bluuebunny/crossref_metadata_2025_split huggingface dataset:
Button battery exposure in children: a systematic review and meta-analysis
Authors: Tran Christopher , Nunez Carlos , Eslick Guy D , Barker Ruth , Elliott Elizabeth J 
Published: October 2024

BackgroundThere is a rising burden of severe and fatal outcomes resulting from button battery exposures (ingestions or insertions). We summarised current evidence following button battery exposures in children and provided pooled prevalence estimates for key clinical characteristics, complications and risk estimates for predictors.MethodsMEDLINE, Embase and Scopus databases were searched up to 19 May 2023. Included studies described complications of button battery exposures in children aged <18 years and reported prevalence data, an OR estimate or allowed OR calculation. Random effects models were used to estimate pooled estimates and event rates.FindingsForty-four articles (3125 children) were included in the analysis. Battery exposures were more common in males (59%) and young children. For ingestions, batteries were most often located in the stomach (43%). Mucosal damage (46%) and oesophageal stricture (10%) were the most common complications. Most (60%) children were asymptomatic at presentation. When symptoms were present, vomiting (26%) and dysphagia (18%) were the most common. Duration of ingestion to removal increased the likelihood of any complication; OR 3.71 (95% CI 1.11 to 12.42) for ≥10 hours and 5.12 (95% CI 1.79 to 14.67) for ≥12 hours. Battery diameter ≥20 mm was associated with any complication OR 4.34 (95% CI 1.16 to 16.27) and oesophageal location OR 18.66 (95% CI 6.99 to 49.82). Death was associated with oesophageal impaction OR 15.52 (95% CI 2.40 to 100.27). For insertions, nasal septal perforation was the most common complication (13%).InterpretationButton batteries are a potentially fatal domestic hazard particularly for young children. Increased prevention efforts through safer battery design are needed to mitigate this risk.
Person-focused interventions for fall risk assessment, fall prevention and fall injury prevention in long-term care facilities: a scoping review
Authors: Jung Wonkyung , Lim Sungwon , Wi Dahee , Ustach Andrew , Thompson Hilaire J 
Published: October 2024

ObjectiveFalls are a significant concern in long-term care facilities (LTCFs) as fall-related injuries can result in functional impairment, disability and death. Older adults living in LTCFs are at greater risk for falls than those in the community. Using scoping review methodology, we aimed to synthesise evidence examining intervention effects of person-focused interventions for risk assessment and prevention in LTCFs in order to identify evidence-based practices in LTCFs.MethodsWe included three databases (Ovid-Medline, CINAHL and EMBASE) to identify original research from 2007 to 2022 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guideline. From the initial search, we identified 988 articles. Following the removal of duplicates, title and abstract screening, and full-text review against inclusion/exclusion criteria, 20 studies remained for analysis. Then, we conducted a narrative synthesis to summarise the included studies.ResultsIdentified evidence-based interventions for fall prevention include (1) exercise programmes (eg, high-intensity functional exercise, aerobic exercise, short stick exercises, etc); (2) multifactorial programmes; and (3) other interventions (eg, lavender olfactory stimulation). Outcomes of included studies included the number of falls, fall rate, risk of falls and fear of falls before and after interventions.ConclusionOverall, most studies reported significant effects of person-focused interventions in LTCFs. Available evidence supports that well-designed person-focused interventions can reduce falls and fear of falls for individuals in LTCFs.
PARP inhibitors enhance antitumor immune responses by triggering pyroptosis via TNF–caspase 8–GSDMD/E axis in ovarian cancer
Authors: Xia Yu , Huang Pu , Qian Yi-yu , Wang Zanhong , Jin Ning , Li Xin , Pan Wen , Wang Si-Yuan , Jin Ping , Drokow Emmanuel Kwateng , Li Xiong , Zhang Qi , Zhang Zhengmao , Li Pingfei , Fang Yong , Yang Xiang-Ping , Han Zhiqiang , Gao Qing-lei 
Published: October 2024

BackgroundIn addition to their established action of synthetic lethality in tumor cells, poly(ADP-ribose) polymerase inhibitors (PARPis) also orchestrate tumor immune microenvironment (TIME) that contributes to suppressing tumor growth. However, it remains not fully understood whether and how PARPis trigger tumor-targeting immune responses.MethodsTo decode the immune responses reshaped by PARPis, we conducted T-cell receptor (TCR) sequencing and immunohistochemical (IHC) analyses of paired clinical specimens before and after niraparib monotherapy obtained from a prospective study, as well as ID8 mouse ovarian tumors. To validate the induction of immunogenic cell death (ICD) by PARPis, we performed immunofluorescence/IHC staining with homologous recombination deficiency tumor cells and patient-derived xenograft tumor tissues, respectively. To substantiate that PARPis elicited tumor cell pyroptosis, we undertook comprehensive assessments of the cellular morphological features, cleavage of gasdermin (GSDM) proteins, and activation of TNF-caspase signaling pathways through genetic downregulation/depletion and selective inhibition. We also evaluated the critical role of pyroptosis in tumor suppression and immune activation following niraparib treatment using a syngeneic mouse model with implanting CRISPR/Cas9 editedGsdme−/−ID8 tumor cells into C57BL/6 mice.ResultsOur findings revealed that PARPis augmented the proportion of neoantigen-recognized TCR clones and TCR clonal expansion, and induced an inflamed TIME characterized by increased infiltration of both innate and adaptive immune cells. This PARPis-strengthened immune response was associated with the induction of ICD, specifically identified as pyroptosis, which possessed distinctive morphological features and GSDMD/E cleavage. It was validated that the cleavage of GSDMD/E was due to elevated caspase 8 activity downstream of the TNFR1, rather than FAS and TRAIL-R. On PARP inhibition, the NF-κB signaling pathway was activated, leading to increased secretion of TNF-α and subsequent initiation of the TNFR1–caspase 8 cascade. Impeding pyroptosis through the depletion ofGsdmesignificantly compromised the tumor-suppressing effects of PARP inhibition and undermined the anti-immune response in the syngeneic ID8 mouse model.ConclusionsPARPis induce a specific type of ICD called pyroptosis via TNF–caspase 8–GSDMD/E axis, resulting in an inflamed TIME and augmentation of tumor-targeting immune responses. These findings deepen our understanding of PARPis activities and point toward a promising avenue for synergizing PARPis with immunotherapeutic interventions.Trial registration numberNCT04507841.
Vaccination generates functional progenitor tumor-specific CD8 T cells and long-term tumor control
Authors: Detrés Román Carlos R , Erwin Megan M , Rudloff Michael W , Revetta Frank , Murray Kristen A , Favret Natalie R , Roetman Jessica J , Roland Joseph T , Washington Mary K , Philip Mary 
Published: October 2024

BackgroundImmune checkpoint blockade (ICB) therapies are an important treatment for patients with advanced cancers; however, only a subset of patients with certain types of cancer achieve durable remission. Cancer vaccines are an attractive strategy to boost patient immune responses, but less is known about whether and how immunization can induce long-term tumor immune reprogramming and arrest cancer progression. We developed a clinically relevant genetic cancer mouse model in which hepatocytes sporadically undergo oncogenic transformation. We compared how tumor-specific CD8 T cells (TST) differentiated in mice with early sporadic lesions as compared with late lesions and tested how immunotherapeutic strategies, including vaccination and ICB, impact TST function and liver cancer progression.MethodsMice with a germline floxed allele of the SV40 large T antigen (TAG) undergo spontaneous recombination and activation of the TAG oncogene, leading to rare early cancerous TAG-expressing lesions that inevitably progress to established liver cancer. We assessed the immunophenotype (CD44, PD1, TCF1, and TOX expression) and function (TNFα and IFNγ cytokine production) of tumor/TAG-specific CD8 T cells in mice with early and late liver lesions by flow cytometry. We vaccinated mice, either alone or in combination with ICB, to test whether these immunotherapeutic interventions could stop liver cancer progression and improve survival.ResultsIn mice with early lesions, a subset of TST were PD1+TCF1+TOX−and could produce IFNγ while TST present in mice with late liver cancers were PD1+TCF1lo/−TOX+and unable to make effector cytokines. Strikingly, vaccination with attenuated TAG epitope-expressingListeria monocytogenes(LMTAG) blocked liver cancer development and led to a population of TST that were PD1-heterogeneous, TCF1+TOX−and polyfunctional cytokine producers. Vaccine-elicited TCF1+TST could self-renew and differentiate, establishing them as progenitor TST. In contrast, ICB administration did not slow cancer progression or improve LMTAGvaccine efficacy.ConclusionVaccination, but not ICB, generated a population of functional progenitor TST and halted cancer progression in a clinically relevant model of sporadic liver cancer. In patients with early cancers or at high risk of cancer recurrence, immunization may be the most effective strategy.
Toripalimab in combination with HBM4003, an anti-CTLA-4 heavy chain-only antibody, in advanced melanoma and other solid tumors: an open-label phase I trial
Authors: Tang Bixia , Chen Yu , Jiang Yu , Fang Meiyu , Gao Quanli , Ren Xiubao , Yao Li , Huang Gang , Chen Jing , Zhang Xiaoshi , Li Rongqing , Zhao Shuai , Gao Meijuan , Luo Ruixuan , Qi Meng , Li Feng , Zheng Fei , Lee Michael , Tao Xiaolu , Duan Rong , Guo Jun , Chi Zhihong , Cui Chuanliang 
Published: October 2024

BackgroundHBM4003 is a novel anti-CTLA-4 heavy chain-only antibody, designed to enhance Treg ablation and antibody-dependent cell-mediated cytotoxicity while ensuring a manageable safety profile. This phase I trial investigated the safety, pharmacokinetics, immunogenicity and preliminary efficacy of HBM4003 plus with anti-PD-1 antibody toripalimab in patients with advanced solid tumors, especially focusing on melanoma.MethodsThe multicenter, open-label phase I trial was divided into two parts: dose-escalation phase (part 1) and dose-expansion phase (part 2). In part 1, HBM4003 was administered at doses of 0.03, 0.1, 0.3 mg/kg in combination with toripalimab with fixed dosage of 240 mg every 3 weeks. The recommended phase II dose (RP2D) was used in the expansion phase. Primary endpoints were safety and RP2D in part 1 and objective response rate (ORR) in part 2. Biomarkers based on cytokines and multiplex immunofluorescence staining were explored.ResultsA total of 40 patients received study treatment, including 36 patients treated with RP2D of HBM4003 0.3 mg/kg plus toripalimab 240 mg every 3 week. 36 participants (90.0%) experienced at least one treatment-related adverse event (TRAE), of which 10 (25.0%) patients experienced grade ≥3 TRAEs and 5 (12.5%) experienced immune-mediated adverse events (irAEs) with maximum severity of grade 3. No grade 4 or 5 irAEs occurred. Efficacy analysis set included 32 melanoma patients treated with RP2D and with available post-baseline imaging data. The ORRs of anti-PD-1/PD-L1 treatment-naïve subgroup and anti-PD-1/PD-L1 treatment-failed subgroup were 33.3% and 5.9%, respectively. In mucosal melanoma, the ORR of the two subgroups were 40.0% and 10.0%, respectively. Baseline high Treg/CD4+ratio in the tumor serves as an independent predictive factor for the efficacy of immunotherapy.ConclusionsHBM4003 0.3 mg/kg plus toripalimab 240 mg every 3 week demonstrated manageable safety in solid tumors and no new safety signal. Limited data demonstrated promising antitumor activity, especially in PD-1 treatment-naïve mucosal melanoma.Trial registration numberNCT04727164.
Antigen-independent activation is critical for the durable antitumor effect of GUCY2C-targeted CAR-T cells
Authors: Qi Changsong , Liu Dongqun , Liu Chang , Wei Xiaofei , Ma Mingyang , Lu Xinan , Tao Min , Zhang Cheng , Wang Xicheng , He Ting , Li Jian , Dai Fei , Ding Yanping , Shen Lin 
Published: October 2024

BackgroundChimeric antigen receptor (CAR)-T cells face many obstacles in solid tumor therapy, including heterogeneous antigen expression and inefficient T cell persistence. Guanylyl cyclase C (GUCY2C) has been identified as a suitable tumor antigen for targeted therapy due to its intestinal-restricted expression pattern in normal tissues and steady overexpression in gastrointestinal tumors, especially colorectal cancer. An antigen-sensitive and long-lasting CAR-T cell targeting GUCY2C was investigated in this study.MethodsUsing constructed tumor cell lines with various GUCY2C expression densities, we screened out an antigen-sensitive single chain variable fragment (scFv) that enabled CAR-T cells to efficiently eradicate the GUCY2C lowly expressed tumor cells. CAR-T cells with different compositions of the hinge, transmembrane and costimulatory domains were also constructed for selection of the long-lasting CAR-T format with durable antitumor efficacy in vitro and in tumor-bearing mice. The underlying mechanism was further investigated based on mutation of the hinge and transmembrane domains.ResultsWe found that the composition of the antigen-sensitive scFv, CD8α hinge, CD8α transmembrane, and CD28 costimulatory domains boosted CAR-T cells to rapidly kill tumors, maintain high expansion capacity, and long-term efficacy in various colorectal cancer models. The durable antitumor function was attributed to the optimal CAR tonic signaling that conferred CAR-T cells with autonomous activation, proliferation, survival and cytokine release in the absence of antigen stimulation. The tonic signaling was associated with the length and the cysteine residues in the CD8α hinge and transmembrane domains.ConclusionsThis study demonstrated a potent GUCY2C-targeted CAR-T cell for gastrointestinal tumor therapy and highlights the importance of adequate tonic signaling for effective CAR-T cell therapy against solid tumors.
INVESTIGATION ON THE STRENGTH OF E-GLASS FIBER/AA5052-H32 FIBER METAL LAMINATES CONNECTED USING RIVETED JOINTS
Authors: RAJESH M. ESAI , ESAKKIMUTHU S. , MOSHI A. ARUL MARCEL , LOGESH K. 
Published: October 2024

Fiber metal laminates (FMLs) belong to a class of composite materials comprising layers of metal sheets and fiber-reinforced polymers (FRP), configured in a specific sequence. This study investigates the tensile strength of FML specimens joined by riveted joints. FML plates were fabricated using AA5052 aluminium alloy, E-glass fibers, epoxy resin, and layered double hydroxide (LDH) via a hand layup process. The experimental parameters included the pattern of rivets, type of rivet materials, and rivet size. Tensile strength, the output response, was evaluated using Taguchi’s L9 orthogonal array design, followed by testing on a universal testing machine. The main effect plot and 3D surface plots were employed to analyze the tensile test results. Maximum tensile strength was held by the test specimen which was connected by the rivets made up of mild steel. From the ANOVA results presented in Table 6 , it was inferred that the number of rivets used for joining the FML specimens (pattern) played a major role in deciding the tensile strength of the specimens (57.25%). A regression equation, derived from Design Expert software, established the relationship between input variables and the tensile strength of FML specimens. ANOVA was conducted to assess the impact of each process variable on achieving optimal tensile strength. This research contributes novelty by integrating LDH into FML fabrication and demonstrates practical significance through systematic optimization of riveting parameters to enhance tensile strength. Quantitative and qualitative analyses underscore the effectiveness of the proposed FML configuration, validating its potential for structural applications.
Measuring and Modifying Threat‐Related Attention Bias in Posttraumatic Stress Disorder: An Attention Bias Modification Study
Authors: Rubin Mikael , Niles Andrea , Evans Travis , Tripp Paige , Neylan Thomas C. , Woolley Joshua , O’Donovan Aoife 
Published: October 2024

Background: Dominant models of posttraumatic stress disorder (PTSD) implicate threat‐related attention biases in both the development and maintenance of posttraumatic stress symptoms. However, the ability to better understand and modify threat‐related attention biases in PTSD has been hampered by the low reliability of attention bias measures more generally.Methods: The current study adopts a new approach to calculate attention bias from a dot‐probe task, response‐based attention bias (RB‐AB) computation, in a sample of 689 individuals reporting significantly elevated PTSD symptoms who participated in a clinical trial of threat‐related attention bias modification training.Results: RB‐AB is a reliable strategy for deriving threat‐related attention bias scores that correlate with both PTSD severity and anxiety. On the other hand, scores from the traditional approach were unreliable and not associated with clinical symptoms. Attention training led to reductions in RB‐AB indices of attention bias, but not the traditional index, although attention bias training conditions did not appear to moderate these effects.Conclusions: Taken together, these findings support evidence that threat‐related attention biases may be a feature of PTSD and that RB‐AB computation is a more reliable and valid approach for studying reaction‐time‐based attentional processes. Using the RB‐AB approach to assess attention bias could allow us to better understand threat‐related attention biases in PTSD and to ultimately develop more precise interventions to reduce threat‐related attentional biases in PTSD and other disorders.
Utilization of Anal Cytology Screening among Sexual and Gender Minority Populations in Pennsylvania
Authors: Bennis Sarah L. , Arsoniadis Elliot G. , Wheldon Christopher W. 
Published: October 2024

Abstract

Background:
Despite the risk of anal cancer in sexual and gender minority (SGM) populations, anal cancer screening remains infrequent and inconsistent in these populations. The objective of this analysis was to identify factors associated with anal cancer screenings among SGM populations using the Andersen’s behavioral model of health services use.

Methods:
Secondary analyses of two cross-sectional surveys from the 2020 (N = 1,125) and 2022 (N = 630) Pennsylvania LGBTQ Health Needs Assessment. Multiple logistic regression analyses were used to identify correlates of anal cytology screening.

Results:
Average age was 37.7 (SD = 13.3) and 39.7 (SD = 13.6) in 2020 and 2022, respectively. Approximately 16% to 18% reported living with human immunodeficiency virus (HIV). A minority of respondents reported past year screening (14.0%, 2020 and 13.6%, 2022). Enabling and need-based factors consistently associated with screening included sexually transmitted infection treatment, living with HIV, preexposure prophylaxis use, and multiple sex partners. Robust factors associated with ever being screened were age and living with HIV.

Conclusions:
Anal cytology screening is being done in Pennsylvania at a small but not insignificant rate. In accordance with existing guidelines, SGM populations living with HIV were most likely to be screened, but still at a low rate. Predictive factors associated with screening in this study can inform future interventions to implement guideline-specific anal cancer prevention.

Impact:
Factors that reflect consistent connection to healthcare are associated with increased rates of screening via anal cytology testing, indicating there are opportunities to implement anal cancer screening as part of a larger, more comprehensive SGM-focused care pathway.
Vitamin A Metabolism and Resistance of Hepatic Metastases to Immunotherapy
Authors: Jones Peter C. , Von Hoff Daniel D. 
Published: October 2024

Abstract
The liver is an immune-tolerant organ, allowing for organ transplantation with less immune suppression compared with other organs. It also provides fertile soil for tumor metastases, which tend to be more resistant to checkpoint blockade immunotherapy than metastases in other organs. This resistance may result from the sum of incremental evolutionary adaptions in various cell types to prevent overaction to antigens absorbed from the gut into the portal circulation or it might involve a central mechanism. Here, we propose that metabolism of vitamin A, which is highly concentrated in the liver, is a root source of tolerance and resistance of hepatic metastases to checkpoint blockade. Suppression of retinoic acid synthesis from vitamin A with disulfiram may mitigate tolerance and produce enhanced immunotherapy treatment results for patients with liver metastases.
Can Ruxolitinib CrashTET2- andIDH2-Driven Clonal Hematopoiesis?
Authors: Khabusheva Elmira , Goodell Margaret A. 
Published: October 2024

Summary:In this issue, Waarts and colleagues developed an advanced ex vivo CRISPR screening platform to identify vulnerabilities in clonal hematopoiesis (CH). This unique system allowed the authors to identify a link between IDH2 and TET2 CH mutations, histone demethylases, and altered cytokine signaling, which enabled targeting by ruxolitinib leading to the elimination of CH clones, offering a possible path for preventing the development of malignancy.See related article by Waarts et al., p. 1860
Transient EZH2 Suppression by Tazemetostat during In Vitro Expansion Maintains T-Cell Stemness and Improves Adoptive T-Cell Therapy
Authors: Hou Yingqin , Zak Jaroslav , Shi Yujie , Pratumchai Isaraphorn , Dinner Brandon , Wang Wenjian , Qin Ke , Weber Evan W. , Teijaro John R. , Wu Peng 
Published: October 2024

Abstract
The histone methyltransferase enhancer of zeste homolog 2 (EZH2) plays important roles in T-cell differentiation, proliferation, and function. Previous studies have demonstrated that genetic deletion of EZH2 in CD8+ or total T cells impairs their antiviral and antitumor activities, cytokine production, and ability to expand upon rechallenge. Contrary to the detrimental role of deleting T cell–intrinsic EZH2, in this study, we demonstrated that transient inhibition of EZH2 in T cells prior to the phenotypic onset of exhaustion with a clinically approved inhibitor, tazemetostat (Taz), delayed their dysfunctional progression and preserved T-cell stemness and polyfunctionality but had no negative impact on cell proliferation. Taz-induced T-cell epigenetic reprogramming increased the expression of the self-renewal T-cell transcription factor TCF1 by reducing H3K27 methylation at its promoter preferentially in rapidly dividing T cells. In a murine melanoma model, T cells depleted of EZH2 induced poor tumor control, whereas adoptively transferred T cells pretreated with Taz exhibited superior antitumor immunity, especially when used in combination with anti–PD-1 blockade. Collectively, these data highlight the potential of transient epigenetic reprogramming by EZH2 inhibition to enhance adoptive T-cell immunotherapy.