Metformin and the Risk of Cancer: Time-Related Biases in Observational Studies.

Metformin and the Risk of Cancer: Time-related biases in observational studies.

Filed under: Drug and Alcohol Rehabilitation

Diabetes Care. 2012 Dec; 35(12): 2665-73
Suissa S, Azoulay L

OBJECTIVE Time-related biases in observational studies of drug effects have been described extensively in different therapeutic areas but less so in diabetes. Immortal time bias, time-window bias, and time-lag bias all tend to greatly exaggerate the benefits observed with a drug. RESEARCH DESIGN AND METHODS These time-related biases are described and shown to be prominent in observational studies that have associated metformin with impressive reductions in the incidence of and mortality from cancer. As a consequence, metformin received much attention as a potential anticancer agent; these observational studies sparked the conduction of randomized, controlled trials of metformin as cancer treatment. However, the spectacular effects reported in these studies are compatible with time-related biases. RESULTS We found that 13 observational studies suffered from immortal time bias; 9 studies had not considered time-window bias, whereas other studies did not consider inherent time-lagging issues when comparing the first-line treatment metformin with second- or third-line treatments. These studies, subject to time-related biases that are avoidable with proper study design and data analysis, led to illusory extraordinarily significant effects, with reductions in cancer risk with metformin ranging from 20 to 94%. Three studies that avoided these biases reported no effect of metformin use on cancer incidence. CONCLUSIONS Although observational studies are important to better understand the effects of drugs, their proper design and analysis is essential to avoid major time-related biases. With respect to metformin, the scientific evidence of its potential beneficial effects on cancer would need to be reassessed critically before embarking on further long and expensive trials.
HubMed – drug

The role of MiRNA in metastatic colorectal cancer and its significance in cancer prognosis and treatment.

Filed under: Drug and Alcohol Rehabilitation

Acta Biochim Pol. 2012 Nov 21;
Tokarz P, Blasiak J

MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression by targeting specific mRNAs. MiRNAs play a role in several physiological processes in the cell, including migration, proliferation, differentiation and apoptosis. Apart from their role in regular metabolism, abnormal profiles of miRNA expression accompany cancer transformation, including colorectal cancer (CRC) metastasis. MiRNAs may play a role in each phase of CRC metastasis including angiogenesis, invasion, intravasation, circulation, extravasation and metastatic colonization. MiRNA levels may serve as a predictive CRC marker, which was confirmed by the serum level of miR-29a targeting KLF4, a marker of cell stemness, and the plasma level of miR-221 down-regulating c-Kit, Stat5A and ETS1, which are signal transducers and transcription factor, respectively. In turn, the level of miR-143 in CRC cells decreasing the amount of MACC1 (metastasis-associated in colon cancer-1) and oncogenic KRAS protein, may be utilized as a prognostic marker. Also, single nucleotide polymorphisms of genes encoding miRNAs, including miR-423 and miR-608, which correlate with tumor recurrence, may be useful as diagnostic, prognostic and predictive indicators in CRC metastasis. Pre-miR-34a and pre-miR-199a decreased the level of Axl, a tyrosine-protein kinase receptor, so they can be considered as drugs in antimetastatic therapy. On the other hand , miR-222 targeting ADAM-17, a disintegrin and metalloproteinase, and miR-328 interacting with ABCG2, an ABC transporter, may overcome drug resistance of cancer cells. MiRNAs may be considered in wide-range application to facilitate CRC metastasis diagnosis, prognosis, prediction and therapy, however, further clinical, epidemiological and in vitro studies should be conducted to verify their utility.
HubMed – drug

Estimation of the Frequency of Intravenous Drug Users in Hamadan City, Iran, Using the Capture-recapture Method.

Filed under: Drug and Alcohol Rehabilitation

Epidemiol Health. 2012; 34: e2012006
Khazaei S, Poorolajal J, Mahjub H, Esmailnasab N, Mirzaei M

The number of illicit drug users is prone to underestimation. This study aimed to use the capture-recapture method as a statistical procedure for measuring the prevalence of intravenous drug users (IDUs) by estimating the number of unknown IDUs not registered by any of the registry centers.This study was conducted in Hamadan City, the west of Iran, in 2012. Three incomplete data sources of IDUs, with partial overlapping data, were assessed including: (a) Volunteer Counseling and Testing Centers (VCTCs); (b) Drop in Centers (DICs); and (c) Outreach Teams (ORTs). A log-linear model was applied for the analysis of three-sample capture-recapture results. Two information criteria were used for model selection including Akaike’s Information Criterion and the Bayesian Information Criterion.Out of 1,478 IDUs registered by three centers, 48% were identified by VCTCs, 32% by DICs, and 20% by ORTs. After exclusion of duplicates, 1,369 IDUs remained. According to our findings, there were 9,964 (95% CI, 6,088 to 17,636) IDUs not identified by any of the centers. Hence, the real number of IDUs is expected to be 11,333. Based on these findings, the overall completeness of the three data sources was around 12% (95% CI, 7% to 18%).There was a considerable number of IDUs not identified by any of the centers. Although the capture-recapture method is a useful and practical approach for estimating unknown populations, due to the assumptions and limitations of the method, the results must be interpreted with caution.
HubMed – drug

Amyloid ?-Peptide 25-35 Self-Assembly and Its Inhibition: A Model Undecapeptide System to Gain Atomistic and Secondary Structure Details of the Alzheimer’s Disease Process and Treatment.

Filed under: Drug and Alcohol Rehabilitation

ACS Chem Neurosci. 2012 Nov 21; 3(11): 952-62
Naldi M, Fiori J, Pistolozzi M, Drake AF, Bertucci C, Wu R, Mlynarczyk K, Filipek S, De Simone A, Andrisano V

Combined results of theoretical molecular dynamic simulations and in vitro spectroscopic (circular dichroism and fluorescence) studies are presented, providing the atomistic and secondary structure details of the process by which a selected small molecule may destabilize the ?-sheet ordered “amyloid” oligomers formed by the model undecapeptide of amyloid ?-peptide 25-35 [A?(25-35)]. A?(25-35) was chosen because it is the shortest fragment capable of forming large ?-sheet fibrils and retaining the toxicity of the full length A?(1-40/42) peptides. The conformational transition, that leads to the formation of ?-sheet fibrils from soluble unordered structures, was found to depend on the environmental conditions, whereas the presence of myricetin destabilizes the self-assembly and antagonizes this conformational shift. In parallel, we analyzed several molecular dynamics trajectories describing the evolution of five monomer fragments, without inhibitor as well as in the presence of myricetin. Other well-known inhibitors (curcumin and (-)-tetracycline), found to be stronger and weaker A?(1-42) aggregation inhibitors, respectively, were also studied. The combined in vitro and theoretical studies of the A?(25-35) self-assembly and its inhibition contribute to understanding the mechanism of action of well-known inhibitors and the peptide amino acid residues involved in the interaction leading to a rational drug design of more potent new molecules able to antagonize the self-assembly process.
HubMed – drug

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