Prostate cancer has been described as a component tumor of Lynch syndrome (LS), with tumors obtained from mutation carriers demonstrating the DNA mismatch repair deficiency phenotype. Previous ...studies quantifying prostate cancer risk in LS have provided conflicting results.
We examined cancer histories of probands and their first- through fourth-degree relatives for 198 independent mutation-positive LS families enrolled in two US familial cancer registries. Modified segregation analysis was used to calculate age-specific cumulative risk or penetrance estimates, with accompanying Wald-type CIs. Cumulative lifetime risks and hazard ratio (HR) estimates for prostate cancer were calculated and compared with those of the general population.
Ninety-seven cases of prostate cancer were observed in 4,127 men. Median age at prostate cancer diagnosis was 65 years (range, 38 to 89 years), with 11.53% of affected individuals diagnosed before age 50 years. The cumulative risk of prostate cancer at ages 60 and 80 years was 6.30% (95% CI, 2.47 to 9.96) and 30.0% (95% CI, 16.54 to 41.30), as compared with the population risk of 2.59% and 17.84%, respectively. The overall prostate cancer HR among carriers was 1.99 (95% CI, 1.31 to 3.03).
The cumulative lifetime risk of prostate cancer in individuals with LS is two-fold higher than in the general population and is slightly higher in carriers diagnosed before age 60 years (HR, 2.48; 95% CI, 1.34 to 4.59). These estimates are clinically valuable to quantify risk for both patients and providers.
The American eel (Anguilla rostrata) has long been regarded as a panmictic fish and has been confirmed as such in the northern part of its range. In this paper, we tested for the first time whether ...panmixia extends to the tropical range of the species. To do so, we first assembled a reference genome (975 Mbp, 19 chromosomes) combining long (PacBio and Nanopore and short (Illumina paired‐end) reads technologies to support both this study and future research. To test for population structure, we estimated genotype likelihoods from low‐coverage whole‐genome sequencing of 460 American eels, collected at 21 sampling sites (in seven geographic regions) ranging from Canada to Trinidad and Tobago. We estimated genetic distance between regions, performed ADMIXTURE‐like clustering analysis and multivariate analysis, and found no evidence of population structure, thus confirming that panmixia extends to the tropical range of the species. In addition, two genomic regions with putative inversions were observed, both geographically widespread and present at similar frequencies in all regions. We discuss the implications of lack of genetic population structure for the species. Our results are key for the future genomic research in the American eel and the implementation of conservation measures throughout its geographic range. Additionally, our results can be applied to fisheries management and aquaculture of the species.
A significant portion of expressed non-coding RNAs in human cells is derived from transposable elements (TEs). Moreover, it has been shown that various long non-coding RNAs (lncRNAs), which come from ...the human endogenous retrovirus subfamily H (HERVH), are not only expressed but required for pluripotency in human embryonic stem cells (hESCs).
To identify additional TE-derived functional non-coding transcripts, we generated RNA-seq data from induced pluripotent stem cells (iPSCs) of four primate species (human, chimpanzee, gorilla, and rhesus) and searched for transcripts whose expression was conserved. We observed that about 30% of TE instances expressed in human iPSCs had orthologous TE instances that were also expressed in chimpanzee and gorilla. Notably, our analysis revealed a number of repeat families with highly conserved expression profiles including HERVH but also MER53, which is known to be the source of a placental-specific family of microRNAs (miRNAs). We also identified a number of repeat families from all classes of TEs, including MLT1-type and Tigger families, that contributed a significant amount of sequence to primate lncRNAs whose expression was conserved.
Together, these results describe TE families and TE-derived lncRNAs whose conserved expression patterns can be used to identify what are likely functional TE-derived non-coding transcripts in primate iPSCs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Enterovirus 71 (EV71) is an important pathogen causing death in children under 5 years old worldwide. However, the underlying pathogenesis remains unclear. This study reveals that EV71 infection in ...rhabdomyosarcoma (RD) and neuroblastoma (SK-N-SH) cells stimulated the autophagic process, which was demonstrated by an increase of punctate GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3), the level of autophagosome-bound LC3-II protein and double-membrane autophagosome formation. EV71-induced autophagy benefited EV71 replication, which was confirmed by the autophagic inducer rapamycin and the inhibitor 3-methyladenine. Signaling pathway investigation revealed that the decreased expression of phosphorylated mTOR and phosphorylated p70S6K is involved in EV71-induced autophagy in a cell-specific manner. The expression of phosphorylated extracellular signal-regulated kinase (Erk) was suppressed consistently in EV71-infected cells. However it did not participate in the autophagic response of the cell. Other signaling pathway molecules, such as Erk, PI3K/Akt, Bcl-2, BNIP3, and Beclin-1 were not affected by infection with EV71. Electron microscopy showed co-localization of autophagosome-like vesicles with either EV71-VP1 or LC3 protein in neurons of the cervical spinal cord in ICR mice infected with EV71. In conclusion, EV71 infection triggered autophagic flux and induced autophagosome formation both in vitro and in vivo. Autophagy induced by EV71 is beneficial for viral replication. Understanding the role of autophagy induced by EV71 in vitro and the formation of autophagosome-like vesicle in vivo provide new insights into the pathogenesis of EV71 infection. J. Med. Virol. 81:1241-1252, 2009.
Uremic pruritus is a common and intractable symptom in patients on chronic hemodialysis, but factors associated with the severity of pruritus remain unclear. This study aimed to explore the ...associations of metabolic factors and dialysis adequacy with the aggravation of pruritus.
We conducted a 5-year prospective cohort study on patients with maintenance hemodialysis. A visual analogue scale (VAS) was used to assess the intensity of pruritus. Patient demographic and clinical characteristics, laboratory parameters, dialysis adequacy (assessed by Kt/V), and pruritus intensity were recorded at baseline and follow-up. Change score analysis of the difference score of VAS between baseline and follow-up was performed using multiple linear regression models. The optimal threshold of Kt/V, which is associated with the aggravation of uremic pruritus, was determined by generalized additive models and receiver operating characteristic analysis.
A total of 111 patients completed the study. Linear regression analysis showed that lower Kt/V and use of low-flux dialyzer were significantly associated with the aggravation of pruritus after adjusting for the baseline pruritus intensity and a variety of confounding factors. The optimal threshold value of Kt/V for pruritus was 1.5 suggested by both generalized additive models and receiver operating characteristic analysis.
Hemodialysis with the target of Kt/V ≥1.5 and use of high-flux dialyzer may reduce the intensity of pruritus in patients on chronic hemodialysis. Further clinical trials are required to determine the optimal dialysis dose and regimen for uremic pruritus.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Québec was the Canadian province most impacted by COVID-19, with 401,462 cases as of September 24th, 2021, and 11,347 deaths due mostly to a very severe first pandemic wave. In April 2020, ...we assembled the Coronavirus Sequencing in Québec (CoVSeQ) consortium to sequence SARS-CoV-2 genomes in Québec to track viral introduction events and transmission within the province. Methods Using genomic epidemiology, we investigated the arrival of SARS-CoV-2 to Québec. We report 2921 high-quality SARS-CoV-2 genomes in the context of > 12,000 publicly available genomes sampled globally over the first pandemic wave (up to June 1st, 2020). By combining phylogenetic and phylodynamic analyses with epidemiological data, we quantify the number of introduction events into Québec, identify their origins, and characterize the spatiotemporal spread of the virus. Results Conservatively, we estimated approximately 600 independent introduction events, the majority of which happened from spring break until 2 weeks after the Canadian border closed for non-essential travel. Subsequent mass repatriations did not generate large transmission lineages (> 50 sequenced cases), likely due to mandatory quarantine measures in place at the time. Consistent with common spring break and "snowbird" destinations, most of the introductions were inferred to have originated from Europe via the Americas. Once introduced into Québec, viral lineage sizes were overdispersed, with a few lineages giving rise to most infections. Consistent with founder effects, the earliest lineages to arrive tended to spread most successfully. Fewer than 100 viral introductions arrived during spring break, of which 7-12 led to the largest transmission lineages of the first wave (accounting for 52-75% of all sequenced infections). These successful transmission lineages dispersed widely across the province. Transmission lineage size was greatly reduced after March 11th, when a quarantine order for returning travellers was enacted. While this suggests the effectiveness of early public health measures, the biggest transmission lineages had already been ignited prior to this order. Conclusions Combined, our results reinforce how, in the absence of tight travel restrictions or quarantine measures, fewer than 100 viral introductions in a week can ensure the establishment of extended transmission chains.
Identification of microsatellite unstable (MSI-H) colorectal cancers (CRCs) is important not only for the identification of hereditary nonpolyposis colorectal cancer syndrome but also because MSI-H ...CRCs have a better prognosis and may respond differently to 5-fluorouracil-based chemotherapy. We present 2 nearly equivalent logistic regression models for clinical use that predict microsatellite instability based on the review of 1649 CRCs from patients of all ages collected in a population-based case control study in northern Israel. One hundred ninety-eight of these 1649 tumors demonstrated a high degree of microsatellite instability (12%). Multivariate analysis found that >2 tumor-infiltrating lymphocyte (TIL) cells per high-powered field, the lack of dirty necrosis, the presence of a Crohn-like reaction, right-sided location, any mucinous differentiation (mucinous or focally mucinous) and well or poor differentiation, and age less than 50 were all independent predictors of MSI-H. We developed 2 logistic regression models that differ only by the statistical approach used to analyze the number of TIL cells per high-powered field, where the slightly more accurate (and complex) model uses the log of the total number of TIL cells. The simpler clinical model uses a cut-off of 2>TIL cells per high-powered field. The accuracy of both models is high, with an 85.4% versus 85.0% probability of correctly classifying tumors as MSI-H. By employing the simpler model, pathologists can predict the likelihood of microsatellite instability by compiling the MSI probability score (Table 4 and Fig. 1) from simple histologic and clinical data available during sign-out. Our model shows that approximately 43% of CRCs have a MSI probability score of 1 or less and hence have little likelihood (<3%) of being MSI-H. Although this model is not perfect in predicting microsatellite instability, its use could improve the efficiency of expensive diagnostic testing.
The primary disease vectors for dengue virus (DENV) transmission between humans are the mosquitoes Aedes aegypti and Aedes albopictus, with Ae. aegypti population size strongly correlated with DENV ...outbreaks. When a mosquito is infected with DENV, the virus migrates from the midgut to the salivary glands to complete the transmission cycle. How the virus crosses the hemocoel, resulting in systemic infection, is still unclear however. During viral infection and migration, the innate immune system is activated in defense. As part of cellular-mediated immunity, hemocytes are known to defend against bacteria and Plasmodium infection and may also participate in defending against DENV infection. Hemocytes are categorized into three cell types: prohemocytes, granulocytes, and oenocytoids. Here, we investigated which hemocytes can be infected by DENV and compare hemocyte infection between Ae. aegypti and Ae. albopictus.
Hemocytes were collected from Ae. aegypti and Ae. albopictus mosquitoes that were intrathoracically infected with DENV2-GFP. The collected hemocytes were then identified via Giemsa staining and examined microscopically for morphological differences and viral infection.
All three types of hemocytes were infected by DENV, though the predominantly infected cell type was prohemocytes. In Ae. aegypti, the highest and lowest infection rates at 7 days post infection occurred in prohemocytes and granulocytes, respectively. Prohemocytes were also the primary infection target of DENV in Ae. albopictus, with similar infection rates across the other two hemocyte groups. The ratios of hemocyte composition did not differ significantly between non-infected and infected mosquitoes for either species.
In this study, we showed that prohemocytes were the major type of hemocyte infected by DENV in both Ae. aegypti and Ae. albopictus. The infection rate of prohemocytes in Ae. albopictus was lower than that in Ae. aegypti, which may explain why systemic DENV infection in Ae. albopictus is less efficient than in Ae. aegypti and why Ae. albopictus is less correlated to dengue fever outbreaks. Future work in understanding the mechanisms behind these phenomena may help reduce arbovirus infection prevalence.
This study investigated a new category of transparent encapsulant materials for light-emitting diodes (LEDs). It comprised a phenyl group that contained siloxane-modified epoxy (SEP-Ph) hybridized ...with a cyclic tetrafunctional siloxane-modified epoxy (SEP-D4) with methylhexahydrophthalic anhydride (MHHPA) as a curing agent. The SEP-Ph/SEP-D4 = 0.5/0.5 (sample 3) and SEP-D4 (sample 4) could provide notably high optical transmittance (over 90% in the visible region), high-temperature discoloration resistance, low stress, and more crucially, noteworthy sulfurization resistance. The lumen flux retention of the SEP encapsulated surface mounted device LEDs remained between approximately 97% and 99% after a sulfurization test for 240 h. The obtained comprehensive optical, mechanical, and sulfurization resistance proved the validity and uniqueness of the present design concept with complementary physical and chemical characteristics.
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