Therapy-induced APOBEC3A drives evolution of persistent cancer cells.

Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1-4, the underlying molecular mechanisms shaping tumour evolution during treatment are incompletely understood. Genomic profiling of patient tumours has implicated apolipoprotein B messenger RNA editing catalytic polypeptide-like (APOBEC) cytidine deaminases in tumour evolution; however, their role during therapy and the development of acquired drug resistance is undefined. Here we report that lung cancer targeted therapies commonly used in the clinic can induce cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Therapy-induced A3A promotes the formation of double-strand DNA breaks, increasing genomic instability in drug-tolerant persisters. Deletion of A3A reduces APOBEC mutations and structural variations in persister cells and delays the development of drug resistance. APOBEC mutational signatures are enriched in tumours from patients with lung cancer who progressed after extended responses to targeted therapies. This study shows that induction of A3A in response to targeted therapies drives evolution of drug-tolerant persister cells, suggesting that suppression of A3A expression or activity may represent a potential therapeutic strategy in the prevention or delay of acquired resistance to lung cancer targeted therapy.

Truncated FGFR2 is a clinically actionable oncogene in multiple cancers.

Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer1. However, clinical responses to FGFR inhibitors have remained variable1-9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening10,11 and tumour modelling in mice12,13, and find that the truncation of exon 18 (E18) of Fgfr2 is a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements, E1-E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing the transcription of E18-truncated FGFR2 (FGFR2ΔE18). Functional in vitro and in vivo examination of a compendium of FGFR2ΔE18 and full-length variants pinpointed FGFR2-E18 truncation as single-driver alteration in cancer. By contrast, the oncogenic competence of FGFR2 full-length amplifications depended on a distinct landscape of cooperating driver genes. This suggests that genomic alterations that generate stable FGFR2ΔE18 variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumour models, and in a clinical trial. We propose that cancers containing any FGFR2 variant with a truncated E18 should be considered for FGFR-targeted therapies.

Medulloblastomas Initiated by Homologous Recombination Defects in Mice.

Germline mutations of homologous-recombination (HR) genes are among the top contributors to medulloblastomas. A significant portion of human medulloblastomas exhibit genomic signatures of HR defects. We queried whether ablation of Brca2 and Palb2, and their related Brca1 and Bccip genes, in the mouse brain can differentially initiate medulloblastomas. Conditional knockout mouse models of these HR genes and a conditional knockdown of Bccip (shBccip-KD) were established. Deletion of any of these genes led to microcephaly and neurologic defects, with Brca1- and Bccip- producing the worst. Trp53 co-deletion significantly rescued the microcephaly with Brca1, Palb2, and Brca2 deficiency but exhibited limited impact on Bccip- mice. For the first time, inactivation of either Brca1 or Palb2 with Trp53 was found to induce medulloblastomas. Despite shBccip-CKD being highly penetrative, Bccip/Trp53 deletions failed to induce medulloblastomas. The tumors displayed diverse immunohistochemical features and chromosome copy number variation. Although there were widespread up-regulations of cell proliferative pathways, most of the tumors expressed biomarkers of the sonic hedgehog subgroup. The medulloblastomas developed from Brca1-, Palb2-, and Brca2- mice were highly sensitive to a poly (ADP-ribose) polymerase inhibitor but not the ones from shBccip-CKD mice. These models recapitulate the spontaneous medulloblastoma development with high penetrance and a narrow time window, providing ideal platforms to test therapeutic agents with the ability to differentiate HR-defective and HR-proficient tumors.

Long-term PM2.5 exposure is associated with asthma prevalence and exhaled nitric oxide levels in children.

BACKGROUND: Exhaled nitric oxide concentration (FENO) is a marker of airway inflammation. This study aimed to evaluate the association of air pollution exposure with FENO levels and asthma prevalence with respiratory symptoms in school children. METHODS: We analyzed 4736 school children who reside in six townships near industrial areas in central Taiwan. We evaluated asthmatic symptoms, FENO, and conducted the environmental questionnaire. The personal exposure of PM2.5, NO, and SO2 was estimated using land-use regression models data on children's school and home addresses. RESULTS: Annual exposure to PM2.5 was associated with increased odds of physician-diagnosed asthma (OR = 1.595), exercise-induced wheezing (OR = 1.726), itchy eyes (OR = 1.417), and current nasal problems (OR = 1.334) (P < 0.05). FENO levels in the absence of infection were positively correlated with age, previous wheezing, allergic rhinitis, atopic eczema, near the road, and for children with high exposure to PM2.5 (P < 0.05). An increase of 1 µg/m3 PM2.5 exposure was significantly associated with a 1.0% increase in FENO levels for children after adjusting for potential confounding variables, including exposures to NO and SO2. CONCLUSIONS: Long-term exposures to PM2.5 posed a significant risk of asthma prevalence and airway inflammation in a community-based population of children. IMPACT: Annual exposure to PM2.5 was associated with increased odds of physician-diagnosed asthma and nasal problems and itchy eyes. Long-term exposures to PM2.5 were significantly associated with FENO levels after adjusting for potential confounding variables. This is first study to assess the association between FENO levels and long-term air pollution exposures in children near coal-based power plants. An increase of 1 µg/m3 annual PM2.5 exposure was significantly associated with a 1.0% increase in FENO levels. Long-term exposures to PM2.5 posed a significant risk of asthma prevalence and airway inflammation in a community-based population of children.

A nationwide case-referent study on elevated risks of adenocarcinoma lung cancer by long-term PM2.5 exposure in Taiwan since 1997.

BACKGROUND: The effects of long-term PM2.5 exposures since 1968 on adenocarcinoma lung cancer (AdLC) were not studied before. METHODS: This case-referent study used nationwide cancer registry data since 1997 and air pollution data since 1968 in Taiwan to estimate risks of 30-year PM2.5 exposures on AdLC. Cases were all AdLC, while references were all non-AdLC. Individuals' 30-year PM2.5 exposures were estimated by PM2.5 levels at their residence for 30 years prior their diagnosis dates. We applied multiple logistic regression analyses to estimate PM2.5 exposures on incidence rate ratios (IRRs) between cases and references, adjusting for sex, age, smoking, cancer stage, and EGFR mutation. RESULTS: Elevation in annual ambient PM2.5 concentrations since 1968 were associated with increase in annual age-adjusted AdLC incidence since 1997. AdLC incidences were higher among females, nonsmokers, the elderly aged above 65, cases of stages IIIB to IV, and EGFR mutation. Study subjects' PM2.5 exposures averaged at 33.7 ± 7.4 µg/m3 with 162 ± 130 high PM2.5 pollution days over 30 years. Multiple logistic models showed an increase in 10 µg/m3 of PM2.5 exposures were significantly associated with 1.044 of IRR between all AdLC and all non-AdLC cases during 2011-2020. Our models also showed that females and nonsmokers and adults less than 65 years had higher IRRs than their respective counterparts. Restricted analyses showed similar effects of PM2.5 exposures on IRRs between stage 0-IIIA and IIIB-IV cases and between EGFR+ and EGFR- cases. CONCLUSIONS: Long-term exposures to PM2.5 over 30 years were associated with elevated risks of AdLC against non-AdLC, regardless of gender, age, smoking status, cancer stage, or EGFR mutation.

Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells.

Autophagy degrades and is thought to recycle proteins, other macromolecules, and organelles. In genetically engineered mouse models (GEMMs) for Kras-driven lung cancer, autophagy prevents the accumulation of defective mitochondria and promotes malignancy. Autophagy-deficient tumor-derived cell lines are respiration-impaired and starvation-sensitive. However, to what extent their sensitivity to starvation arises from defective mitochondria or an impaired supply of metabolic substrates remains unclear. Here, we sequenced the mitochondrial genomes of wild-type or autophagy-deficient (Atg7(-/-)) Kras-driven lung tumors. Although Atg7 deletion resulted in increased mitochondrial mutations, there were too few nonsynonymous mutations to cause generalized mitochondrial dysfunction. In contrast, pulse-chase studies with isotope-labeled nutrients revealed impaired mitochondrial substrate supply during starvation of the autophagy-deficient cells. This was associated with increased reactive oxygen species (ROS), lower energy charge, and a dramatic drop in total nucleotide pools. While starvation survival of the autophagy-deficient cells was not rescued by the general antioxidant N-acetyl-cysteine, it was fully rescued by glutamine or glutamate (both amino acids that feed the TCA cycle and nucleotide synthesis) or nucleosides. Thus, maintenance of nucleotide pools is a critical challenge for starving Kras-driven tumor cells. By providing bioenergetic and biosynthetic substrates, autophagy supports nucleotide pools and thereby starvation survival.

Fear of falling as a mediator in the association between social frailty and health-related quality of life in community-dwelling older adults.

BACKGROUND: Social frailty is associated with Fear of Falling (FoF) and health-related quality of life (HrQoL). However, how social frailty simultaneously influences FoF and HrQoL remains unclear. The study aims to understand the links between social frailty, FoF, and HrQoL in older adults and the mediating role of FoF in the relations between social frailty and HrQoL. METHODS: In this cross-sectional survey, 1,933 community-dwelling older adults from Changhua County, Taiwan, were interviewed using a self-administrated questionnaire. In total, 1,251 participants with complete data were included for analysis. Data were analyzed using the SPSS PROCESS macro. A simple mediation was employed using social frailty as the independent variable, FoF as the mediator variable, and HrQoL as the outcome variable. RESULTS: Social frailty was associated with HrQoL and indirectly with HrQoL through FoF, and FoF was directly associated with HrQoL. Of the 5-item social frailty index, "going out less frequently" was correlated with HrQoL and indirectly with HrQoL through FoF. Individuals who felt unhelpful toward family or friends had the worst physical HrQoL and did not talk to someone daily had the most negative influence on mental HrQoL. CONCLUSIONS: Social frailty can directly and indirectly, through FoF decrease HrQoL. It also emphasizes the importance of social connectivity in reducing the risk of falls. This study points to the need for social connectivity and fall prevention programs as essential components of strategies to enhance the health and well-being of community-dwelling older adults.

Long-Term Efficacy and Safety of Repeated Rituximab to Maintain Remission in Idiopathic Childhood Nephrotic Syndrome: An International Study.

BACKGROUND: Long-term outcomes after multiple courses of rituximab among children with frequently relapsing, steroid-dependent nephrotic syndrome (FRSDNS) are unknown. METHODS: A retrospective cohort study at 16 pediatric nephrology centers from ten countries in Asia, Europe, and North America included children with FRSDNS who received two or more courses of rituximab. Primary outcomes were relapse-free survival and adverse events. RESULTS: A total of 346 children (age, 9.8 years; IQR, 6.6-13.5 years; 73% boys) received 1149 courses of rituximab. A total of 145, 83, 50, 28, 22, and 18 children received two, three, four, five, six, and seven or more courses, respectively. Median (IQR) follow-up was 5.9 (4.3-7.7) years. Relapse-free survival differed by treatment courses (clustered log-rank test P<0.001). Compared with the first course (10.0 months; 95% CI, 9.0 to 10.7 months), relapse-free period and relapse risk progressively improved after subsequent courses (12.0-16.0 months; HRadj, 0.03-0.13; 95% CI, 0.01 to 0.18; P<0.001). The duration of B-cell depletion remained similar with repeated treatments (6.1 months; 95% CI, 6.0 to 6.3 months). Adverse events were mostly mild; the most common adverse events were hypogammaglobulinemia (50.9%), infection (4.5%), and neutropenia (3.7%). Side effects did not increase with more treatment courses nor a higher cumulative dose. Only 78 of the 353 episodes of hypogammaglobulinemia were clinically significant. Younger age at presentation (2.8 versus 3.3 years; P=0.05), age at first rituximab treatment (8.0 versus 10.0 years; P=0.01), and history of steroid resistance (28% versus 18%; P=0.01) were associated with significant hypogammaglobulinemia. All 53 infective episodes resolved, except for one patient with hepatitis B infection and another with EBV infection. There were 42 episodes of neutropenia, associated with history of steroid resistance (30% versus 20%; P=0.04). Upon last follow-up, 332 children (96%) had normal kidney function. CONCLUSIONS: Children receiving repeated courses of rituximab for FRSDNS experience an improving clinical response. Side effects appear acceptable, but significant complications can occur. These findings support repeated rituximab use in FRSDNS.

Sex-specific autosomal genetic effects across 26 human complex traits.

Previous studies have shown that men and women have different genetic architectures across many traits. However, except waist-to-hip ratio (WHR) and waist circumference (WC), it remains unknown whether the genetic effects of a certain trait are weaker or stronger on men/women. With ~18 000 Taiwan Biobank subjects, we comprehensively investigate sexual heterogeneity in autosomal genetic effects, for traits regarding cardiovascular health, diabetes, kidney, liver, anthropometric profiles, blood, etc. 'Gene-by-sex interactions' (G $\times$ S) were detected in 18 out of 26 traits, each with an interaction P-value (${{P}}_{{INT}}$) less than $0.05/104={0.00048}$, where 104 is the number of tests conducted in this study. The most significant evidence of G $\times$ S was found in WHR (${{P}}_{{INT}}$ = 3.2 $\times{{10}}^{-{55}}$) and WC (${{P}}_{{INT}}$ = 2.3$\times{{10}}^{-{41}}$). As a novel G$\times$S investigation for other traits, we here find that the autosomal genetic effects are weaker on women than on men, for low-density lipoprotein cholesterol (LDL-C), uric acid (UA) and diabetes-related traits such as fasting glucose and glycated hemoglobin. For LDL-C and UA, the evidence of G$\times$S is especially notable in subjects aged less than 50 years, where estrogen can play a role in attenuating the autosomal genetic effects of these two traits. Men and women have systematically distinct environmental contexts caused by hormonal milieu and their specific society roles, which may trigger diverse gene expressions despite the same DNA materials. As many environmental exposures are difficult to collect and quantify, sex can serve as a good surrogate for these factors.

Multicenter study on the genetics of glomerular diseases among southeast and south Asians: Deciphering Diversities - Renal Asian Genetics Network (DRAGoN).

Multinational studies have reported monogenic etiologies in 25%-30% of children with steroid-resistant nephrotic syndrome. Such large studies are lacking in Asia. We established Deciphering Diversities: Renal Asian Genetics Network (DRAGoN) and aimed to describe the genetic and clinical spectrums in Asians. We prospectively studied a cohort of 183 probands with suspected genetic glomerulopathies from South and Southeast Asia, of whom 17% had positive family history. Using multi-gene panel sequencing, we detected pathogenic variants in 26 (14%) probands, of whom one-third had COL4A4 or COL4A5 variants (n = 9, 5%). Of those with COL4A5 defects, only 25% had features suggestive of Alport syndrome. Besides traditional predictors for genetic disease (positive family history and extrarenal malformations), we identified novel predictors, namely older age (6.2 vs. 2.4 years; p = 0.001), hematuria (OR 5.6; 95% CI 2.1-14.8; p < 0.001), and proteinuria in the absence of nephrotic syndrome (OR 4.6; 95% CI 1.8-11.8; p = 0.001) at first manifestation. Among patients who first presented with proteinuria without nephrotic syndrome, the genetic diagnostic rates were >60% when a second risk factor (positive family history or extrarenal manifestation) co-existed. The genetic spectrum of glomerulopathies appears different in Asia. Collagen IV genes may be included in sequencing panels even when suggestive clinical features are absent.

Urban Fine Particulate Matter and Elements Associated with Subclinical Atherosclerosis in Adolescents and Young Adults.

The relationships between the elemental constituents of PM2.5 and atherosclerosis remain limited, especially in young populations. This study included 755 subjects aged 12-30 years in the Taipei metropolis. A land use regression model was used to estimate residential annual mean concentrations of PM2.5 and eight elemental constituents. We evaluated the percent differences in carotid intima-media thickness (CIMT) with PM2.5 and elemental constituent exposures by linear regressions. Interquartile range increments for PM2.5 (4.5 µg/m3), sulfur (108.6 ng/m3), manganese (2.0 ng/m3), iron (34.5 ng/m3), copper (3.6 ng/m3), and zinc (20.7 ng/m3) were found to associate with 0.92% (95% confidence interval (CI): 0.17-1.66), 0.51% (0.02-1.00), 0.36% (0.05-0.67), 0.98% (0.15-1.82), 0.74% (0.01-1.48), and 1.20% (0.33-2.08) higher CIMTs, respectively. Factor analysis identified four air pollution source-related factors, and the factors interpreted as traffic and industry sources were associated with higher CIMTs. Stratified analyses showed the estimates were more evident in subjects who were ≥18 years old, females, or who had lower household income. Our study results provide new insight into the impacts of source-specific air pollution, and future research on source-specific air pollution effects in young populations, especially in vulnerable subpopulations, is warranted.

'I Knew I Should Stop, but I Couldn't Control Myself': a qualitative study to explore the factors influencing adolescents' consumption of sugar-sweetened beverages and sugary snacks from a socio-ecological perspective.

OBJECTIVE: To explore the factors influencing Taiwanese adolescents' consumption of sugar-sweetened beverages (SSB) and sugary snacks from a socio-ecological perspective. DESIGN: This study adopted a qualitative design by using face-to-face, in-depth interviews guided by a semistructured questionnaire. SETTING: Eight junior high schools in New Taipei City and Changhua County, Taiwan, September to November 2018. PARTICIPANTS: Fifty-nine participants aged 12-14 years participated in this study. RESULTS: Reflexive thematic analysis was used to analyse the data. This study identified four themes to address the multifaceted factors that influence adolescents' consumption of SSB and sugary snacks. At the intrapersonal level, physiological factors, psychological factors, individual economic factors and taste preferences were mentioned in connection with people's consumption of SSB and sugary snacks. Positive or negative influences of parents, siblings, peers and teachers on SSB and sugary snack intake were identified at the interpersonal level. The availability of SSB and sugary snacks at home, their availability in vending machines or in school stores in the school environment and participants' access to convenience stores and hand-shaken drink shops in the broader community influenced SSB and sugary snack consumption. Additionally, food culture and food advertising were identified as influencing societal factors. CONCLUSIONS: Overall, this qualitative study determined not only that the consumption of SSB and sugary snacks is influenced by intrapersonal factors but also that interpersonal, environmental and societal factors affect adolescents' increased sugar intake. The findings are helpful to broaden the options for designing and developing interventions to decrease SSB and sugary snack consumption by adolescents.

Sex differences in the association between sugar-sweetened beverages consumption and metabolic risks among the working-age population in Taiwan.

OBJECTIVE: Sugar-sweetened beverages (SSBs) are linked to increased metabolic risk. However, the sex differences in the relationship between SSB intake and adverse health effects remain unclear. Therefore, the present study examined the association between SSB consumption and metabolic risks among working-age males and females from Taiwanese communities. DESIGN: A community-based study utilized data from a comprehensive health screening project conducted by the Public Health Bureau in Changhua County, Taiwan. Metabolic risks included waist circumference, systolic blood pressure, diastolic blood pressure, total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL), and fasting glucose level using serum tests. SETTING: Participants were recruited in Changhua County, Taiwan. PARTICIPANTS: Between 2005 and 2014, 92,724 citizens participated in the health screening; our data analysis included 75,278 respondents between 30 and 64. RESULTS: The results showed that the frequency of SSB consumption was associated with abnormal waist circumference and elevated total cholesterol, triglycerides, LDL, and glucose in both men and women. Increased SSB consumption frequency was associated with elevated glucose and hypertension in women. Even a slight increase in SSB intake frequency was related to raising the metabolic risks. Similar patterns were evident when models included body mass index (BMI); however, the associations were attenuated. In the BMI-stratified subgroup analysis, the relationship between SSB consumption and metabolic risks was more pronounced in participants without obesity. CONCLUSION: The present study suggests that SSB consumption carries metabolic risk among working-age Taiwanese, particularly women and those without obesity. Health promotion programs should raise awareness of the health hazards associated with SSBs.

Performing different kinds of physical exercise differentially attenuates the genetic effects on obesity measures: Evidence from 18,424 Taiwan Biobank participants.

Obesity is a worldwide health problem that is closely linked to many metabolic disorders. Regular physical exercise has been found to attenuate the genetic predisposition to obesity. However, it remains unknown what kinds of exercise can modify the genetic risk of obesity. This study included 18,424 unrelated Han Chinese adults aged 30-70 years who participated in the Taiwan Biobank (TWB). A total of 5 obesity measures were investigated here, including body mass index (BMI), body fat percentage (BFP), waist circumference (WC), hip circumference (HC), and waist-to-hip ratio (WHR). Because there have been no large genome-wide association studies on obesity for Han Chinese, we used the TWB internal weights to construct genetic risk scores (GRSs) for each obesity measure, and then test the significance of GRS-by-exercise interactions. The significance level throughout this work was set at 0.05/550 = 9.1x10-5 because a total of 550 tests were performed. Performing regular exercise was found to attenuate the genetic effects on 4 obesity measures, including BMI, BFP, WC, and HC. Among the 18 kinds of self-reported regular exercise, 6 mitigated the genetic effects on at least one obesity measure. Regular jogging blunted the genetic effects on BMI, BFP, and HC. Mountain climbing, walking, exercise walking, international standard dancing, and a longer practice of yoga also attenuated the genetic effects on BMI. Exercises such as cycling, stretching exercise, swimming, dance dance revolution, and qigong were not found to modify the genetic effects on any obesity measure. Across all 5 obesity measures, regular jogging consistently presented the most significant interactions with GRSs. Our findings show that the genetic effects on obesity measures can be decreased to various extents by performing different kinds of exercise. The benefits of regular physical exercise are more impactful in subjects who are more predisposed to obesity.

Governmental public health in Taiwan.

A healthy and safe public health environment is a fundamental responsibility of government; achieving it requires collaboration across multiple sectors. Public health services include, for example, vaccination and quarantine for infectious diseases; health promotion, such as anti-smoking campaigns for noncommunicable diseases; and health insurance for universal health coverage. All these services require intersectoral actions in which the government must play a fundamental role, either partially or totally. The Taiwanese outlook on governmental public health infrastructure and professionalization of public health is given in this paper. It also describes the national governmental public health measures that were employed during the Covid-19 pandemic and discusses the challenges ahead for the country's governmental public health. Governmental public health is essential and should not be affected by changes in political forms or socioeconomic development. Instead, effective governmental public health will promote these developments while protecting citizens' right to health.

Open space and adult's chronic kidney disease, overweight and diabetes in the metropolitan area of New Taipei City.

BACKGROUND: The beneficial effects of urban open green space on residential health had few investigations in Taiwan. METHODS: A total of 40,375 participants older than 30-year-old attended the health screening program during 2007-2009 in the Metropolitan area in the New Taipei City. We defined urban open green spaces (UOGS) if land use belongs to parks, green, plaza, public schools and sport venues. Small public urban open space (SPUOS) is defined as UOGS with area less than 1 hector and with at least three of the followings: vegetations, sport facilities and benches. Greenness is defined as the mean Normalized Difference Vegetation Index (NDVI). Air quality was accessed by land use regression model. Logistic regression model was used to calculate odds ratios of diseases for proximity to UOGS or greenness. RESULTS: We found that CKD was significantly associated with proximity to SPUOS. No relationship was found between proximity to UOGS or NDVI and overweight or diabetes. The adjusted odds ratio of CKD comparing distance to SPUOS >200 m and ≤200 m was 1.144 (95% CI, 1.059-1.237). The effect of open space on CKD was similar if we incorporated public schools to SPUOS. Greenness was not associated with CKD. Subgroups analyses revealed the effect of SPUOS on CKD was more prominent in health residents, including in those who never smoke, no hypertension, no diabetes and no hypertriglyceridemia. CONCLUSION: Proximity to SPUOS or schools is associated with lower risk of CKD for adults living in the Metropolitan area in New Taipei City.

The evolution of thymic lymphomas in p53 knockout mice.

Germline deletion of the p53 gene in mice gives rise to spontaneous thymic (T-cell) lymphomas. In this study, the p53 knockout mouse was employed as a model to study the mutational evolution of tumorigenesis. The clonality of the T-cell repertoire from p53 knockout and wild-type thymic cells was analyzed at various ages employing TCRß sequencing. These data demonstrate that p53 knockout thymic lymphomas arose in an oligoclonal fashion, with tumors evolving dominant clones over time. Exon sequencing of tumor DNA revealed that all of the independently derived oligoclonal mouse tumors had a deletion in the Pten gene prior to the formation of the TCRß rearrangement, produced early in development. This was followed in each independent clone of the thymic lymphoma by the amplification or overexpression of cyclin Ds and Cdk6. Alterations in the expression of Ikaros were common and blocked further development of CD-4/CD-8 T cells. While the frequency of point mutations in the genome of these lymphomas was one per megabase, there were a tremendous number of copy number variations producing the tumors' driver mutations. The initial inherited loss of p53 functions appeared to delineate an order of genetic alterations selected for during the evolution of these thymic lymphomas.

Characteristics of neonicotinoid and metabolite residues in Taiwanese tea leaves.

BACKGROUND: Neonicotinoids are widely used insecticides, and tea is a popular non-alcoholic beverage in Taiwan. However, the levels of neonicotinoids in Taiwanese tea leaves remain unclear. Therefore, this study aims to understand the characteristics of neonicotinoid and metabolite residues in Taiwanese tea leaves. METHODS: In this study, 12 tea leaf samples were collected in Taiwan and extracted by solid-phase extraction before analysis by liquid chromatography-tandem mass spectrometry. In addition, the levels of neonicotinoids were compared with the maximum residue level standards from other countries. RESULTS: In Taiwanese tea leaves, five neonicotinoids and seven metabolites were detected. Different tea species influenced the levels of neonicotinoids and their metabolites in the present study. Moreover, the levels of neonicotinoids and their metabolites in partially fermented leaves were higher than in completely fermented leaves. In Jin-Xuan tea, the levels of neonicotinoids and their metabolites in most winter-harvested teas were lower than in summer-harvested teas. CONCLUSION: The residue levels of neonicotinoids and their metabolites were detectable in Taiwanese tea leaves. Moreover, different tea species, manufacturing processes, and harvest seasons might influence the levels of these pesticides. Therefore, the government should monitor the use of neonicotinoids. © 2021 Society of Chemical Industry.

Mass eradication of Helicobacter pylori to reduce gastric cancer incidence and mortality: a long-term cohort study on Matsu Islands.

OBJECTIVE: Although mass eradication of Helicobacter pylori has been proposed as a means to eliminate gastric cancer, its long-term effects remain unclear. DESIGN: Mass eradication of H. pylori infection was launched in 2004 and continued until 2018 for a high-risk Taiwanese population aged 30 years or older dwelling on Matsu Islands with prevalent H. pylori infection. Test positives for the 13C-urea breath test underwent eradication therapy. We evaluated the effectiveness of the mass eradication in reducing two main outcomes, incidence and mortality rates of gastric cancer, until the end of 2016 and 2018, respectively. RESULTS: After six rounds of mass screening and eradication, the coverage rate reached 85.5% (6512/7616). The referral rate for treatment was 93.5% (4286/4584). The prevalence rates of H. pylori fell from 64.2% to 15.0% with reinfection rates of less than 1% per person-year. The presence and severity of atrophic gastritis and intestinal metaplasia also decreased with time. Compared with the historical control period from 1995 to 2003, the effectiveness in reducing gastric cancer incidence and mortality during the chemoprevention period was 53% (95% CI 30% to 69%, p<0.001) and 25% (95% CI -14% to 51%, p=0.18), respectively. No significant changes were noted in the incidence rates of other digestive tract cancers or the antibiotic resistance rate of H. pylori. CONCLUSION: Population-based eradication of H. pylori has significantly reduced gastric cancer incidence with no increase in the likelihood of adverse consequences. A significant reduction in mortality is likely to be achieved with a longer follow-up period. TRIAL REGISTRATION NUMBER: NCT00155389.