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Identifying rare germline variants associated with metastatic prostate cancer through an extreme phenotype study
No full text[[abstract]]BACKGROUND: Studies of germline variants in prostate cancer (PCa) have largely focused on their connections to cancer predisposition. However, an understanding of how heritable factors contribute to cancer progression and metastasis remain limited. OBJECTIVE: To identify low frequency to rare germline nonsynonymous variants associated with increased risk for metastatic PCa (mPCa), while providing functional validation. DESIGN: We assembled an extreme phenotype cohort (EPC) of 52 patients diagnosed with predominantly high-grade (Gleason Score (GS) ≥ 8) PCa and > 7 years of follow-up for which localized treatment naïve tumor tissues were available. In half of the cases, the tumor had metastasized to bone, providing an even distribution of bone mPCa and non mPCa cases. Tumor and matched distant benign DNA samples were exome sequenced and analyzed for germline variants with population-wide minor allelic frequencies ≤ 2%. Findings were validated using two independent PCa germline cohorts, including a closely matched Australian study biased to aggressive disease (n = 53) and Pan Prostate Cancer Group (PPCG, n = 976). Two mPCa-promoting candidate variants in KDM6B and BRCA2 were engineered into cell lines and functionalized. RESULTS: Germline nonsynonymous rare variants (gnsRVs) identified in 25 DNA Damage Repair (DDR) genes were significantly enriched in the mPCa patients (p=4.57e-06). Conversely, the prevalence of synonymous variants at minor allele frequencies of ≤ 2% were similar between the mPCa and non mPCa patients. The predictive power of variants in 53 non-DDR genes was validated in the Australian cohort (p=0.028) and correlated with high-risk PCa in PPCG (p=0.03). KDM6B K973Q showed functional significance despite being annotated as benign in ClinVar, while BRCA2 I1962T showed sensitivity to Olaparib. In total, six EPC variants related to DNA repair or epigenetics were found to alter enzymatic activity. CONCLUSIONS: EPCs coupled with low frequency/rare variant analyses may advance understanding of interactions between the germline and tumor in PCa. We identified a series of germline variants that were enriched among mPCa patients. Moreover, we showed that one of these variants confers a metastatic phenotype. Our findings suggest that germline testing at diagnosis may improve treatment stratification in PCa. PATIENT SUMMARY: The presence of specific genetic variants among men with PCa may elevate the risk of mPCa once PCa develops. Knowledge of the variant burden at time of diagnosis may enable accurate stratification of some patients for aggressive therapeutic interventions
Durvalumab plus chemotherapy in advanced biliary tract cancer: 3-year overall survival update from the phase III TOPAZ-1 study
No full text[[abstract]]BACKGROUND: At the TOPAZ-1 (NCT03875235) primary analysis, durvalumab plus gemcitabine and cisplatin (GemCis) significantly improved overall survival (OS) in advanced biliary tract cancer (aBTC). We report updated exploratory analyses of OS and safety, characterisation of extended long-term survivors (eLTS), and subsequent anticancer therapy (SAT) use. METHODS: Participants with aBTC received durvalumab+GemCis or placebo+GemCis every 3 weeks (≤8 cycles), then durvalumab or placebo monotherapy every 4 weeks until progressive disease or other discontinuation criteria were met. OS and serious adverse events (SAEs) were assessed in the full analysis and safety analysis sets (FAS/SAS), respectively. eLTS outcomes were assessed (FAS participants alive ≥30 months after randomisation). RESULTS: 685 participants were randomised: durvalumab+GemCis (n = 341); placebo+GemCis (n = 344). After a median 41.3 (95% confidence interval [CI] 39.3-44.1) months' follow-up in all participants, median OS (95% CI) for durvalumab+GemCis versus placebo+GemCis was 12.9 (11.6-14.1) versus 11.3 (10.1-12.5) months (hazard ratio, 0.74 [95% CI 0.63-0.87]); 36-month OS rate was 14.6% versus 6.9%, respectively. In participants who achieved disease control (566/685; 82.6%), the 36-month OS rate was higher for durvalumab+GemCis (17.0%) versus placebo+GemCis (7.6%). Overall, 12.8% were eLTS, with more eLTS in the durvalumab+GemCis (17.0%) versus placebo+GemCis (8.7%) arms; eLTS included all clinically relevant subgroups. Durvalumab+GemCis improved OS regardless of SAT use. In eLTS, SAEs were comparable between arms and less frequent than in the full SAS. CONCLUSIONS: Survival benefit and manageable safety continued with durvalumab+GemCis versus placebo+GemCis approximately 3 years after the last participant was randomised. All clinically relevant subgroups were represented in eLTS, supporting standard-of-care status for durvalumab+GemCis in aBTC. LAY SUMMARY: The TOPAZ-1 study found that treatment with durvalumab plus gemcitabine and cisplatin (chemotherapy, also known as GemCis), helped people with advanced biliary tract cancer (BTC) to live longer on average than those treated with a placebo plus GemCis. The latest results from TOPAZ-1 showed that these benefits continued for over 3 years in participants treated with durvalumab plus GemCis and side effects continued to be manageable. At an updated analysis, carried out 3 years after the last participant started the study, twice as many participants treated with durvalumab plus GemCis were alive compared to those treated with placebo plus GemCis. Results also showed that the positive effect of durvalumab plus GemCis compared with placebo plus GemCis was not affected by the use of other therapies some participants received after they finished the study treatment. These results continue to support durvalumab plus GemCis as a standard first-line treatment for people with advanced BTC
Sedative-hypnotics are associated with additional risk of suicide in older adults: A population-based case-control study
No full text[[abstract]]STUDY OBJECTIVES: To examine the pattern of sedative-hypnotic prescriptions associated with the risk of suicide behavior among older adults with and without insomnia. METHODS: The study included 8 319 suicide cases and age- and sex-matched controls from the population-wide National Health Insurance Research Database. Suicide methods and insomnia were defined using diagnostic codes. The sedative-hypnotic use pattern was categorized by half-life, prescription volume measured in Defined Daily Doses (DDDs), and its temporal relationship with suicide. Odds ratios were employed to assess the risk of insomnia and the prescription patterns of sedative-hypnotics on suicide. Additionally, we compared suicide methods between sedative-hypnotics users and nonusers. RESULTS: Insomnia was mildly associated with suicide behavior after adjusting for mental illnesses (adjusted RR = 1.82, OR = 1.86, 95% CI = 1.76-1.97), but the prescription of sedative-hypnotics was associated with 5-fold suicide risk (adjusted RR = 5.22, OR = 5.90, 95% CI = 5.11-6.82). Among patients with insomnia, a prescription volume of ≥ 31 DDDs per year, and a prescription within 90 days of the suicide index date were associated with increased suicide risk. Individuals prescribed sedative-hypnotics were more likely to suicide by methods involving sedative-hypnotic poisoning (21% vs. 0%). CONCLUSIONS: Among older adults, sedative-hypnotic prescription is associated with increased suicide risk and suicide by self-poisoning using such medications. Non-pharmacological treatment for insomnia, such as cognitive behavioral therapy, is essential for suicide prevention
RNA rolyA tailing assay to qualitatively analyze circular RNA manufacturing
No full text[[abstract]]A covalently closed loop structure provides circular RNA (circRNA) with more stability than conventional RNAs in linear form, making circRNA an emerging tool in RNA therapeutics. The qualification and quantification of circRNA after production is critical for its design and effectiveness assessments, particularly when the following applications could be affected by byproduct RNAs. Despite PCR-based methods effectively detecting low-abundance circRNA, they are unsuitable for assessing uncircularized RNA in a mass production fraction to maintain quality control. Here, we present a straightforward protocol for evaluating uncircularized byproduct RNAs from circRNA production. This method enrolls the template-independent RNA polymerase activity to add adenine tails (polyA) to the 3' ends of a linear RNA, making it easy to distinguish trace byproducts or uncircularized RNA from a pool of mass circRNA products. With conventional linear RNA and RNase R-treated circRNA as the positive and negative controls, the purity of a circRNA preparation could be readily resolved. Regardless of circRNA production strategies, this protocol provides a reliable and practical way to ensure the consistent quality of homemade circRNAs or to recheck circRNA quality from commercial manufacturing. Key features • The RNA circularization assessment relies on detecting a free 3' end OH group of the non-circRNA in the circRNA products. • An RNA denaturing electrophoresis is required to detect nucleotide length changes of the non-circRNA post-3' end tailing. • Rather than quantitatively, the molecular weight changes qualitatively highlight the trace non-circRNA in a circRNA preparation. • While there are different techniques for producing circRNA, the tailing method is effective for most, detecting leftover linear RNA contaminants
Microvascular complications and cancer risk in type 2 diabetes: A population-based study
No full text[[abstract]]Background: Microvascular complications in type 2 diabetes (T2D) and cancer share biological pathways, including chronic inflammation, dysregulated angiogenesis, and endothelial dysfunction, yet their impact on cancer risk and mortality remains unclear. This study evaluated whether T2D patients with microvascular complications face increased cancer incidence or cancer-related mortality. Methods: Using the Taiwan National Health Insurance Research Database, we identified individuals newly diagnosed with T2D (2008-2021) and assessed the outcomes with multivariable Cox proportional hazards models. Results: Our findings indicate that T2D patients with diabetic neuropathy, retinopathy, or chronic kidney disease do not have a significantly increased risk of major cancers, including those of the oral cavity, thyroid, breast, respiratory tract, digestive system, or lymphoid tissues. Similarly, microvascular complications were not associated with higher cancer-related mortality. However, microvascular complications significantly increased all-cause mortality in a dose-dependent manner: adjusted hazard ratio (aHR) 1.16 [95% CI: 1.15-1.17] for one complication, aHR 1.42 [1.38-1.45] for two, and aHR 1.71 [1.60-1.83] for three. Conclusions: In this nationwide cohort study, we demonstrate that while microvascular complications are associated with increased all-cause mortality in T2D, they do not appear to elevate cancer risk or cancer-specific mortality. These findings provide crucial epidemiological insights into the relationship between diabetes complications and cancer
Simultaneous biomonitoring of common food carcinogen acrylamide and its major metabolites using fast urinary metabolites extraction technique coupled with LC-MS/MS analysis
No full text[[abstract]]Acrylamide (AA) is a probable carcinogen, often found in the environment and food, which causes various cancers in humans. Therefore, it is vital to have a facile, quick, sensitive analytical method for biomonitoring AA and its metabolites (including glycidamide (GA), N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA), N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine (GAMA)) in human urine sample for exposure risk and toxicology assessment applications. In this study, we presented a rapid sample pre-treatment technique named "fast urinary metabolites extraction technique" (FaUMEx) coupled with UHPLC-MS/MS method for efficient biomonitoring of AA and its metabolites in human urine samples. In the FaUMEx technique, two syringes were integrated for liquid-liquid extraction, followed by a micro-solid phase clean-up process. The fully optimized and validated FaUMEx/UHPLC-MS/MS technique yielded good detection and quantification levels (LOD of 0.01 to 0.2 ng/mL, and LOQ of 0.5 to 0.05 ng/mL for AA, GA, AAMA, and GAMA, respectively). The inter- and intra-day analysis shows reliable relative recoveries ranging from 82.90-116.80% with <12% RSD. Moreover, the matrix effect ranged from -8.9 % to +7.7%, demonstrating the excellent cleanup efficiency towards quantifying AA and its metabolites from the human urine samples with minimal matrix interferences. Thus, the presented method is simple, efficient, and sensitive, and can be applied for biomonitoring applications
用于鼻黏膜的纳米级乳液免疫载剂及其制备方法
No full text[[abstract]]本发明提供了一种纳米级乳液免疫载剂及其制备方法，其由下列组成成分所组成：一含有H2O分子的一连续水相；含有油脂的一油相物质；以及用于稳定连续水相和油相界面的一乳化统，且该乳化统为乳化剂混合物，该免疫载剂的特征在于，该乳化统不含离子型乳化剂，且该乳液的粒径大小介于20纳米至200纳米之间。通过该纳米级乳液免疫载剂，其可有效避免离子型乳化剂对人体细胞带来的毒性及可能的危害，同时提供能诱导高度免疫反应的疫苗制剂
高成长肠病毒71型病毒株及其疫苗
No full text[[abstract]]本发明是关于一种用于提高哺乳动物疫苗产量的驯化肠病毒71型(EV71)疫苗株。该EV71疫苗株包含至少一个经修饰的肠病毒蛋白，可自哺乳动物宿主细胞(如Vero细胞)快速增殖EV71病毒。本发明亦关于一种从驯化的EV71病毒疫苗株产生的疫苗以及该疫苗的制造方法
[[alternative]]Method of producing exosomes by using ep4-antagonist to induce exosomes releasing from stem cells and the use thereof
No full text[[abstract]]本發明係關於一種製造外泌體囊泡的方法，特徵在於將幹細胞以前列腺素受體拮抗劑(EP4-antagonist)刺激，而轉化為失去其幹細胞的特性之非-幹細胞，並大量釋放出帶有高含量用以維持幹細胞特性所需之蛋白分子及miRNAs的外泌體囊泡。本發明之方法所製備的外泌體囊泡，具有將非幹細胞轉化為幹細胞的能力