Coffee contains many bioactive chemicals and associations with cancer have been reported in observational studies. In this Mendelian randomisation (MR) study we investigated the causal associations ...of coffee consumption with a broad range of cancers.
Twelve independent genetic variants proxied coffee consumption. Genetically-predicted risk of any cancer (59,647 cases) and 22 site-specific cancers was estimated in European-descent individuals in UK Biobank. Univariable and multivariable MR analyses were conducted.
Genetically-predicted coffee consumption was not associated with risk of any cancer in the main analysis (OR 1.05, 95% CI 0.98–1.14, p = 0.183) but was associated with an increased risk of digestive system cancer (OR 1.28, 95% CI 1.09–1.51, p = 0.003), driven by a strong association with oesophageal cancer (OR 2.79, 95% CI 1.73–4.50, p = 2.5×10−5). This association was consistent after adjustment for genetically-predicted body mass index, smoking and alcohol consumption. There was no strong evidence supporting a causal relationship between genetically-predicted coffee consumption and the majority of cancers studied. However, genetically-predicted coffee consumption was associated with increased risk of multiple myeloma (OR 2.25, 95% CI 1.30–3.89, p = 0.004) and reduced ovarian cancer risk (OR 0.63, 95% CI 0.43–0.93, p = 0.020).
This MR study provides strong support for a causal association of coffee consumption with oesophageal cancer, but not for the majority of cancer types, and the underlying mechanisms require investigation.
Saccharomyces cerevisiae Hop2 and Mnd1 are abundant meiosis-specific chromosomal proteins, and mutations in the corresponding genes lead to defects in meiotic recombination and in homologous ...chromosome interactions during mid-prophase. Analysis of various double mutants suggests that HOP2, MND1, and DMC1 act in the same genetic pathway for the establishment of close juxtaposition between homologous meiotic chromosomes. Biochemical studies indicate that Hop2 and Mnd1 proteins form a stable heterodimer with a higher affinity for double-stranded than single-stranded DNA, and that this heterodimer stimulates the strand assimilation activity of Dmc1 in vitro. Together, the genetic and biochemical results suggest that Hop2, Mnd1, and Dmc1 are functionally interdependent during meiotic DNA recombination.
Polymyalgia rheumatica (PMR) is an age-related inflammatory disease of unknown cause. We aimed to identify potentially modifiable risk factors and therapeutic targets for preventing or treating PMR.
...We meta-analysed genetic association data from 8,156 cases of PMR (defined using diagnostic codes and self-report) and 416,495 controls of European ancestry from the UK Biobank and FinnGen. We then performed Mendelian randomization analyses to estimate the association between eight modifiable risk factors (using data from up to 1.2 million individuals) and 65 inflammation-related circulating proteins (up to 55,792 individuals), using the inverse variance weighted and pleiotropy robust methods.
We identified three novel genome-wide significant loci in the IL1R1, NEK6 and CCDC88B genes and confirmation of previously described associations with HLA-DRB1 and ANKRD55. Genetically predicted smoking intensity (OR 1.32; 95%CI 1.08-1.60; p = 0.006) and visceral adiposity (OR 1.22; 95%CI 1.10-1.37; p = 3.10x10-4) were associated with PMR susceptibility. Multiple circulating proteins related to IL-1 family signaling were associated with PMR. IL-1 receptor-like 2, also known as IL-36 receptor (OR 1.25; p = 1.89x10-32), serum amyloid A2 (OR 1.06, 9.91x10-10) and CXCL6 (OR 1.09, p = 4.85x10-7) retained significance after correction for multiple testing.
Reducing smoking and visceral adiposity at a population level might reduce incidence of PMR. We identified proteins that may play causal roles in PMR, potentially suggesting new therapeutic opportunities. Further research is needed before these findings are applied to clinical practice.
Ribosome biogenesis is a canonical hallmark of cell growth and proliferation. Here we show that execution of Epithelial-to-Mesenchymal Transition (EMT), a migratory cellular program associated with ...development and tumor metastasis, is fueled by upregulation of ribosome biogenesis during G1/S arrest. This unexpected EMT feature is independent of species and initiating signal, and is accompanied by release of the repressive nucleolar chromatin remodeling complex (NoRC) from rDNA, together with recruitment of the EMT-driving transcription factor Snai1 (Snail1), RNA Polymerase I (Pol I) and the Upstream Binding Factor (UBF). EMT-associated ribosome biogenesis is also coincident with increased nucleolar recruitment of Rictor, an essential component of the EMT-promoting mammalian target of rapamycin complex 2 (mTORC2). Inhibition of rRNA synthesis in vivo differentiates primary tumors to a benign, Estrogen Receptor-alpha (ERα) positive, Rictor-negative phenotype and reduces metastasis. These findings implicate the EMT-associated ribosome biogenesis program with cellular plasticity, de-differentiation, cancer progression and metastatic disease.
Background/Aims We previously demonstrated that two linked single nucleotide polymorphisms (SNPs) at −408 and −3 of type I interferon receptor 1 ( IFNAR1 ) promoter are associated with susceptibility ...to chronic HBV infection. We aimed to elucidate the mechanism by which −3 and/or −408 C/T SNPs had such profound effects. Methods A functional SNP in IFNAR1 promoter was defined by reporter gene assay, mutational analysis, flow cytometry analysis and gel shift assay. The nuclear protein binding to the essential polymorphic site was identified and its effect on transcriptional regulation of IFNAR1 was further demonstrated in a series of ex vivo and in vivo experiments. Results We found C > T change at the −3 locus reduced the transcriptional activity of IFNAR1 promoter. High mobility group B protein 1 (HMGB1) and PARP-1 were co-recruited to the IFNAR1 promoter to regulate its transcription. We demonstrated HMGB1-binding affinity to IFNAR1 promoter was reduced in the −3T variant. Additionally, PARP-1, a cofactor for IFNAR1 transcription activation, was significantly suppressed by HBV. Conclusion Upon HBV infection, decreased binding affinity of HMGB1 to the IFNAR1 promoter −3T variant is aggravated by the suppressed PARP-1 expression caused by HBV, resulting in a further attenuated IFNAR1 expression. This compromises the antiviral and immuno-regulatory effects of IFN-α/β, which may in turn affect the clinical outcome of HBV infection.
Here we present a preclinical model to assess drug–drug interactions due to inhibition of glucuronidation. Treatment with the antiepileptics phenobarbital (PB) or phenytoin (PH) has been associated ...with increased incidence of acetaminophen (APAP) hepatotoxicity in patients. In human hepatocytes, we found that the toxicity of APAP (5 mM) was increased by simultaneous treatment with phenobarbital (2 mM) or phenytoin (0.2 mM). In contrast, pretreatment with PB for 48 h prior to APAP treatment did not increase APAP toxicity unless both drugs were present simultaneously. Cells treated with APAP in combination with PB or PH experienced decreases in protein synthesis as early as 1 h, ultrastructural changes by 24 h, and release of liver enzymes by 48 h. Toxicity correlated with inhibition of APAP glucuronidation. PB or PH also inhibited APAP glucuronidation in rat and human liver microsomes and expressed human UGT1A6, 1A9, and 2B15. As with intact hepatocytes, PB and PH were neither hydroxylated nor glucuronidated, suggesting the direct inhibition of UGTs. Our findings suggest that, in multiple drug therapy, an inhibitory complex between UGT and one of the drugs can lead to decreased glucuronidation and increased systemic exposure and toxicity of a coadministered drug.
Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome associated with ribosomal protein (RP) gene mutations. Recent studies have also demonstrated an increased risk of cancer ...predisposition among DBA patients. In this study, we report the formation of soft tissue sarcoma in the Rpl5 and Rps24 heterozygous mice. Our observation suggests that even though one wild-type allele of the Rpl5 or Rps24 gene prevents anemia in these mice, it still predisposes them to cancer development.
The Ca-deficient apatite (CDHA) was prepared from the precursors of (CH
3COO)
2Ca·
xH
2O, Ca(NO
3)
2·4H
2O and H
3PO
4, (NH
4)H
2PO
4 to investigate the transformation mechanism of
β-tricalcium ...phosphate (
β-TCP). X-ray diffraction analysis shows that the development of
β-TCP is not via direct reaction between Ca and P for all the different combinations between Ca and P precursors. The activation energy of
β-TCP formation with (NH
4)H
2PO
4 as precursor was higher than that with H
3PO
4. Following the Johnson–Mehl–Avrami equation, the reaction kinetics of
β-TCP phase formation is found one-dimension growth with interface-controlled and diffusion controlled growth depending on the annealing temperature. There exists a transition between 750°C and 825°C, and the transition rate from interface-controlled to diffusion-controlled growth is precursor-dependent.
Capsaicin was reported to inhibit cancer cell growth. The aim of this study was to evaluate the antitumor potential of capsaicin by studying antitumor activity in vitro as well as in vivo. The in ...vitro studies are to examine the effects of capsaicin on human colon cancer colo 205 cells after exposure to capsaicin. The results showed that capsaicin induced cytotoxic effects in a time- and dose-dependent manner and increased reactive oxygen species (ROS) and Ca2+ but decreased the level of mitochondrial membrane potential (ΔΨm) in colo 205 cells. Data from Western blotting analysis indicated that the levels of Fas, cytochrome c, and caspases were increased, leading to cell apoptosis. Capsaicin decreased the levels of anti-apoptotic proteins such as Bcl-2 and increased the levels of pro-apoptotic proteins such as Bax. Capsaicin-induced apoptosis in colo 205 cells was also done through the activations of caspase-8, -9 and -3. In vivo studies in immunodeficient nu/nu mice bearing colo 205 tumor xenografts showed that capsaicin effectively inhibited tumor growth. The potent in vitro and in vivo antitumor activities of capsaicin suggest that capsaicin might be developed for the treatment of human colon cancer.
To examine the joint associations of multiple modifiable lifestyle factors with the risk of symptomatic peripheral artery disease (PAD) referred to secondary care in the healthy, community based ...population.
A prospective cohort study was conducted including 37 633 men from the Cohort of Swedish Men and 31 816 women from the Swedish Mammography Cohort who were free of clinically diagnosed PAD and 45 – 83 years of age at baseline. Healthy lifestyle factors were defined as avoidance of excessive alcohol consumption (≤ 2 drinks/day), high adherence to a healthy diet (modified Mediterranean diet score ≥ 4), moderate to high level of physical activity (≥ 30 minutes/day), and never smoking. PAD cases were ascertained by linkage with the Swedish National Patient Registry. Cox proportional hazards regression was used to analyse the data.
During a mean of 18.1 years of follow up (from 1 January 1998 to 31 December 2019), 2 795 incident symptomatic PAD cases were ascertained. All healthy lifestyle factors were associated with a reduced PAD risk. Individuals who adhered to all four healthy lifestyle factors had a 45% (95% confidence interval CI 38 – 51) lower risk of PAD compared with the remainder of the population (0 – 3 healthy lifestyle factors) and a 71% (95% CI 61 – 79) lower risk of PAD compared with the group without any healthy lifestyle factor. Adherence to the combination of four healthy lifestyle factors was estimated to prevent 40% (95% CI 34 – 47) of PAD cases.
Healthy lifestyle factors were associated with a reduced risk of PAD.
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