This study used the Disability-Adjusted Life Years (DALYs) to quantify the long-term trends for four cancers (oral cancer, colorectal cancer, breast cancer, and cervical cancer) that have undergone cancer screening in Taiwan. DALYs were calculated as the sum of Years of Life Lost (YLL) due to premature mortality and Years Lived with Disability (YLD). YLLs were determined using cancer-specific mortality data from the Health Promotion Administration (HPA), Ministry of Health and Welfare, based on age-specific life expectancy. YLDs were estimated by combining the incidence rates of the cancers, average disability durations, and disability weights, with data sourced from the Taiwan Cancer Registry. Results were expressed as DALYs per 100,000 population. The disease burden has significantly increased over the past 12 years. Oral cancer rose from 263 to 368 DALYs per 100,000 population (40 % increase), colorectal cancer from 343 to 563 DALYs (64 % increase), and breast cancer from 446 to 782 DALYs (75 % increase), while the burden of cervical cancer decreased from 168 to 147 DALYs per 100,000 population from 2010 to 2017, showing a 13 % reduction. At the cancer stages, the impact of YLDs was mostly at cancer stage IV (oral cancer), cancer stage 0 (colorectal and cervical cancer), and stage I (breast cancer). Oral cancer increased by 40 %, colorectal cancer by 64 %, and breast cancer by 75 % from 2005 to 2017, while cervical cancer decreased by 13 % between 2010 and 2017. YLD contributions were highest in stage IV for oral cancer, stage 0 for colorectal and cervical cancers, and stage I for breast cancer. The highest DALYs consistently occurred in the 50-69 age group across all cancer types, highlighting the significant burden on middle-aged populations.
Abstract Immune checkpoint inhibition (ICI) via anti-PD-1/PD-L1 and anti-CTLA4, has improved clinical outcomes for multiple cancers, including non-small cell lung cancer (NSCLC), kidney cancer, and melanoma. Despite this success, response rates remain low, highlighting the need for more robust predictive biomarkers. In this study, we used cell-free DNA (cfDNA) profiles from patients undergoing ICI therapy to identify common signatures associated with responses shared among the three cancers. Whole-genome sequencing (mean coverage=18X) of cfDNA was performed on pre-treatment plasma samples from 126 patients across three cancers (NSCLC, n=91; kidney, n=21; melanoma, n=14). Transcriptional activation for protein-coding genes was then inferred by modeling fragment distribution around each transcription start site (TSS-GAP). Transcription factor binding activity (TFBA) was estimated by measuring binding site accessibility across the genome. To delineate potential signatures of response, we performed a gene set enrichment analysis (GSEA) based on weighted average effect sizes of TSS-GAP levels between response groups across the three cancer types. GSEA results showed an enrichment of DNA repair and cell cycle genes in non-responders and of EMT processing genes in responders. To identify shared signatures of ICI response, we performed a meta-analysis by (1) computing the effect size between response groups for TFBA and TSS-GAP features in each cancer type; (2) calculating a weighted-average effect size across cancer types; (3) performing gene selection based on the degree of heterogeneity among cancer types, followed by false discovery rate correction and assessment of significance through Monte Carlo permutation testing. This analysis identified 13 transcription factors and 269 genes consistently enriched in response groups across these cancer types. Notably, this analysis revealed significantly higher accessibility in STAT5A (p=0.02), JUN (p=0.02) and JUNB (p=0.03) in non-responders, suggesting JAK/STAT-pathway dependency as a common feature in ICI resistance. Using our platform that detects both tumor and non-tumor-derived signals, we identified common signatures of ICI response, revealing a potential pathway of resistance through JAK/STAT signaling and a possible EMT signature of response in kidney, melanoma, and NSCLC. These findings warrant further investigation into using cfDNA signatures for patient stratification and response monitoring. Citation Format: Hayley Donnella, Yue Zhang, Irving Wang, Francesco Vallania, Maggie Louie, C. Jimmy Lin. Whole genome cfDNA profiles reveal common signatures of Immune checkpoint inhibition response in kidney, melanoma, and lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2138.
Abstract Background Chronic hepatitis C virus (HCV) infection is associated with early onset of chronic diseases and increased risk of chronic disorders. Chronic viral infections have been linked to accelerated biological aging based on epigenetic clocks. In this study, we aimed to investigate the association between HCV infection and clinical measures of biological aging among 8 306 adults participating in the 2015–2018 waves of the National Health and Nutrition Examination Survey (NHANES). Methods NHANES 2015–2018 participants aged 20 years and older who had complete data on clinical blood markers and HCV-related tests were included in the current study. We estimated biological age using 2 approaches including phenotypic age (PhenoAge) and allostatic load (AL) score based on 9 clinical biomarkers. Results After adjusting for demographic and other confounding factors, HCV antibody-positivity was associated with advanced PhenoAge (β = 2.43, 95% confidence interval: 1.51–3.35), compared with HCV antibody-negativity. Additionally, both active HCV infection (HCV RNA (+)) and resolved infection were associated with greater PhenoAge acceleration. The positive association with the AL score was not statistically significant. We did not observe any significant interactions of potential effect modifiers, including smoking and use of drug/needle injection, with HCV infection on measures of biological aging. Conclusions Our findings suggest that HCV infection is independently associated with biological aging measured by phenotypic age in the U.S. general population. Further studies are warranted to confirm the findings.
We investigated the effects of early intervention with maternal fecal microbiota and antibiotics on gut microbiota and the metabolites. Five litters of healthy neonatal piglets (Duroc × Landrace × Yorkshire, nine piglets in each litter) were used. Piglets in each litter were orally treated with saline (CO), amoxicillin treatment (AM), or maternal fecal microbiota transplantation (MFMT) on days 1–6, with three piglets in each treatment. Results were compared to the CO group. MFMT decreased the relative abundances of Clostridium sensu stricto and Parabacteroides in the colon on day 7, whereas the abundance of Blautia increased, and the abundance of Corynebacterium in the stomach reduced on day 21. AM reduced the abundance of Arcanobacterium in the stomach on day 7 and reduced the abundances of Streptococcus and Lachnoclostridium in the ileum and colon on day 21, respectively. The metabolite profile indicated that MFMT markedly influenced carbohydrate metabolism and amino acid (AA) metabolism on day 7. On day 21, carbohydrate metabolism and AA metabolism were affected by AM. The results suggest that MFMT and AM discriminatively modulate gastrointestinal microflora and alter the colonic metabolic profiles of piglets and show different effects in the long-term. MFMT showed a location-specific influence on the gastrointestinal microbiota.
Hypercoagulability is a recognized feature in SARS-CoV-2 infection. There exists a need for a dedicated risk assessment model (RAM) that can risk-stratify hospitalized COVID-19 patients for venous thromboembolism (VTE) and guide anticoagulation. We aimed to build a simple clinical model to predict VTE in COVID-19 patients. This large-cohort, retrospective study included adult patients admitted to four hospitals with PCR-confirmed SARS-CoV-2 infection. Model training was performed on 3531 patients hospitalized between March and December 2020 and validated on 2508 patients hospitalized between January and September 2021. Diagnosis of VTE was defined as acute deep vein thrombosis (DVT) or pulmonary embolism (PE). The novel RAM was based on commonly available parameters at hospital admission. LASSO regression and logistic regression were performed, risk scores were assigned to the significant variables, and cutoffs were derived. Seven variables with assigned scores were delineated as: DVT History = 2; High D-Dimer (>500−2000 ng/mL) = 2; Very High D-Dimer (>2000 ng/mL) = 5; PE History = 2; Low Albumin (<3.5 g/dL) = 1; Systolic Blood Pressure <120 mmHg = 1, Tachycardia (heart rate >100 bpm) = 1. The model had a sensitivity of 83% and specificity of 53%. This simple, robust clinical tool can help individualize thromboprophylaxis for COVID-19 patients based on their VTE risk category.
The establishment of a stable bacterial flora in early life is associated with host metabolism. Studies of faecal microbiota transplantation (FMT) and antibiotics on neonatal pig mainly focused on intestinal development and mucosal immunity, but the information on metabolism is lacking. The objective of this study was to investigate the responses of metabolome and transcriptome in the livers of neonatal piglets that were orally inoculated with maternal faecal bacteria suspension and amoxicillin (AM) solution. Five litters of Duroc × Landrace × Yorkshire neonatal piglets were used as five replicates and nine piglets in each litter were randomly assigned to the control (CO), AM or FMT groups. Neonatal piglets in three groups were fed with 3 mL saline (0.9%), AM solution (6.94 mg/mL) or faecal bacteria suspension (>109/mL), respectively, on days 1–6. At the age of 7 and 21 days, one piglet from each group in each litter was sacrificed, and the serum and liver were collected for analysis. The RNA sequencing analysis showed that the mRNA expressions of arachidonate 12-lipoxygenase (ALOX12), acetyl-CoA acyltransferase 2 (ACAA2), cytochrome P450 family 1 subfamily A member 2 (CYP1A2), glutamic–pyruvic transaminase 2 (GPT2) and argininosuccinate synthase 1 (ASS1) were downregulated (P < 0.05) by AM on day 7, and that the mRNA expressions of arachidonate 15-lipoxygenase (ALOX15), CYP1A2 and GPT2 were downregulated (P < 0.05) by FMT on day 7. GC-MS analysis showed that AM and FMT treatments mainly affected fatty acid metabolism and amino acid metabolism on days 7 and 21. AM and FMT both reduced (P < 0.05) the blood levels of triglycerides and low density lipoprotein cholesterol (LDL-C) on day 7. AM reduced (P < 0.05) the blood level of cholesterol on day 21, and FMT reduced the blood levels of cholesterol, triglycerides and LDL-C on day 21. These results indicate that early intervention with FMT or AM can reduce fatty acid oxidative catabolism and amino acid biosynthesis of neonatal piglets, which provides a reference for regulation host metabolism through early intervention in animal production and even human health.
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