Identification of genes associated with hereditary cancers facilitates management of patients with family histories of cancer. We performed exome sequencing of DNA from 3 individuals from a family ...with colorectal cancer who met the Amsterdam criteria for risk of hereditary nonpolyposis colorectal cancer. These individuals had mismatch repair-proficient tumors and each carried nonsense variant in the FANCD2/FANCI-associated nuclease 1 gene ( FAN1 ), which encodes a nuclease involved in DNA inter-strand cross-link repair. We sequenced FAN1 in 176 additional families with histories of colorectal cancer and performed in vitro functional analyses of the mutant forms of FAN1 identified. We detected FAN1 mutations in approximately 3% of families who met the Amsterdam criteria and had mismatch repair-proficient cancers with no previously associated mutations. These findings link colorectal cancer predisposition to the Fanconi anemia DNA repair pathway, supporting the connection between genome integrity and cancer risk.
Predictors of subclinical atherosclerosis in HIV Fernández Soto, Julia; Romero-Jiménez, Manuel J; Alarcón García, José Carlos ...
BMC infectious diseases,
01/2023, Letnik:
23, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Cardiovascular disease is a major cause of morbidity and mortality in people with HIV. The detection of subclinical atherosclerosis through vascular ultrasound allows us to identify patients at an ...increased risk of cardiovascular disease as a primary prevention strategy; this test is not routine. Our objective is to identify predictors of subclinical atherosclerosis in a population with HIV.
People with HIV infection were selected for primary prevention and underwent carotid and femoral ultrasound to detect atheromatous plaques. Logistic regression analysis including vascular risk factors was performed to predict the presence of atherosclerosis.
One hundred eighty-three patients were included, 54% of whom were smokers; the mean duration of HIV infection was 9.52 years, and all patients were undergoing antiretroviral treatment. Subclinical atherosclerosis was present in 62.29% of the patients; 83.32% had plaque in the carotid territory, 57.93% in the femoral territory and 25.6% in both vascular territories. Compared to those without atherosclerosis, patients with atherosclerosis were on average 5.35 years older (53.86 vs. 48.51, p < 0.001) and had a higher prevalence of smoking (63.23% vs. 39.12%, p = 0.020) and a CD4/CD8 ratio below 0.7 (44.23% vs. 29.02%, p = 0.043). A CD4/CD8 ratio lower than 0.3 was always associated with subclinical atherosclerosis (95% confidence interval (CI): 83.9-100%). The inclusion of smoking, the CD4/CD8 ratio and age in the logistic regression analysis led to a diagnostic yield of 72% measured by the area under the receiving operator characteristic (ROC) curve (95% CI: 64-80%).
Tobacco use, age and a CD4/CD8 ratio below 0.7 allow prediction of the presence of subclinical atherosclerosis in primary prevention. A CD4/CD8 ratio below 0.3 was a diagnostic indicator of atherosclerosis in HIV patients undergoing primary prevention in our sample.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Se identificó el límite superior de bosque continuo y discontinuo en las montañas superiores a 4000 metros sobre el nivel del mar en México. El estudio se basó en el índice de vegetación de ...diferencia normalizada y mediante el análisis de componentes principales. Para el primer caso, se encontró que en cada vertiente el límite de bosque alcanza una altitud distinta; sin embargo, en promedio el bosque continuo culmina a 4019 y el discontinuo a 4072 msnm. Por su parte, el análisis estadístico permitió determinar que la precipitación, el tipo de suelo y la tasa de radiación solar a nivel de superficie son los principales factores que rigen su altitud. Finalmente se halló que el régimen de temperatura encontrado en esta frontera se aproxima a los valores estándares de la zona intertropical.
Germ-line mutations in the exonuclease domains of POLE and POLD1 have been recently associated with polyposis and colorectal cancer (CRC) predisposition. Here, we aimed to gain a better understanding ...of the phenotypic characteristics of this syndrome to establish specific criteria for POLE and POLD1 mutation screening and to help define the clinical management of mutation carriers.
The exonuclease domains of POLE and POLD1 were studied in 529 kindred, 441 with familial nonpolyposis CRC and 88 with polyposis, by using pooled DNA amplification and massively parallel sequencing.
Seven novel or rare genetic variants were identified. In addition to the POLE p.L424V recurrent mutation in a patient with polyposis, CRC and oligodendroglioma, six novel or rare POLD1 variants (four of them, p.D316H, p.D316G, p.R409W, and p.L474P, with strong evidence for pathogenicity) were identified in nonpolyposis CRC families. Phenotypic data from these and previously reported POLE/POLD1 carriers point to an associated phenotype characterized by attenuated or oligo-adenomatous colorectal polyposis, CRC, and probably brain tumors. In addition, POLD1 mutations predispose to endometrial and breast tumors.
Our results widen the phenotypic spectrum of the POLE/POLD1-associated syndrome and identify novel pathogenic variants. We propose guidelines for genetic testing and surveillance recommendations.
J. Neurochem. (2009) 109, 879–888.
The ability of aluminium to affect the oxidant status of specific areas of the brain (cerebellum, ventral midbrain, cortex, hippocampus, striatum) was investigated ...in rats intraperitoneally treated with aluminium chloride (10 mg Al3+/kg/day) for 10 days. The potential of aluminium to act as an etiological factor in Parkinson’s disease (PD) was assessed by studying its ability to increase oxidative stress in ventral midbrain and striatum and the striatal dopaminergic neurodegeneration induced by 6‐hydroxydopamine in an experimental model of PD. The results showed that aluminium caused an increase in oxidative stress (TBARS, protein carbonyl content, and protein thiol content) for most of the brain regions studied, which was accompanied by a decrease in the activity of some antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase). However, studies in vitro confirmed the inability of aluminium to affect the activity of those enzymes. The reported effects exhibited a regional‐selective behaviour for all the cerebral structures studied. Aluminium also enhanced the ability of 6‐hydroxydopamine to cause oxidative stress and neurodegeneration in the dopaminergic system, which confirms its potential as a risk factor in the development of PD.
Germline mutations in DNA polymerase ɛ (POLE) and δ (POLD1) have been recently identified in families with multiple colorectal adenomas and colorectal cancer (CRC). All reported cases carried POLE ...c.1270C>G (p.Leu424Val) or POLD1 c.1433G>A (p.Ser478Asn) mutations. Due to the scarcity of cases reported so far, an accurate clinical phenotype has not been defined. We aimed to assess the prevalence of these recurrent mutations in unexplained familial and early-onset CRC and polyposis, and to add additional information to define the clinical characteristics of mutated cases. A total of 858 familial/early onset CRC and polyposis patients were studied: 581 familial and early-onset CRC cases without mismatch repair (MMR) deficiency, 86 cases with MMR deficiency and 191 polyposis cases. Mutation screening was performed by KASPar genotyping assays and/or Sanger sequencing of the involved exons. POLE p.L424V was identified in a 28-year-old polyposis and CRC patient, as a de novo mutation. None of the 858 cases studied carried POLD1 p.S478N. A new mutation, POLD1 c.1421T>C (p.Leu474Pro), was identified in a mismatch repair proficient Amsterdam II family. Its pathogenicity was supported by cosegregation in the family, in silico predictions, and previously published yeast assays. POLE and POLD1 mutations explain a fraction of familial CRC and polyposis. Sequencing the proofreading domains of POLE and POLD1 should be considered in routine genetic diagnostics. Until additional evidence is gathered, POLE and POLD1 genetic testing should not be restricted to polyposis cases, and the presence of de novo mutations, considered.
We study how capital controls and domestic macroprudential policy tame credit supply booms, either directly or by enhancing the local bank-lending channel of monetary policy. We exploit credit ...registry data and the introduction of capital controls on foreign exchange (FX) debt inflows and increase of reserve requirements on domestic bank deposits in Colombia during a boom. We find that capital controls strengthen the bank-lending channel. Increasing the local monetary policy rate widens the interest rate differential with the U.S.; hence, relatively more FX-indebted banks carry-trade cheap FX-funds with expensive peso lending, especially towards riskier firms. Capital controls tax FX-debt and break the carry-trade. Differently, raising reserve requirements on domestic deposits directly reduces credit supply, particularly for riskier firms, rather than enhancing the bank-lending channel. Importantly, banks differentially finance credit with domestic vis-à-vis FX-financing; hence, capital controls and domestic macroprudential policy complementarily mitigate the credit boom and related bank risk-taking.
The removal of boron from drinking water is a concern in various parts of the world due to the toxic effects of this metalloid in high concentrations. In this paper, zeolites LTL and FAU X were ...synthesized and modified with salts of nickel (NiCl2), iron (FeCl3), and aminopropyltriethoxysilane (APS) in order to promote their affinity for boron species present in aqueous systems. The adsorption capacity of modified zeolites for boron was evaluated in a synthetic boron solution and with groundwater samples for human use. The effect of the pH and zeolite dose was studied in adsorption tests using groundwater. The modified zeolites were characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, nitrogen physisorption, and Fourier-transform infrared spectroscopy. Results indicated that the modification of zeolites favors affinity for boron species. The highest adsorption capacity of boron on zeolites was achieved in the synthetic solution. The adsorption capacity of the modified zeolites depended on the pH, the electrical conductivity, the modifying agent, the zeolitic structure, and the dose of adsorbent. The zeolitic structure-modifying agent interaction was decisive for boron adsorption capacity, with LTL-Ni zeolite being the best-performing adsorbent, thanks to its textural properties and nickel's ability to form complexes with boron species.
A number of C‐3 spirocyclic 2‐benzazepine analogs of α‐phenyl‐N‐tert‐butyl nitrone (PBN) were synthesized and tested for their activity in protecting rat brain mitochondria and dopaminergic (DA) ...neurons against 6‐hydroxydopamine (6‐OHDA), a toxin inducing destruction of the DA nigro‐striatal pathway in rodent models of Parkinson's disease. The newly synthesized nitrone derivatives were firstly investigated for their activity in decreasing the level of hydroxyl radicals generated during 6‐OHDA oxidation, and inhibit lipid peroxidation (TBARS assay) and protein carbonyl content (PCC) in rat brain mitochondria. Most of the studied 2‐benzazepine nitrones showed inhibitory potencies in both TBARS and PCC assays at least two magnitude orders higher than that of PBN. The data obtained usefully complemented the known structure–activity relationships. In particular, 5 and 10, bearing C‐3 spiro cyclopentyl and tetrahydropyranyl moieties, respectively, at 8 µM concentration proved to be significantly more effective than PBN in protecting cultured DA neurons exposed to 6‐OHDA, which alone causes about 45% cell loss in 24 h. In addition, we found that 5 inhibited butyrylcholinesterase with an IC50 value of 16.8 µM, which would enhance its potential as neuroprotective agent in Alzheimer's neurodegeneration. These findings extend the utility of benzazepine‐based PBN analogs in the treatment of age‐related free radical‐mediated disorders.
A number of 2‐benzazepine nitrones were synthesized and tested for their ability to protect rat brain mitochondria and dopaminergic (DA) neurons against the Parkinson‐inducing toxin 6‐hydroxydopamine (6‐OHDA). Compounds 5 and 10, bearing C‐3 spiro cyclopentyl and tetrahydropyranyl moieties, respectively, proved to be significantly more effective than the reference PBN in protecting cultured DA neurons exposed to 6‐OHDA. These findings extend the utility of benzazepine‐based nitrones in the treatment of age‐related free radical‐mediated disorders.
An increased risk of developing colorectal cancer (CRC) and other types of tumor is associated to Lynch syndrome (LS), an inherited condition caused by germline mutations in mismatch repair genes. We ...selected a cohort of LS patients that had developed CRC and had undergone surgical resection. Formalin-fixed paraffin embedded (FFPE) tissue blocks from matched colorectal and normal mucosa were used for genomic DNA extraction with a commercial kit and sequenced by high-throughput sequencing. A metagenomic approach enabled the taxonomic and functional identification of the microbial community and associated genes detected in the specimens. Slightly lower taxonomic diversity was observed in the tumor compared to the non-tumor tissue. Furthermore, the most remarkable differences between tumors and healthy tissue was the significant increase in the genus Fusobacterium in the former, in particular the species F. nucleatum, as well as Camplylobacter or Bacteroides fragilis, in accordance with previous studies of CRC. However, unlike prior studies, the present work is not based on directed detection by qPCR but instead uses a metagenomic approach to retrieve the whole bacterial community, and addresses the additional difficulty of using long-term stored FFPE samples.
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