which can be leveraged to predict sex. Finally, we introduce a technique to quantify how much a signal contributes to the classification performance. Using this technique and the signals identified, we are able to explain ∼44% of the total performance. This analysis not only underscores the importance of cautious AI application in healthcare but also opens avenues for improving the transparency and reliability of AI-driven diagnostic tools.
Protocol for the development and validation of a Rheumatoid Arthritis PredIction moDel using primary care health records (RAPID)
Authors: Hammond Ben , Baranskaya Aliaksandra , Adderley Nicola , Zemedikun Dawit , d’Elia Alexander , Falahee Marie , Mallen Christian , Insch Elspeth , Chandan Joht Singh , Nirantharakumar Krishnarajah , Snell Kym , Raza Karim 
Published: April 2024

AbstractBackgroundRheumatoid Arthritis (RA) is a chronic rheumatological condition which causes inflammation of both the joint lining and extra-articular sites. It affects around 1% of the UK population and, if not properly treated, can lead joint damage, disability, and significant socioeconomic burden. The risk of long-term damage is reduced if treatment is started in an early disease stage with treatment in the first 3 months being associated with significantly improved clinical outcomes. However, treatment is often delayed due to long referral waits and challenges in identifying early RA in primary care. We plan to use large primary care datasets to develop and validate an RA risk prediction model for use in primary care, with the aim to provide an additional mechanism for early diagnosis and referral for treatment.MethodsWe identified candidate predictors from literature review, expert clinical opinion, and patient research partner input. Using coded primary care data held in Clinical Practice Research Datalink (CPRD) Aurum, we will use a time to event Cox proportional hazards model to develop a 1-year risk prediction model for RA. This will be validated first in CPRD GOLD and then independently in the Secure Anonymised Information Linkage dataset. We will also conduct a sensitivity analysis for the same model at 2–5-year risk, with a secondary outcome of RA and initiation of a disease modifying drug, and with the addition of laboratory test results as candidate predictors.DiscussionThe resulting risk prediction model may provide an additional mechanism to distinguish early RA in primary care and reduce treatment delays through earlier referral.
Consensus Guideline for the Management of Malignant Gastrointestinal Obstruction in Patients with Peritoneal Surface Malignancies
Authors:   PSM Writing Group,   PSM Consortium Group, Turaga Kiran K. 
Published: April 2024

AbstractBackgroundMalignant gastrointestinal obstruction (MGIO), a frequent complication of peritoneal surface malignancies (PSM), often portends a poor prognosis. The lack of high-quality evidence on optimal management strategies necessitated a national consensus to address this clinical problem.MethodsA clinical management pathway was designed through a Delphi consensus process with national experts in peritoneal disease. Two rounds of voting were conducted to assess agreement levels with pathway blocks. Supporting evidence regarding procedural interventions for MGIO underwent evaluation via a rapid literature review.ResultsOf 111 participants responding in the first round, 90 (81%) responded in the second round. Over 90% consensus was achieved in 4/6 and 6/6 pathway blocks during rounds I and II, respectively. Encouraging a multidisciplinary approach, the pathway emphasized early palliative care assessments and iterative goals of care evaluation throughout treatment. Management was delineated based on obstruction acuity, and selection criteria for palliative-intent surgical interventions and stenting were elucidated. Studies demonstrated limited benefits for such interventions in patients with multifocal obstructions, poor performance status, and high-grade and/or high-burden PSMs. In these cases, a recommendation for supportive care or upper GI decompression tube placement was favored. The overall level of evidence was generally low-moderate in existing literature.ConclusionGiven limited evidence, the consensus-driven pathway provides crucial clinical guidance for practitioners dealing with MGIO in PSM patients. There is a need for high-quality prospective evidence in this domain.
Spatial and single-cell transcriptomics onSSPOPTV mutant mice reveals SCO-spondin’s function in mood regulation through brain barriers
Authors: Gao Yue , Xu Jiahui , Li Shuangyan , Yi Wenjuan , Xiao Liuyan , Feng Fei , Zhang Bin , Li Jiahui , Yang Xinping 
Published: April 2024

AbstractThe schizoaffective disorder presents mixed symptoms of schizophrenia and a mood disorder, posing an enormous challenge to its taxonomy and etiology. A recent hypothesis proposes independent genetic risk components from schizophrenia and affective disorders. By whole exome sequencing of a family with schizoaffective disorder, we identified four genes with protein-truncating variants (PTVs) that fit autosomal dominant inheritance model. Among these four genes,SSPO(encoding SCO-spondin) has exclusive expression in the subcommissural organ (SCO), a functionally highly intriguing organ in the brain, known to be potentially involved in CSF homeostasis. We generated a knock-in mouse model for the identified PTV ofSSPO, and the mutant mice exhibited enhanced anxiety-like and anti-depression-like behaviors. We further performed multilayer transcriptomics analyses on the mouse brain, and found that the genes involved in stress response, anxiety, depression and bipolar disorder are dysregulated in the SCO and brain barriers, which have direct contact with CSF. Several cell-cell communication pathways involving brain barrier cells, including the WNT signaling pathways, are altered in the mutant mice. Our results demonstrate that SCO-spondin plays a key role in stress response and mood regulation through modulating brain barriers, and thus strongly suggest that the PTV ofSSPOmay contribute to the affective symptoms of schizoaffective disorder.
Consensus guideline for the management of patients with appendiceal tumors Part 1: Appendiceal tumors without peritoneal involvement
Authors:   PSM Appendiceal Tumor Writing Group,   PSM Consortium Group, Turaga Kiran K 
Published: April 2024

AbstractBackgroundAppendiceal tumors comprise a heterogeneous group of tumors which may be localized or disseminate throughout the peritoneum. Limited high quality clinical data exists and many practices have been extrapolated from colorectal cancer without validation in appendiceal cohorts. Many controversies exist regarding their treatment, and practices vary widely between centers and care settings. A national consensus update of best management practices for appendiceal malignancies was performed to better standardize care.MethodsThe 2018 Chicago consensus guideline was updated via modified Delphi consensus, performed over two rounds using nationally circulated surveys. Supporting evidence was evaluated using rapid systematic reviews. Key systemic therapy concepts were summarized by content experts.ResultsMost supporting literature consists of observational studies, but increasingly high-quality studies are becoming available to drive management. Two consensus-based pathways were generated for localized appendiceal tumors, one for epithelial mucinous neoplasms and another for appendiceal adenocarcinoma. Of 138 participants responding in the first round, 133 (96%) engaged in the second round. Over 90% consensus was achieved for all pathway blocks. Key points include minimizing intervention invasiveness where permitted by pathologic classification and margin status, and determining what margin and pathologic findings are indications for consideration of cytoreduction with or without intraperitoneal chemotherapy. Surveillance and systemic therapy recommendations are also presented.ConclusionWith growing but still primarily observational evidence currently dictating care, these consensus recommendations provide expert guidance in the treatment of appendiceal tumors without peritoneal involvement.
Synaptic gene expression changes in frontotemporal dementia due to theMAPT10+16 mutation
Authors: Dando Owen , McGeachan Robert , McQueen Jamie , Baxter Paul , Rockley Nathan , McAlister Hannah , Prasad Adharsh , He Xin , King Declan , Rose Jamie , Jones Phillip B , Tulloch Jane , Chandran Siddharthan , Smith Colin , Hardingham Giles , Spires-Jones Tara L 
Published: April 2024

AbstractMutations in theMAPTgene encoding tau protein can cause autosomal dominant neurodegenerative tauopathies including frontotemporal dementia (often with Parkinsonism). In Alzheimer’s disease, the most common tauopathy, synapse loss is the strongest pathological correlate of cognitive decline. Recently, PET imaging with synaptic tracers revealed clinically relevant loss of synapses in primary tauopathies; however, the molecular mechanisms leading to synapse degeneration in primary tauopathies remain largely unknown. In this study, we examined post-mortem brain tissue from people who died with frontotemporal dementia with tau pathology (FTDtau) caused by theMAPTintronic exon 10+16 mutation, which increases splice variants containing exon 10 resulting in higher levels of tau with four microtubule binding domains. We used RNA sequencing and histopathology to examine temporal cortex and visual cortex, to look for molecular phenotypes compared to age, sex, and RNA integrity matched participants who died without neurological disease (n=12 per group). Bulk tissue RNA sequencing reveals substantial downregulation of gene expression associated with synaptic function. Upregulated biological pathways in humanMAPT10+16 brain included those involved in transcriptional regulation, DNA damage response, and neuroinflammation. Histopathology confirmed increased pathological tau accumulation in FTDtau cortex as well as a loss of presynaptic protein staining, and region-specific increased colocalization of phospho-tau with synapses in temporal cortex. Our data indicate that synaptic pathology likely contributes to pathogenesis in FTDtau caused by theMAPT10+16 mutation.