A systematic review and a meta‐analysis were performed to quantify the accumulated information from genetic association studies investigating the impact of the CYP4F2 rs2108622 (p.V433M) polymorphism ...on coumarin dose requirement. An additional aim was to explore the contribution of the CYP4F2 variant in comparison with, as well as after stratification for, the VKORC1 and CYP2C9 variants. Thirty studies involving 9,470 participants met prespecified inclusion criteria. As compared with CC‐homozygotes, T‐allele carriers required an 8.3% (95% confidence interval (CI): 5.6–11.1%; P < 0.0001) higher mean daily coumarin dose than CC homozygotes to reach a stable international normalized ratio (INR). There was no evidence of publication bias. Heterogeneity among studies was present (I2 = 43%). Our results show that the CYP4F2 p.V433M polymorphism is associated with interindividual variability in response to coumarin drugs, but with a low effect size that is confirmed to be lower than those contributed by VKORC1 and CYP2C9 polymorphisms.
Clinical Pharmacology & Therapeutics (2012); 92 6, 746–756. doi:10.1038/clpt.2012.184
The role of pharmacogenomics and tamoxifen was investigated by analyzing several polymorphisms of cytochrome P450 and SULT1A1 gene in a nested case control study from the Italian Tamoxifen Prevention ...Trial. This study included 182 Caucasian subjects, 47 breast cancer (BC) cases and 135 matched controls. We used the AmpliChip CYP450 Test to screen 33 alleles of CYP2D6 and 3 of CYP2C19. One more variant for CYP2C19*17 and two single-nucleotide polymorphisms for the gene SULT1A1 were also performed. By using the AmpliChip CYP450 Test, out of 182 subjects, we identified 8 poor metabolizer (PM), 17 intermediate metabolizer (IM), 151 extensive metabolizer (EM) and 3 ultrarapid metabolizer (UM). PM women allocated to the tamoxifen arm showed a higher risk of developing BC compared to the remaining phenotypes (P=0.035). In an exploratory analysis, among 58 women with a CYP2D6*2A allele, 9 BCs were diagnosed in the placebo arm and only 1 in the tamoxifen arm (P=0.0001). CYP2C19 and SULT1A1 polymorphisms did not show any correlation with tamoxifen efficacy. Tamoxifen showed reduced efficacy in CYP2D6 PMs in the chemoprevention setting. Conversely, the CYP2D6*2A allele may be associated with increased efficacy of tamoxifen. These findings support the relevance of pharmaco-genomics in tailoring tamoxifen treatment.
Celotno besedilo
Dostopno za:
DOBA, EMUNI, GIS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK
The optimal amount of anticoagulation for critically ill COVID-19 patients is controversial. Therefore, we aimed to evaluate the efficacy and safety of escalated doses of anticoagulation in ...critically ill patients with severe COVID-19.
We conducted a systematic search of three major databases, including PubMed, Cochrane Library, and Embase, from inception to May 2022. Randomized controlled trials (RCTs) were included comparing therapeutic or intermediate doses to standard prophylactic doses of anticoagulants in critically ill COVID-19 patients, with heparins as the only anticoagulation therapy considered.
Out of the six RCTs, 2130 patients were administered escalated dose anticoagulation (50.2%) and standard thromboprophylaxis therapy (49.8%). The escalated dose showed no significant impact on mortality (RR, 1.01; 95% CI, 0.90–1.13). Although there was no significant difference in DVT (RR, 0.81; 95% CI, 0.61–1.08), the risk of PE was significantly reduced in patients receiving escalated dose anticoagulation (RR, 0.35; 95% CI, 0.21–0.60), with an increased risk of bleeding events (RR, 1.65; 95% CI, 1.08–2.53).
This systematic review and meta-analysis fail to support escalated anticoagulation doses to reduce mortality in critically ill COVID-19 patients. However, higher doses of anticoagulants appear to reduce thrombotic events while increasing the risk of bleeding effectively.
•Meta-analysis evaluates efficacy and safety of escalated-intensity prophylactic heparins in critically ill COVID-19 patients, addressing controversy.•Escalated anticoagulation does not reduce all-cause mortality but significantly lowers thrombotic events in critically ill COVID-19 patients.•Balance thrombotic and bleeding risks when using antithrombotic therapies in critically ill COVID-19 patients, considering inflammation and comorbidities.
Aims: To determine any associations between the Helicobacter pylori genes babA2, oipA, cagA and the s and m alleles of vacA. In addition, to verify whether these genes work synergistically or ...independently in causing gastritis, peptic ulcer, and intestinal metaplasia. Methods: One hundred and sixty seven H pylori positive patients were studied (52 antral gastritis, 41 diffuse gastritis, 41 peptic ulcer, and 33 duodenitis). Helicobacter pylori virulence genes were amplified by means of the polymerase chain reaction. Results: Significant associations were found between babA2 and the other H pylori genes studied. When considered singly, all the genes were associated with disease diagnosis, inflammation, and intestinal metaplasia. Four H pylori groups were defined. Group A: cagA−, s2m2, babA2−; group B: cagA+, s1m1, babA2+; group C: cagA+, s1m2, babA2+; group D: cagA+, s1m2, babA2−. Group A infecting strains were associated with less severe endoscopic and inflammatory conditions, whereas group B strains were associated with the worst endoscopic and inflammatory findings. Intestinal metaplasia was a rare finding in group A infected patients (< 10%), whereas it was frequent in those infected with group B strains (48%). Conclusions: The H pylori genes cagA, oipA “on”, s1 and m1 vacA, and babA2 are associated with each other, possibly as a result of shared selective pressure. When coexpressed by the same H pylori strain, cagA, s1 and m1 vacA, and babA2 work synergistically in worsening inflammation. Infections caused by strains coexpressing cagA, s1m1 vacA, and babA2 are those at higher risk for intestinal metaplasia.
Summary Background Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of ...the effectiveness of health systems, and to inform global policy on cancer control. Methods Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15–99 years) and 75 000 children (age 0–14 years) diagnosed with cancer during 1995–2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. Findings 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005–09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15–19% in North America, and as low as 7–9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10–20% between 1995–99 and 2005–09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995–99 and 2005–09 have generally been slight. For women diagnosed with ovarian cancer in 2005–09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005–09 was high (54–58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18–23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. Interpretation International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems. Funding Canadian Partnership Against Cancer (Toronto, Canada), Cancer Focus Northern Ireland (Belfast, UK), Cancer Institute New South Wales (Sydney, Australia), Cancer Research UK (London, UK), Centers for Disease Control and Prevention (Atlanta, GA, USA), Swiss Re (London, UK), Swiss Cancer Research foundation (Bern, Switzerland), Swiss Cancer League (Bern, Switzerland), and University of Kentucky (Lexington, KY, USA).
The number of infiltrating polymorphonuclear cells varies depending on the virulence of the infecting strain, being much greater when infections are caused by cagA positive strains. 3, 5, 7- 9 The ...inflammatory cells infiltrating Hpylori infected gastric mucosa produce a pattern of proinflammatory cytokines. 10, 11 High mucosal levels of mononuclear cytokines (IL8, IL6, IL1β, tumour necrosis factor α (TNFα), and interferon GAMMA (IFNGAMMA)) and lymphocytic derived cytokines (IL2, IL2R) have been described in Hpylori infected patients. 10- 13 Hpylori infection also induces the production of IL12, 14- 16 a heterodimeric proinflammatory protein that triggers the production of IFNGAMMA and favours the differentiation of T helper 1 (Th1) cells, 17, 18 which, in Hpylori infected mucosa, prevail over Th2 cells. 15, 16, 19 The ability of IL12 to induce Th1 is one of the biological bases of the importance of this cytokine in resisting most bacteria, including Hpylori, and also intracellular protozoa and fungal pathogens. 18, 20, 21 Cellular sources of IL12 in response to infections are mainly dendritic cells and phagocytes. 16- 21 The two subunits of IL12-p35 and p40-are encoded by different genes, named IL12A and IL12B respectively, which are unrelated and are located on separate chromosomes (3p12-q13.2 and 5q31-33). According to the Lauren description of gastric cancers, tumours were classified as "intestinal-type" in 82 patients and "diffuse" in 28.
An impaired host immunity might concur in determining the dismal prognosis of patients with pancreatic cancer (PC). Our aim was to ascertain whether the immunophenotype pattern of blood lymphocytes ...in PC correlates with tumor stage, grade, or survival.
We studied 115 patients with PC, 44 with chronic pancreatitis (CP), 23 with tumors of the pancreatico-biliary tract, and 34 healthy controls (CS). Survival data were available for 77 patients with PC. Lymphocyte subsets were determined by fluorescent activated cell sorter (FACS) analysis.
In patients with PC, total lymphocyte counts were lower than in CP or CS, and CD8 lymphocyte subset levels were higher with respect to CS. Lower circulating lymphocytes were found in advanced PC stages (IIB-IV; chi2 = 11.55, P < 0.05) compared with stages 0 to IIA. Cox regression analysis, made considering total lymphocyte counts and tumor stage as covariates, was found to be significant for both tumor stage (P < 0.001) and total lymphocyte counts (P < 0.05).
The reduction of total lymphocytes in blood is the main immunologic change in advanced PC. The survival of these patients depends mainly on tumor stage, but it is also affected by the number of circulating lymphocytes, suggesting that the immune system plays an important role in pancreatic adenocarcinoma immunosurveillance and immunoediting.
The aim of this study was to evaluate whether there was any correlation between
Helicobacter pylori-associated diseases and (1)
H. pylori virulence genes or (2)
IL-1B,
IL-1RN,
IFN-G,
TNF-A,
IL-10 ...genetic polymorphisms. Patients with non-cardia gastric cancer (NCGC,
n
=
129) or benign gastroduodenal diseases (
n
=
792) were studied.
IL-1RN intron 2 VNTR polymorphism (PCR),
IL-1B −31 C/T (RFLP), the SNPs of
IFN-G (+874 A/T),
TNF-A (−1031 C/T, −857 C/T, −376 A/G, −308 A/G, −238 A/G),
IL-10 (−1082 A/G, −819 C/T, −592 A/C) (Taqman chemistry) were studied.
cagA, s1 and m1
vacA, were PCR amplified. Duodenal ulcer was more frequent in
TNF-A −857 TT and in
IL-1RN 1,2 subjects.
TNF-A −857 TT genotype was also correlated with gastric ulcer.
IL-10 −819 TT genotype was associated with intestinal metaplasia and NCGC. Antral inflammation was associated with
TNF-A −1031 TT, while corpus activity with
IL-10 −819 CC.
H. pylori infection was associated with
TNF-A −308 AG genotype, while
IFN-G +874 AA genotype was associated with
cagA. In conclusion, among host genetic factors contributing to
H. pylori disease outcome,
IFN-G +874 AA genotype favors
cagA positive infections,
TNF-A −857 TT duodenal ulcer while
IL-10 −819 TT intestinal metaplasia and NCGC.
Vectors combining the heat shock proteins (HSPs) promoter with the catalytic subunit A of the diphtheria toxin (DTA) or its variants, cross-reacting material (CRM) 176 and 197, were engineered to ...investigate the effect of bacterial toxins on pancreatic cancer (PC) cells. Three heat-inducible enhanced green fluorescent protein (eGFP)-expression vectors were obtained: V1 (91% homology to HSPA6), V2 (five heat shock elements upstream the minimal HSPA6 promoter) and V3 (V1 and V2 combined). The highest eGFP transcription and translation levels were found in V3 transfected PC cells. The V3 promoter was used to control DTA, CRM176 and CRM197 expression, treatment response being investigated in four PC cell lines. DTAwt or CRM176 transfected cell growth was completely arrested after heat shock. CRM197 toxin presumed to be inactive, caused mild distress at 37 degrees C and induced a 25-50% reduction in cell growth after heat shock. Preliminary in vivo findings showed that heat treatment arrests tumor growth in DTA197 stably transfected PSN1 cells. In conclusion, the efficient HSP promoter identified in this study may be extremely useful in controlling the transcription of toxins such as CRM197, which have lethal dose-related effects, and may thus be a promising tool in PC gene therapy in vivo.
MALDI‐TOF profiling of low molecular weight peptides (peptidome) usage is limited due to the lack of reproducibility from the confounding inferences of sample preparation, data acquisition, and ...processing. We applied MALDI‐TOF analysis to profile urine peptidome with the aims to: (i) compare centrifugal ultrafiltration and dialysis pretreatments, (ii) determine whether using signal LOD (sLOD), together with data normalization, may reduce MALDI‐TOF variability. We also investigated the influence of peaks detection on reproducibility. Dialysis allowed to obtain better MALDI‐TOF spectra than ultrafiltration. Within the 1000–4000 m/z range, we identified 120 and 129 peaks in intra‐ and interassay studies, respectively. To estimate the sLOD, serial dilution of pooled urines up to 1/256 were analyzed in triplicate. Six data normalization strategies were investigated–the mean, median, internal standard, relative intensity, TIC, and linear rescaling normalization. Normalization methods alone performed poorly in reducing features variability while when combined to sLOD adjustment showed an overall reduction in features CVs. Applying a feedback signal processing approach, after median normalization and sLOD adjustment, CVs were reduced from 103 to 26% and 113 to 25% for the intra‐ and interassay, respectively, and spectra became more comparable in terms of data dispersion.
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