Enhancing social behavior in an autism spectrum disorder mouse model: investigating the underlying mechanisms of Lactiplantibacillus plantarum intervention.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting over 1% of the global population. Individuals with ASD often exhibit complex behavioral conditions, including significant social difficulties and repetitive behaviors. Moreover, ASD often co-occurs with several other conditions, including intellectual disabilities and anxiety disorders. The etiology of ASD remains largely unknown owing to its complex genetic variations and associated environmental risks. Ultimately, this poses a fundamental challenge for the development of effective ASD treatment strategies. Previously, we demonstrated that daily supplementation with the probiotic Lactiplantibacillus plantarum PS128 (PS128) alleviates ASD symptoms in children. However, the mechanism underlying this improvement in ASD-associated behaviors remains unclear. Here, we used a well-established ASD mouse model, induced by prenatal exposure to valproic acid (VPA), to study the physiological roles of PS128 in vivo. Overall, we showed that PS128 selectively ameliorates behavioral abnormalities in social and spatial memory in VPA-induced ASD mice. Morphological examination of dendritic architecture further revealed that PS128 facilitated the restoration of dendritic arborization and spine density in the hippocampus and prefrontal cortex of ASD mice. Notably, PS128 was crucial for restoring oxytocin levels in the paraventricular nucleus and oxytocin receptor signaling in the hippocampus. Moreover, PS128 alters the gut microbiota composition and increases the abundance of Bifidobacterium spp. and PS128-induced changes in Bifidobacterium abundance positively correlated with PS128-induced behavioral improvements. Together, our results show that PS128 treatment can effectively ameliorate ASD-associated behaviors and reinstate oxytocin levels in VPA-induced mice, thereby providing a promising strategy for the future development of ASD therapeutics.

Invasive pulmonary aspergillosis among patients with severe community-acquired pneumonia and influenza in ICUs: a retrospective cohort study.

RATIONALE: The prevalence, clinical characteristics, and outcomes of invasive pulmonary aspergillosis in patients with severe community-acquired pneumonia (CAP) in intensive care units remain underestimated because of the lack of a disease-recognition scheme and the inadequacy of diagnostic tests. OBJECTIVES: To identify the prevalence, risk factors, and outcomes of severe CAP complicated with invasive pulmonary aspergillosis (IPA) in intensive care units (ICUs). METHODS: We conducted a retrospective cohort study including recruited 311 ICU-hospitalized patients with severe CAP without influenza or with influenza. Bronchoalveolar lavage fluid (BALF) samples were from all patients and subjected to mycological testing. Patients were categorized as having proven or probable Aspergillus infection using a modified form of the AspICU algorithm comprising clinical, radiological, and mycological criteria. MEASUREMENTS AND MAIN RESULTS: Of the 252 patients with severe CAP and 59 influenza patients evaluated, 24 met the diagnostic criteria for proven or probable Aspergillus infection in the CAP group and 9 patients in the influenza group, giving estimated prevalence values of 9.5% and 15.3%, respectively. COPD and the use of inhaled corticosteroids were independent risk factors for IPA. IPA in patients with severe CAP was significantly associated with the duration of mechanical support, the length of ICU stay, and the 28-day mortality. CONCLUSIONS: An aggressive diagnostic approach for IPA patients with severe CAP and not only influenza or COVID-19 should be pursued. Further randomized controlled trials need to evaluate the timing, safety, and efficacy of antifungal therapy in reducing IPA incidence and improving clinical outcomes.

PROM2 upregulation promotes cancer cell migration and confers a poor prognosis in lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) remains a difficult-to-treat disease with a poor prognosis. While prominin-1 (PROM1/CD-133) is largely investigated in a variety of malignancies, the role of prominin-2 (PROM2), the other member of the prominin family, has not been studied in LUSC. Transcriptomic data derived from matched tumor and adjacent non-tumorous lung tissues of LUSC patients were employed to conduct an in-depth analysis of the genetic and epigenetic regulation of prominin genes within LUSC, utilizing bioinformatic approaches. Furthermore, cellular behavior experiments were executed to discern the biological functions of PROM2. It was observed that PROM2, in contrast to PROM1, exhibited significant upregulation and overexpression at both the mRNA and protein levels in LUSC, and this upregulation was correlated with shortened patient survival. Transcriptomic analysis unveiled DNA methylation as an epigenetic regulatory mechanism associated with PROM2 expression. Notably, two transcription factors, CBFB and NRIP1, were identified as potential regulators of PROM2 expression. Subsequent in vitro investigations demonstrated that knocking down PROM2 led to the inhibition of cancer cell migration and the epithelial-to-mesenchymal transition (EMT). In summary, the pronounced upregulation of PROM2 in LUSC patients was linked to an unfavorable prognosis, possibly attributable to its influence on cancer cell migration and EMT. These findings suggest that PROM2 could serve as a promising diagnostic biomarker and therapeutic target in the management of LUSC. Consequently, further research into the mechanistic aspects and potential therapeutic interventions targeting PROM2 is warranted in the clinical context.

Peripheral inflammation is associated with impaired sadness recognition in euthymic bipolar patients.

BACKGROUND: Inflammation impairs cognitive function in healthy individuals and people with psychiatric disorders, such as bipolar disorder (BD). This effect may also impact emotion recognition, a fundamental element of social cognition. Our study aimed to investigate the relationships between pro-inflammatory cytokines and emotion recognition in euthymic BD patients and healthy controls (HCs). METHODS: We recruited forty-four euthymic BD patients and forty healthy controls (HCs) and measured their inflammatory markers, including high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and TNF-α. We applied validated cognitive tasks, the Wisconsin Card-Sorting Test (WCST) and Continuous Performance Test (CPT), and a social cognitive task for emotion recognition, Diagnostic Analyses of Nonverbal Accuracy, Taiwanese Version (DANVA-2-TW). We analyzed the relationships between cytokines and cognition and then explored possible predictive factors of sadness recognition accuracy. RESULTS: Regarding pro-inflammatory cytokines, TNF-α was elevated in euthymic BD patients relative to HCs. In euthymic BD patients only, higher TNF-α levels were associated with lower accuracy of sadness recognition. Regression analysis revealed that TNF-α was an independent predictive factor of sadness recognition in patients with euthymic BD when neurocognition was controlled for. CONCLUSIONS: We demonstrated that enhanced inflammation, indicated by increased TNF-α, was an independent predictive factor of impaired sadness recognition in BD patients but not in HCs. Our findings suggested a direct influence of TNF-α on sadness recognition and indicated vulnerability to depression in euthymic BD patients with chronic inflammation.

Administration of oral prednisolone to prevent esophageal stricture after balloon-type radiofrequency ablation for ultralong-segment esophageal neoplasia.

BACKGROUND AND AIMS: Endoscopic radiofrequency ablation (RFA) has shown good efficacy and safety in eradicating flat-type early esophageal squamous cell neoplasia (ESCN). However, post-RFA stricture is still a major concern, especially when treating ultralong-segment ESCNs. The aim of this study was to investigate the efficacy and safety of oral prednisolone to prevent post-RFA stricture. METHODS: We prospectively enrolled 48 patients treated with balloon-type RFA who had Lugol-unstained or mosaic-like flat-type ESCNs with an expected treatment area more than 10 cm. Oral prednisolone was started at a dose of 30 mg/day on the third day after RFA and continued for 4 weeks. The results were compared to a historical control group of 25 patients who received RFA without oral steroids. The primary endpoint was the frequency of post-RFA stricture. Secondary endpoints were the number of balloon dilation sessions and adverse event rate. RESULTS: There were no significant differences in the worst pathology grade at baseline, length of unstained lesions between the two groups. The complete response rates after 1 session of RFA were 73% and 72%, respectively. Compared to the control group, the oral prednisolone group had a significantly lower stricture rate (4%, 2/48 patients vs. 44%, 11/25 patients; P<0.0001) and a lower number of balloon dilation sessions (median 0, range 0-4 vs. median 6, range 0-10). There were two cases of asymptomatic candida esophagitis in the study group, and no severe adverse effects. CONCLUSIONS: Oral prednisolone may offer a useful and safe preventive option for post-RFA stricture in ultralong ESCNs. CLINICAL TRIAL REGISTRATION NUMBER: NCT05768282.

Concatenated ScaA and TSA56 Surface Antigen Sequences Reflect Genome-Scale Phylogeny of Orientia tsutsugamushi: An Analysis Including Two Genomes from Taiwan.

Orientia tsutsugamushi is an obligate intracellular bacterium associated with trombiculid mites and is the causative agent of scrub typhus, a life-threatening febrile disease. Strain typing of O. tsutsugamushi is based on its immunodominant surface antigen, 56-kDa type-specific antigen (TSA56). However, TSA56 gene sequence-based phylogenetic analysis is only partially congruent with core genome-based phylogenetic analysis. Thus, this study investigated whether concatenated surface antigen sequences, including surface cell antigen (Sca) proteins, can reflect the genome-scale phylogeny of O. tsutsugamushi. Complete genomes were obtained for two common O. tsutsugamushi strains in Taiwan, TW-1 and TW-22, and the core genome/proteome was identified for 11 O. tsutsugamushi strains. Phylogenetic analysis was performed using maximum likelihood (ML) and neighbor-joining (NJ) methods, and the congruence between trees was assessed using a quartet similarity measure. Phylogenetic analysis based on 691 concatenated core protein sequences produced identical tree topologies with ML and NJ methods. Among TSA56 and core Sca proteins (ScaA, ScaC, ScaD, and ScaE), TSA56 trees were most similar to the core protein tree, and ScaA trees were the least similar. However, concatenated ScaA and TSA56 sequences produced trees that were highly similar to the core protein tree, the NJ tree being more similar. Strain-level characterization of O. tsutsugamushi may be improved by coanalyzing ScaA and TSA56 sequences, which are also important targets for their combined immunogenicity.

Downregulated antisense lncRNA ENTPD3-AS1 contributes to the development of lung adenocarcinoma.

The poor outcome of patients with lung adenocarcinoma (LUAD) highlights the importance to identify novel effective prognostic markers and therapeutic targets. Long noncoding RNAs (lncRNAs) have generally been considered to serve important roles in tumorigenesis and the development of various types of cancer, including LUAD. Here, we aimed to investigate the role of ENTPD3-AS1 (ENTPD3 Antisense RNA 1) in LUAD and to explore its potential mechanisms by performing comprehensive bioinformatic analyses. The regulatory effect of ENTPD3-AS1 on the expression of NR3C1 was validated by siRNA-based silencing. The effect of miR-421 on the modulation of NR3C1 was determined by miRNA mimics and inhibitors transfection. ENTPD3-AS1 was expressed at lower levels in tumor parts and negatively correlated with unfavorable prognosis in LUAD patients. It exerted functions as a tumor suppressor gene by competitively binding to oncomir, miR-421, thereby attenuating NR3C1 expression. Transfection of lung cancer A549 cells with miR-421 mimics decreased the expression of NR3C1. Transfection of lung cancer A549 cells with miR-421 inhibitors increased the expression of NR3C1 with lower cellular functions as proliferation and migration via epithelial-mesenchymal transition. In addition, inhibition of ENTPD3-AS1 by siRNA transfection decreased the levels of NR3C1, supporting the ENTPD3-AS1/miR-421/NR3C1 cascade. Moreover, the bioinformatic analysis also showed that ENTPD3-AS1 could interact with the RNA-binding proteins (RBPs), CELF2 and QKI, consequently regulating RNA expression and processing. Taken together, we identified that ENTPD3-AS1 and its indirect target NR3C1 can act as novel biomarkers for determining the prognosis of patients with LUAD, and further study is required.

Epidemiology of Murine Typhus in Taiwan from 2013 to 2020.

Murine typhus is a flea-borne disease caused by Rickettsia typhi infection. The disease is a notifiable infectious disease in Taiwan. Specimens from suspected cases are required to be sent to the Taiwan Centers for Disease Control and Prevention for laboratory diagnosis. In this study, 204 cases of murine typhus were identified by bacterial isolation, real-time polymerase chain reaction, or indirect immunofluorescence assay between 2013 and 2020. The average incidence rate was 0.11/100,000 person-years (95% CI: 0.08-0.13). Murine typhus occurred throughout the year, but it was most prevalent in summer (May to August). The majority of patients were males (75%), residents of Kaohsiung city (31%), and worked in agriculture, forestry, fishing, and animal husbandry (27%). Fever was the most common symptom, present in 95.6% of patients, followed by headache (41%), myalgia (33%), and liver dysfunction (33%). Only 13% of patients had a rash. Up to 80% of cases were among hospitalized patients, and 43% of patients developed severe manifestations. Serological assays also indicated coinfection events. Seven patients showed a 4-fold increase in antibody titers against Orientia tsutsugamushi (N = 2), Coxiella burnetii (n = 2), and Leptospira (N = 3). In conclusion, murine typhus is an endemic and important zoonotic rickettsial disease in Taiwan that cannot be ignored. Further epidemiological surveillance and clinical characteristics should be continuously investigated to prevent and control murine typhus.

First report of Anaplasma spp., Ehrlichia spp., and Rickettsia spp. in Amblyomma gervaisi ticks infesting monitor lizards (Varanus begalensis) of Pakistan.

Ticks pose significant health risks to both wildlife and humans due to their role as vectors for various pathogens. In this study, we investigated tick infestation patterns, tick-associated pathogens, and genetic relationships within the tick species Amblyomma gervaisi, focusing on its prevalence in monitor lizards (Varanus bengalensis) across different districts in Pakistan. We examined 85 monitor lizards and identified an overall mean intensity of 19.59 ticks per infested lizard and an overall mean abundance of 11.98 ticks per examined lizard. All collected ticks (n = 1019) were morphologically identified as A. gervaisi, including 387 males, 258 females, 353 nymphs, and 21 larvae. The highest tick prevalence was observed in the Buner district, followed by Torghar and Shangla, with the lowest prevalence in Chitral. Lizard captures primarily occurred from May to October, correlating with the period of higher tick infestations. Molecular analysis was conducted on tick DNA, revealing genetic similarities among A. gervaisi ticks based on 16S rDNA and ITS2 sequences. Notably, we found the absence of A. gervaisi ITS2 sequences in the NCBI GenBank, highlighting a gap in existing genetic data. Moreover, our study identified the presence of pathogenic microorganisms, including Ehrlichia sp., Candidatus Ehrlichia dumleri, Anaplasma sp., Francisella sp., Rickettsia sp., and Coxiella sp., in these ticks. BLAST analysis revealed significant similarities between these pathogenic sequences and known strains, emphasizing the potential role of these ticks as vectors for zoonotic diseases. Phylogenetic analyses based on nuclear ITS2 and mitochondrial 16S rDNA genes illustrated the genetic relationships of A. gervaisi ticks from Pakistan with other Amblyomma species, providing insights into their evolutionary history. These findings contribute to our understanding of tick infestation patterns, and tick-borne pathogens in monitor lizards, which has implications for wildlife health, zoonotic disease transmission, and future conservation efforts. Further research in this area is crucial for a comprehensive assessment of the risks associated with tick-borne diseases in both wildlife and humans.

Investigating the impact of probiotic on neurological outcomes in Rett syndrome: A randomized, double-blind, and placebo-controlled pilot study.

LAY ABSTRACT: Rett syndrome often involves gastrointestinal symptoms and gut microbiota imbalances. We conducted a study to explore the feasibility of probiotic Lactobacillus plantarum PS128 and the impact on neurological functions in Rett syndrome. The results of our investigation demonstrated that the supplementation of probiotic L. plantarum PS128 was feasible and well tolerated, with 100% retention rate and 0% withdrawal rate. In addition, there was only one participant who had loose stool after taking L. plantarum PS128. Further, there was a tendency to enhance overall cognitive developmental level, as assessed using Mullen Scales of Early Learning. In addition, it significantly improved dystonia, as assessed using the Burke-Fahn-Marsden Movement Scale, in comparison with the placebo group. This study provides a strong foundation for future research and clinical trials exploring the potential of L. plantarum PS128 probiotics as a complementary therapy for individuals with Rett syndrome.

Hepatitis B core-related antigen dynamics and risk of subsequent clinical relapses after nucleos(t)ide analog cessation.

BACKGROUND/AIMS: Finite nucleos(t)ide analog (NA) therapy has been proposed as an alternative treatment strategy for chronic hepatitis B (CHB), but biomarkers for post-treatment monitoring are limited. We investigated whether measuring hepatitis B core-related antigen (HBcrAg) after NA cessation may stratify the risk of subsequent clinical relapse (CR). METHODS: This retrospective multicenter analysis enrolled adults with CHB who were prospectively monitored after discontinuing entecavir or tenofovir with negative HBeAg and undetectable HBV DNA at the end of treatment (EOT). Patients with cirrhosis or malignancy were excluded. CR was defined as serum alanine aminotransferase > two times the upper limit of normal with recurrent viremia. We applied time-dependent Cox proportional hazard models to clarify the association between HBcrAg levels and subsequent CR. RESULTS: The cohort included 203 patients (median age, 49.8 years; 76.8% male; 60.6% entecavir) who had been treated for a median of 36.9 months (interquartile range [IQR], 36.5-40.1). During a median post-treatment follow-up of 31.7 months (IQR, 16.7-67.1), CR occurred in 104 patients with a 5-year cumulative incidence of 54.8% (95% confidence interval [CI], 47.1-62.4%). Time-varying HBcrAg level was a significant risk factor for subsequent CR (adjusted hazard ratio [aHR], 1.53 per log U/mL; 95% CI, 1.12-2.08) with adjustment for EOT HBsAg, EOT anti-HBe, EOT HBcrAg and time-varying HBsAg. During follow-up, HBcrAg <1,000 U/mL predicted a lower risk of CR (aHR, 0.41; 95% CI, 0.21-0.81). CONCLUSION: Dynamic measurement of HBcrAg after NA cessation is predictive of subsequent CR and may be useful to guide post-treatment monitoring.

Mandatory monthly outpatient visits could improve therapeutic inertia in patients with poorly controlled type 2 diabetes.

AIMS/INTRODUCTION: Delayed intensification of treatment, or therapeutic inertia, increases the risk of diabetic complications and death. The aim of this study was to determine the effect of mandatory monthly outpatient visits on therapeutic inertia in patients with suboptimal control of type 2 diabetes. MATERIALS AND METHODS: This retrospective cohort study used data from the Chang Gung Research Database and defined two study periods: the baseline period and the intervention period. The intervention period began when the Kaohsiung branch initiated a mandatory monthly outpatient visits program. Type 2 diabetes patients with baseline glycated hemoglobin (HbA1c) >7% and a follow-up HbA1c measurement were enrolled in each period, and divided into a Kaohsiung branch (intervention) group and the other branches (control) group. Therapy intensification was evaluated by comparing prescriptions after the follow-up HbA1c measurement with the prescriptions after the baseline HbA1c measurement. RESULTS: A total of 5,045 patients at the Kaohsiung branch and 13,400 participants at other branches were enrolled in the baseline period; and 5,573 and 15,603 patients, respectively, were enrolled in the intervention period. The adjusted odds ratio (AOR) for therapy intensification in patients with baseline HbA1c ≥9% was not significantly higher at 1.21 (95% CI, 1.00-1.47) in the intervention period at the Kaohsiung branch, but was significantly higher (AOR, 1.53; 95% CI, 1.02-2.30) in the subgroup with worsened HbA1c. CONCLUSIONS: Mandatory monthly outpatient visits could improve therapeutic inertia in patients with poorly controlled type 2 diabetes, especially in those with worsened control. The trajectory of HbA1c could significantly influence the assessment of the prevalence of therapeutic inertia.

KDM3B Single-Nucleotide Polymorphisms Impact Radiation Therapy Toxicity Through Circular RNA-Mediated KDM3B Expression and Inflammatory Responses.

PURPOSE: Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) associated with radiation therapy (RT) toxicities in patients with prostate cancer. SNP rs17599026 in intron 21 of KDM3B is significantly associated with the development of late urinary toxicity, specifically in the increase in urinary frequency 2 years after RT compared with pretreatment conditions. The present study aimed to provide mechanistic insights for this association. METHODS AND MATERIALS: Using human tissues and cell lines, we examined the protein expression of KDM3B and molecular mechanisms underlying the SNP modulation by variants of KDM3B SNP alleles. In animals with normal and heterozygous expressions of Kdm3b, we examined the relationship between Kdm3b expression and radiation toxicity. RESULTS: KDM3B rs17599026 lies in a motif important for circular RNA expression that is responsible for sponging miRNAs to regulate KDM3B expression. Using a murine model with heterozygous deletion of the Kdm3b gene, we found that lower Kdm3b expression is associated with altered pattern of urination after bladder irradiation, which is related to differential degrees of tissue inflammation as measured by analyses of gene expression, lymphocyte infiltration, and noninvasive ultrasound imaging. CONCLUSIONS: KDM3B SNPs can impact its expression through regulating noncoding RNA expression. Differential KDM3B expression underlies radiation toxicity through tissue inflammation at the molecular and physiological level. Our study outcome offers a foundation for mechanism-based mitigation for radiation toxicity for prostate cancer survivors.

Low-dose CT screening among never-smokers with or without a family history of lung cancer in Taiwan: a prospective cohort study.

BACKGROUND: In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis. We aimed to assess the efficacy of low-dose CT (LDCT) screening among never-smokers, who had other risk factors for lung cancer. METHODS: The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) was a nationwide, multicentre, prospective cohort study done at 17 tertiary medical centres in Taiwan. Eligible individuals had negative chest radiography, were aged 55-75 years, had never smoked or had smoked fewer than 10 pack-years and stopped smoking for more than 15 years (self-report), and had one of the following risk factors: a family history of lung cancer; passive smoke exposure; a history of pulmonary tuberculosis or chronic obstructive pulmonary disorders; a cooking index of 110 or higher; or cooking without using ventilation. Eligible participants underwent LDCT at baseline, then annually for 2 years, and then every 2 years up to 6 years thereafter, with follow-up assessments at each LDCT scan (ie, total follow-up of 8 years). A positive scan was defined as a solid or part-solid nodule larger than 6 mm in mean diameter or a pure ground-glass nodule larger than 5 mm in mean diameter. Lung cancer was diagnosed through invasive procedures, such as image-guided aspiration or biopsy or surgery. Here, we report the results of 1-year follow-up after LDCT screening at baseline. The primary outcome was lung cancer detection rate. The p value for detection rates was estimated by the χ2 test. Univariate and multivariable logistic regression analyses were used to assess the association between lung cancer incidence and each risk factor. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of LDCT screening were also assessed. This study is registered with ClinicalTrials.gov, NCT02611570, and is ongoing. FINDINGS: Between Dec 1, 2015, and July 31, 2019, 12 011 participants (8868 females) were enrolled, of whom 6009 had a family history of lung cancer. Among 12 011 LDCT scans done at baseline, 2094 (17·4%) were positive. Lung cancer was diagnosed in 318 (2·6%) of 12 011 participants (257 [2·1%] participants had invasive lung cancer and 61 [0·5%] had adenocarcinomas in situ). 317 of 318 participants had adenocarcinoma and 246 (77·4%) of 318 had stage I disease. The prevalence of invasive lung cancer was higher among participants with a family history of lung cancer (161 [2·7%] of 6009 participants) than in those without (96 [1·6%] of 6002 participants). In participants with a family history of lung cancer, the detection rate of invasive lung cancer increased significantly with age, whereas the detection rate of adenocarcinoma in situ remained stable. In multivariable analysis, female sex, a family history of lung cancer, and age older than 60 years were associated with an increased risk of lung cancer and invasive lung cancer; passive smoke exposure, cumulative exposure to cooking, cooking without ventilation, and a previous history of chronic lung diseases were not associated with lung cancer, even after stratification by family history of lung cancer. In participants with a family history of lung cancer, the higher the number of first-degree relatives affected, the higher the risk of lung cancer; participants whose mother or sibling had lung cancer were also at an increased risk. A positive LDCT scan had 92·1% sensitivity, 84·6% specificity, a PPV of 14·0%, and a NPV of 99·7% for lung cancer diagnosis. INTERPRETATION: TALENT had a high invasive lung cancer detection rate at 1 year after baseline LDCT scan. Overdiagnosis could have occurred, especially in participants diagnosed with adenocarcinoma in situ. In individuals who do not smoke, our findings suggest that a family history of lung cancer among first-degree relatives significantly increases the risk of lung cancer as well as the rate of invasive lung cancer with increasing age. Further research on risk factors for lung cancer in this population is needed, particularly for those without a family history of lung cancer. FUNDING: Ministry of Health and Welfare of Taiwan.

Upregulated enhancer of rudimentary homolog promotes epithelial­mesenchymal transition and cancer cell migration in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the deadliest cancers regarding both mortality rate and number of deaths and warrants greater effort in the development of potential therapeutic targets. The enhancer of rudimentary homolog (ERH) has been implicated in the promotion and progression of certain types of cancer. In the present study, ERH was assessed for its expression pattern and survival association with LUAD in public transcriptomic and proteomic databases. Bioinformatic methods and data from websites, including University of Alabama at Birmingham CANcer data analysis Portal and The Cancer Genome Atlas, were utilized to demonstrate the functional behaviors and corresponding pathways of ERH in LUAD. Human A549 and CL1­0 cell lines were used to validate the findings via functional assays. It was demonstrated that the expression of ERH, at both the transcriptomic and proteomic levels, was higher in LUAD compared with in adjacent non­tumor lung tissue and was associated with worse survival prognosis. Moreover, high ERH expression was correlated with more aggressive functional states, such as cell cycle and invasion in LUAD, and the positive ERH­correlated gene set was associated with worse survival and an immunosuppressive tumor microenvironment. Small nuclear ribonucleoprotein polypeptide G was identified as a molecule that potentially interacted with ERH. Lastly, it was demonstrated that ERH promoted epithelial­mesenchymal transition and cell migration in vitro, but not proliferation. In conclusion, higher expression of ERH in LUAD may facilitate cancer progression and confer worse outcomes. Further deep investigation into the role of ERH in LUAD is needed.

Pyruvate Kinase Differentially Alters Metabolic Signatures during Head and Neck Carcinogenesis.

During glycolysis, the muscle isoform of pyruvate kinase PKM2 produces ATP in exchange for dephosphorylation of phosphoenolpyruvate (PEP) into pyruvate. PKM2 has been considered as a tumor-promoting factor in most cancers, whereas the regulatory role of PKM2 during head and neck carcinogenesis remained to be delineated. PKM2 mRNA and protein expression was examined in head and neck tumorous specimens. The role of PKM2 in controlling cellular malignancy was determined in shRNA-mediated PKM2-deficient head and neck squamous cell carcinoma (HNSC) cells. In agreement with the results in other cancers, PKM2 expression is enriched in both mouse and human HNSC tissues. Nevertheless, PKM2 mRNA expression reversely correlated with tumor stage, and greater recurrence-free survival rates are evident in the PKM2high HNSC population, arguing that PKM2 may be tumor-suppressive. Multifaceted analyses showed a greater in vivo xenografic tumor growth and an enhanced cisplatin resistance in response to PKM2 loss, whereas PKM2 silencing led to reduced cell motility. At the molecular level, metabolic shifts towards mitochondrial metabolism and activation of oncogenic Protein kinase B (PKB/Akt) and extracellular signal-regulated kinase (ERK) signals were detected in PKM2-silencing HNSC cells. In sum, our findings demonstrated that PKM2 differentially modulated head and neck tumorigenicity via metabolic reprogramming.

Polygenic Risk Score, Environmental Tobacco Smoke, and Risk of Lung Adenocarcinoma in Never-Smoking Women in Taiwan.

Importance: Estimating absolute risk of lung cancer for never-smoking individuals is important to inform lung cancer screening programs. Objectives: To integrate data on environmental tobacco smoke (ETS), a known lung cancer risk factor, with a polygenic risk score (PRS) that captures overall genetic susceptibility, to estimate the absolute risk of lung adenocarcinoma (LUAD) among never-smokers in Taiwan. Design, Setting, and Participants: The analyses were conducted in never-smoking women in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma, a case-control study. Participants were recruited between September 17, 2002, and March 30, 2011. Data analysis was performed from January 17 to July 15, 2022. Exposures: A PRS was derived using 25 genetic variants that achieved genome-wide significance (P < 5 × 10-8) in a recent genome-wide association study, and ETS was defined as never exposed, exposed at home or at work, and exposed at home and at work. Main Outcomes and Measures: The Individualized Coherent Absolute Risk Estimator software was used to estimate the lifetime absolute risk of LUAD in never-smoking women aged 40 years over a projected 40-year span among the controls by using the relative risk estimates for the PRS and ETS exposures, as well as age-specific lung cancer incidence rates for never-smokers in Taiwan. Likelihood ratio tests were conducted to assess an additive interaction between the PRS and ETS exposure. Results: Data were obtained on 1024 women with LUAD (mean [SD] age, 59.6 [11.4] years, 47.9% ever exposed to ETS at home, and 19.5% ever exposed to ETS at work) and 1024 controls (mean [SD] age, 58.9 [11.0] years, 37.0% ever exposed to ETS at home, and 14.3% ever exposed to ETS at work). The overall average lifetime 40-year absolute risk of LUAD estimated using PRS alone was 2.5% (range, 0.6%-10.3%) among women never exposed to ETS. When integrating both ETS and PRS data, the estimated absolute risk was 3.7% (range, 0.6%-14.5%) for women exposed to ETS at home or work and 5.3% (range, 1.2%-12.1%) for women exposed to ETS at home and work. A super-additive interaction between ETS and the PRS (P = 6.5 × 10-4 for interaction) was identified. Conclusions and Relevance: This study found differences in absolute risk of LUAD attributed to genetic susceptibility according to levels of ETS exposure in never-smoking women. Future studies are warranted to integrate these findings in expanded risk models for LUAD.