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Background: The association of the p53 rs1042522 and rs17878362 polymorphisms with cervical cancer risk has been reported in several published original studies and meta-analyses. However, the conclusions of these studies were contradictory. Consequently, we conducted an updated meta-analysis to further validate these debates. Objective: To evaluate the association between the p53 rs1042522 and rs17878362 polymorphisms and cervical cancer risk. Materials and Methods: PubMed, Medline, Ovid, Embase, CNKI, and China Wanfang databases were searched. Association was assessed using odds ratio (OR) with 95% confidence interval (CI). Moreover, the false-positive reporting probability (FPRP), Bayesian false-finding probability (BFDP), and Venice criteria were used to assess the credibility of statistically significant association. Results: A significantly decreased cervical cancer risk was revealed for the p53 rs1042522 polymorphism (Pro/Pro +Arg/Pro vs. Arg/Arg: OR = 0.79, 95% CI = 0.71-0.87; Pro/Pro vs. Arg/Arg: OR = 0.80, 95% CI = 0.70-0.91; Arg/Pro vs. Arg/Arg: OR = 0.78, 95% CI = 0.71-0.86; Pro vs. Arg: OR = 0.87, 95% CI = 0.81-0.93) in overall analysis and several subgroup analyses, such as in Caucasians, Asians, Indians, and so on. However, no significant association was found between the p53 rs17878362 polymorphism and cervical cancer risk. Despite these statistically significant results, reliability analysis using FPRP, BFDP, and Venice criteria deemed all associations "unreliable". Conclusions: After considering the reliability of the results, this study indicates that the p53 rs1042522 polymorphism is not associated with the cervical cancer risk. [ABSTRACT FROM AUTHOR]

This study aimed to manage Helicobacter pylori (H. pylori) infection through a family-centered approach. It conducted a two-year follow-up on infected individuals’ family members in Yichun, Jiangxi, China, to gain comprehensive insights into the transmission dynamics, treatment adherence, and associated risk factors of H. pylori within households. A retrospective analysis was performed on the data obtained from households in Yichun City that participated in the nationwide multicenter H. pylori prevalence study in 2021, along with the corresponding subsequent follow-up data. The collected information encompassed fundamental demographic details of the families, their lifestyle patterns, and the status of H. pylori infection. Among 514 households, 222 comprised two individuals, whereas 68 constituted larger families with five or more members. All member was infected in 9.34% of households. Larger family sizes (≥ 5 individuals) and higher generational counts were closely associated with H. pylori infection (e.g., family size > 6: OR 4.46, 95%CI 1.29 to 15.46). Adult age, marital status, and household members’ infections were identified as primary risk factors (e.g., married individuals: OR 2.03, 95%CI 1.56 to 2.65). Students and previously uninfected individuals exhibited lower infection risks (e.g., tested as negative: OR 0.48, 95%CI 0.31 to 0.73). Maternal, paternal, or sibling infections were linked to increased risks of child infections (e.g., mother infected: OR 2.58 95%CI 1.37 to 4.87). Successful eradication in ≥ 2 individuals reduced the infection risk for other members (OR 0.25, 95%CI (0.07 to 0.89). H. pylori displayed noticeable clustering infection characteristics within families. This study lends support to family-based management strategies, but given suboptimal adherence to household management, there is a need to enhance education on the hazards of H. pylori before implementing screening programs. [ABSTRACT FROM AUTHOR]

Nowadays, the development of plant extracts as corrosion inhibitors to protect metals from corrosion is a popular research direction. However, given the vast diversity of plant species in nature, it is imperative to explore effective methods to improve screening efficiency in order to quickly identify the corrosion inhibition potential of plants. In this work, a new strategy for developing plant-extracted eco-friendly corrosion inhibitors based on the family and genus of plants is proposed. Three plants of different genera in the Asteraceae family, including Artemisia argyi extract (AAE), Chrysanthemum indicum extract (CIE), and Centipeda minima extract (CME), were selected and successfully prepared as novel corrosion inhibitors for Q235 steel in a sulfuric acid solution. The corrosion inhibition behavior and corresponding mechanism were systematically investigated by using some electrochemical tests (open circuit potential, potentiodynamic polarization, and electrochemical impedance spectroscopy) and surface characterizations (Fourier transform infrared spectroscopy, scanning electron microscopy, and X-ray photoelectron spectroscopy). The experimental results illustrated that the main components of the three extracts were similar and that when combined with KI as mixed-type corrosion inhibitors, they could dramatically slow down the metal corrosion rate. The maximum value of the corrosion inhibition efficiency reached 96.29%, 96.50%, and 97.52%, respectively, at 200 mg/L and could increase to 98.64%, 97.65%, and 99.06%, respectively, with a prolonged immersion time. A synergistic effect exists between the three plant extracts and KI, leading to the firm adsorption of the three plant extract molecules onto a Q235 steel surface, thereby forming a robust protective film. This work demonstrated that plants of different genera in the Asteraceae family possessed similar corrosion inhibition capabilities, providing a novel way to select potential corrosion inhibitors from numerous plants based on family and genus classification. [ABSTRACT FROM AUTHOR]

Fever is one of the most common clinical conditions and is characterized by pyrogenic infection, malignancy, inflammation, and tissue damage, among others. Ellagic acid (EA) can inhibit the expression of related proteins on the pathway by blocking the nuclear factor kappa-B(NF-κB) signaling pathway, inhibit the levels of pro-inflammatory factors interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α), increase the level of anti-inflammatory factor IL-10, and effectively alleviate inflammatory symptoms. In addition, EA can also reduce the levels of malondialdehyde(MDA) and nitric oxide(NO) in the body, increase the activities of superoxide dismutase (SOD), glutathione (GSH), and catalase(CAT), scavenge oxidative free radicals, inhibit lipid oxidation, and achieve antipyretic and anti-inflammatory effects. The purpose of this study was to establish the relationship between EA and various inflammatory markers, such as TNF-α, IL-6, IL-1β, prostaglandin E2(PGE2), and cyclic adenosine monophosphate(cAMP), and clarify the mechanism of the cyclooxidase-2(COX-2)/NF-κB signaling pathway. Combined with the metabolomics analysis, our study revealed the effects of EA on multiple endogenous biomarkers, reflecting the characteristics of a multi-component, multi-target, and multi-pathway mechanism. Compared to lipopolysaccharide (LPS)- treated animals, subsequent administration of EA significantly lowered the LPS-induced rectal temperature increase (p < 0.05 or p < 0.01), significantly increased serum SOD and GSH levels (p < 0.05 or p < 0.01), and significantly decreased serum MDA, IL-1β, IL-6, and TNF-α levels (p < 0.05 or p < 0.01). In addition, compared to LPS-treated animals, subsequent administration of EA significantly decreased cerebrospinal fluid cAMP and PGE2 levels (p < 0.05 or p < 0.01), significantly decreased cAMP, significantly increased 5-HT levels (p < 0.05 or p < 0.01), and significantly down-regulated p-NF-κB p65 and COX-2 protein levels in the hypothalamus. Subsequent gas chromatography mass spectrometry(GC-MS) metabolite analysis indicated that 12 differential metabolites were detected in serum isolated 4 h after LPS treatment, and 10 differential metabolites were detected in serum collected 7 h after LPS treatment. Next, Pearson correlation analysis was used to systematically characterize the relationship between the identified metabolites and TNF-α, IL-6, MDA, SOD, PGE2, and cAMP. The levels of propionic acid, pyridine, and L-valine were up-regulated by EA, which inhibited the expression of MDA, IL-1β, and TNF-α and increased the activity of GSH. The levels of inositol, urea, and 2-monopalmitin were down-regulated by EA, which inhibited the expression of MDA, IL-1β, and TNF-α, increased the activity of SOD and GSH, reduced the inflammatory response, and alleviated the oxidative stress state. Combined with the results of the metabolic pathway analysis, we suggest that the pathways of the galactose metabolism, synthesis and degradation of ketone bodies, as well as ascorbic acid and aldehyde acid metabolism are closely related to the antipyretic and anti-inflammatory effects of EA. Our study established the relationship between EA and various inflammatory markers, such as TNF-α, IL-6, IL-1β, PGE2, and cAMP, and clarified the mechanism of the COX-2/NF-κB signaling pathway. Combined with the metabolomics analysis, our study revealed the effects of EA on multiple endogenous biomarkers, reflecting the characteristics of a multi-component, multi-target, and multi-pathway mechanism.

Chronic Pseudomonas aeruginosa (PA) infection significantly contributes to morbidity and mortality in bronchiectasis patients. Initiating antibiotics early may lead to the eradication of PA. Here we outline the design of a trial (ERASE; NCT06093191) assessing the efficacy and safety of inhaled tobramycin, alone or with oral ciprofloxacin, in bronchiectasis patients with a new isolation of PA. This multicentre, 2×2 factorial randomised, double-blind, placebo-controlled, parallel-group trial includes a 2-week screening period, a 12-week treatment phase (with a combination of ciprofloxacin or a placebo at initial 2 weeks) and a 24-week follow-up. 364 adults with bronchiectasis and a new PA isolation will be randomly assigned to one of four groups: placebo (inhaled saline and ciprofloxacin placebo twice daily), ciprofloxacin alone (750 mg ciprofloxacin and inhaled saline twice daily), inhaled tobramycin alone (inhaled 300 mg tobramycin and ciprofloxacin placebo twice daily) or a combination of both drugs (inhaled 300 mg tobramycin and 750 mg ciprofloxacin twice daily). The primary objective of this study is to assess the proportion of patients successfully eradicating PA in each group by the end of the study. Efficacy will be evaluated based on the eradication rate of PA at other time points (12, 24 and 36 weeks), the occurrence of exacerbations and hospitalisations, time to first pulmonary exacerbations, patient-reported outcomes, symptom measures, pulmonary function tests and the cost of hospitalisations. To date no randomised trial has evaluated the benefit of different PA eradication strategies in bronchiectasis patients. The ERASE trial will therefore generate crucial data to inform future clinical guidelines.

Background: Uptake to anastrozole for breast cancer prevention is low, partly due to women’s concerns about side effects including gains in weight and specifically gains in body fat. Previous evidence does not link anastrozole with gains in weight, but there is a lack of data on any effects on body composition i.e. changes in fat and fat free mass. Here we assess association of anastrozole with body composition changes in a prospective sub-study from the second international breast intervention trial (IBIS-II). Methods: Participants had DXA scans at baseline and for five years of anastrozole/placebo and beyond (between March 2004 and September 2017. Primary outcomes were changes in body weight, body fat and fat free mass at 9–18 months. A linear model was used to estimate the size of a differential effect in these outcomes by randomised treatment allocation adjusted for baseline value and time since last scan, age, 10-year breast cancer risk, smoking and HRT status. Results: 203 postmenopausal women were recruited (n = 95 anastrozole, n = 108 placebo), mean age 58 years (SD = 5.4), BMI 28.0 kg/m2 (SD = 5.5). There was no evidence of a strong association between anastrozole or placebo and endpoints at 9–18 months; effect size (95 %CI) for anastrozole minus placebo for body weight (per/kg) −0.11 (−1.29–1.08); body fat 0.11 (−0.75–0.96) and fat free mass −0.30 (−0.79–0.19). Conclusions: There is unlikely to be a clinically significant change to body composition with anastrozole for breast cancer prevention.

Ferroptosis, a nonapoptotic form of cell death, is an emerging potential therapeutic target for various diseases, including cancer. However, the role of ferroptosis in pancreatic cancer remains poorly understood. Pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor prognosis and chemotherapy resistance, attributed to its high Kirsten rats arcomaviral oncogene homolog mutation rate and severe nutritional deficits resulting from a dense stroma. Several studies have linked rat sarcoma (RAS) mutations to ferroptosis, suggesting that inducing ferroptosis may be an effective strategy against oncogenic RAS-bearing tumors. We investigated the role of Family With Sequence Similarity 60 Member A (FAM60A) in this study, a protein closely associated with a poor prognosis and highly expressed in PDAC and tumor tissue from KrasG12D/+;Trp53R172H/+; Pdx1-Cre mice, in regulating ferroptosis, tumor growth, and gemcitabine sensitivity in vitro and in vivo. Our results demonstrate that FAM60A regulates 3 essential metabolic enzymes, ACSL1/4 and GPX4, to protect PDAC cells from ferroptosis. Furthermore, we found that YY1 transcriptionally regulates FAM60A expression by promoting its transcription, and the Hippo-YY1 pathway is restricted in the low-amino-acid milieu in the context of nutrient deprivation, leading to downstream suppression of peroxisome proliferator-activated receptor and ACSL1/4 and activation of GPX4 pathways. Importantly, FAM60A knockdown sensitized PDAC cells to gemcitabine treatment. A new understanding of FAM60A transcriptional regulation pattern in PDAC and its dual function in ferroptosis reliever and chemotherapy resistance is provided by our study. Targeting FAM60A may therefore offer a promising therapeutic approach for PDAC by simultaneously addressing 2 major features of the disease (high RAS mutation rate and tumor microenvironment nutrient deficiency) and preventing tumor cell metabolic adaptation.

The lysosome protein RAGA interacts with and promotes lysosome localization and degradation of the macrophage-specific immune checkpoint protein CD47, with possible relevance to lung adenocarcinoma

Abstract Ibrutinib is a drug that inhibits the protein Burton’s tyrosine kinase and thereby the nuclear translocation of Nrf2, which played a key role in mediating the activation of antioxidants during stress conditions and ferroptosis resistance. This study aimed to identify the effect of Ibrutinib and ferroptosis inducer on colorectal cancer (CRC) treatment and its underlying mechanism. In our study, we found the upregulation of Nrf2 was correlated with CRC progression and antioxidant proteins. Ibrutinib sensitized CRC to ferroptosis inducers, suggested by further reduced CRC cell viability, proliferation and decreased antioxidant protein levels in CRC cells after combination treatment of Ibrutinib and RSL3 or Ibrutinib and Erastin both in vivo and in vitro. Knockout of Nrf2 diminished the regulatory effect of Ibrutinib on CRC sensitivity to ferroptosis inducers. Altogether, this study demonstrated that Ibrutinib increases the sensitivity of CRC cell to ferroptosis inducers by inhibiting Nrf2.

Background: The establishment of the anterior-posterior (A-P) axis is a crucial step during tissue repair and regeneration. Despite the association reported recently of N6-methyladenosine (m6A) with regeneration, the mechanism underlying the regulation of m6A in A-P axis specification during regeneration remains unknown. Herein, we deciphered the m6A landscape at a single-base resolution at multiple time points during A-P axis regeneration and constructed the de novo transcriptome assembly of the Dugesia japonica planarian. Results: Immunofluorescence staining and comparative analysis revealed that m6A is widespread across the planarian and dynamically regulated during regeneration along the A-P axis, exhibiting a strong spatiotemporal feature. The resulting datasets of m6A-modified genes identified 80 anterior-specific genes and 13 posterior-specific genes, respectively. In addition, we showed that YTHDC1 serves as the primary m6A reader to be involved in the m6A-mediated specification of A-P axis during regeneration in Dugesia japonica planarian. Conclusions: Our study provides an RNA epigenetic explanation for the specification of the A-P axis during tissue regeneration in planarian.

The need to study language use in literary texts arises due to linguistic complexity, writers’ linguistic choices and subjective understanding of the contextual meaning conveyed by writers. By using Halliday’s (1994) transitivity system, this study analysed ‘The Clay Marble’ novel which highlights the Cambodian Civil War and its implications through the representation of events and characters. By looking at the transitivity processes through the clausal structures and word choices, findings showed that all six processes were employed with material process (69 clauses) used most, followed by relational (42 clauses) and mental (31 clauses) process. Material and relational process is dominantly used to represent themes such as the effects of war, community life among refugees as well as the growth and character development of young refugees during the war. Therefore, transitivity analysis on literary texts helps to uncover writer’s language use and the contextual meaning conveyed through the writer’s linguistic choices.

Abstract Brain calcification is a critical aging-associated pathology and can cause multifaceted neurological symptoms. Cerebral phosphate homeostasis dysregulation, blood-brain barrier defects, and immune dysregulation have been implicated as major pathological processes in familial brain calcification (FBC). Here, we analyzed two brain calcification families and identified calcification co-segregated biallelic variants in the CMPK2 gene that disrupt mitochondrial functions. Transcriptome analysis of peripheral blood mononuclear cells (PBMCs) isolated from these patients showed impaired mitochondria-associated metabolism pathways. In situ hybridization and single-cell RNA sequencing revealed robust Cmpk2 expression in neurons and vascular endothelial cells (vECs), two cell types with high energy expenditure in the brain. The neurons in Cmpk2-knockout (KO) mice have fewer mitochondrial DNA copies, down-regulated mitochondrial proteins, reduced ATP production, and elevated intracellular inorganic phosphate (Pi) level, recapitulating the mitochondrial dysfunction observed in the PBMCs isolated from the FBC patients. Morphologically, the cristae architecture of the Cmpk2-KO murine neurons was also impaired. Notably, calcification developed in a progressive manner in the homozygous Cmpk2-KO mice thalamus region as well as in the Cmpk2-knock-in mice bearing the patient mutation, thus phenocopying the calcification pathology observed in the patients. Together, our study identifies biallelic variants of CMPK2 as novel genetic factors for FBC; and demonstrates how CMPK2 deficiency alters mitochondrial structures and functions, thereby highlighting the mitochondria dysregulation as a critical pathogenic mechanism underlying brain calcification.

Objective: Expand genetic screening for atypical Type I sialidosis (ST‐1) could address its underdiagnosed in both progressive myoclonic ataxia (PMA) and ataxia patients. To evaluate the potential founder effect of mutation in the population. Methods: We enrolled 231 patients with PMA or ataxia from the First Affiliated Hospital of Fujian Medical University. Through Whole Exome Sequencing and Sanger sequencing, we identified the causative gene in patients. Haplotype analysis was employed to explore a potential founder effect of the NEU1 c.544A>G mutation. Results: A total of 31 patients from 23 unrelated families were genetically diagnosed with ST‐1. A significant 80.6% of these patients were homozygous for the c.544A>G mutation. We discovered six different NEU1 variants, including two novel mutations: c.951_968del and c.517T>G. The mean age of onset was 18.0 ± 7.1 years. The clinical spectrum of ST‐1 featured ataxia and myoclonus as the most common initial symptoms. Over 40% suffered from controlled generalized tonic–clonic seizures. Mobility and independence varied greatly across the cohort. Cherry‐red spots were rare, occurring in just 9.5% (2/21) of patients. Brain MRIs were typically unremarkable, except for two patients with unusual findings. EEGs showed diffuse paroxysmal activity in 17 patients. The c.544A>G mutation in NEU1 is a founder variant in Fujian, with a unique haplotype prevalent in East Asians. Interpretation: ST‐1 should be suspected in patients with PMA or ataxia in Southeast China, even without macular cherry‐red spots and seizures, and the premier test could be a variant screening of the founder variant NEU1 c.544A>G. [ABSTRACT FROM AUTHOR]

Understanding the relative contributions of historical and anthropogenic factors to declines in genetic diversity is important for informing conservation action. Using genome-wide DNA of fresh and historic specimens, including that of two species widely thought to be extinct, we investigated fluctuations in genetic diversity and present the first complete phylogenomic tree for all nine species of the threatened shorebird genus Numenius, known as whimbrels and curlews. Most species faced sharp declines in effective population size, a proxy for genetic diversity, soon after the Last Glacial Maximum (around 20,000 years ago). These declines occurred prior to the Anthropocene and in spite of an increase in the breeding area predicted by environmental niche modeling, suggesting that they were not caused by climatic or recent anthropogenic factors. Crucially, these genetic diversity declines coincide with mass extinctions of mammalian megafauna in the Northern Hemisphere. Among other factors, the demise of ecosystem-engineering megafauna which maintained open habitats may have been detrimental for grassland and tundra-breeding Numenius shorebirds. Our work suggests that the impact of historical factors such as megafaunal extinction may have had wider repercussions on present-day population dynamics of open habitat biota than previously appreciated.

Cancer survivors have reduced health-related quality of life (HRQOL) and high levels of distress during and after active treatment, due to physical, psychological, and social problems. Understanding the prevalence and associations of HRQOL and distress in a patient population in the community is important when designing rehabilitation programs. This was a cross-sectional observational study conducted at a community-based cancer rehabilitation center, with the aim of investigating the prevalence and associations of HRQOL and distress in cancer patients. There were 304 patients who were recruited. We found low levels of HRQOL and high levels of distress in patients, with a mean FACT-G7 total score of 11.68, and a mean distress thermometer score of 3.51. In the multivariate regression model, significant factors for low HRQOL were metastatic disease (p = 0.025) and Malay ethnicity (p < 0.001). Regression analyses also found that significant distress was associated with family health issues (p = 0.003), depression (p = 0.001), worry (p = 0.005), breathing (p = 0.007), getting around (p = 0.012) and indigestion (p = 0.039). A high prevalence of impaired HRQOL and distress was reported in cancer survivors even in a community rehabilitation setting. The physical and psychosocial well-being of cancer survivors should be monitored and managed as part of community-based cancer rehabilitation.

Introduction: Singapore’s enhanced surveillance programme for COVID-19 identifies and isolates hospitalised patients with acute respiratory symptoms to prevent nosocomial spread. We developed risk prediction models to identify patients with low risk for COVID-19 from this cohort of hospitalised patients with acute respiratory symptoms. Methods: This was a single-centre retrospective observational study. Patients admitted to our institution’s respiratory surveillance wards from 10 February to 30 April 2020 contributed data for analysis. Prediction models for COVID-19 were derived from a training cohort using variables based on demographics, clinical symptoms, exposure risks and blood investigations fitted into logistic regression models. The derived prediction models were subsequently validated on a test cohort. Results: Of the 1,228 patients analysed, 52 (4.2%) were diagnosed with COVID-19. Two prediction models were derived, the first based on age, presence of sore throat, dormitory residence, blood haemoglobin level (Hb), and total white blood cell counts (TW), and the second based on presence of headache, contact with infective patients, Hb and TW. Both models had good diagnostic performance with areas under the receiver operating characteristic curve of 0.934 and 0.866, respectively. Risk score cut-offs of 0.6 for Model 1 and 0.2 for Model 2 had 100% sensitivity, allowing identification of patients with low risk for COVID-19. Limiting COVID-19 screening to only elevated-risk patients reduced the number of isolation days for surveillance patients by up to 41.7% and COVID-19 swab testing by up to 41.0%. Conclusion: Prediction models derived from our study were able to identify patients at low risk for COVID-19 and rationalise resource utilisation.

Abstract Background Liver fibrosis is a wound-healing response to chronic injury, featuring with excess accumulation of extracellular matrix secreted by the activated hepatic stellate cells (HSC). Disulfiram (DSF), also known as Antabuse, has been used for the treatment of alcohol addiction and substance abuse. Recently, overwhelming studies had revealed anti-cancer effects of DSF in multiple cancers, including liver cancer. But the actual effects of DSF on liver fibrosis and liver function remain unknown. Methods In this study, we evaluated the effects of low-dose DSF in CCl4- and Bile Duct Ligation (BDL)—induced hepatic fibrosis rat models. Cell proliferation was detected by using the Cell-Light™ EdU Apollo®567 Cell Tracking Kit. Cell apoptosis was analyzed using a TdT-mediated dUTP nick end labeling (TUNEL) kit, viability was measured with Cell Counting Kit-8(CCK8). Relative mRNA expression of pro-fibrogenic was assessed using quantitative RT-PCR. The degree of liver fibrosis, activated HSCs, were separately evaluated through Sirius Red-staining, immunohistochemistry and immunofluorescence. Serum alanine aminotransferase (ALT) and asparagine aminotransferase (AST) activities were detected with ALT and AST detecting kits using an automated analyzer. Results Liver fibrosis was distinctly attenuated while liver functions were moderately ameliorated in the DSF-treated group. Activation and proliferation of primary rat HSCs isolated from rat livers were significantly suppressed by low-dose DSF. DSF also inhibited the viability of in vitro cultured rat or human HSC cells dose-dependently but had no repressive role on human immortalized hepatocyte THLE-2 cells. Interestingly, upon DSF treatment, the viability of LX-2 cells co-cultured with THLE-2 was significantly inhibited, while that of THLE-2 co-cultured with LX-2 was increased. Further study indicated that HSCs apoptosis was increased in DSF/CCl4-treated liver samples. These data indicated that DSF has potent anti-fibrosis effects and protective effects toward hepatocytes and could possibly be repurposed as an anti-fibrosis drug in the clinic. Conclusions DSF attenuated ECM remodeling through suppressing the transformation of quiet HSCs into proliferative, fibrogenic myofibroblasts in hepatic fibrosis rat models. DSF provides a novel approach for the treatment of liver fibrosis.