Management of Liver Hydatid Cysts with a Large Biliocystic Fistula: Multicenter Retrospective Study

apd: 18 December 2000     

Insights into the cholecystokinin 2 receptor binding site and processes of activation

The cholecystokinin (CCK) 2 receptor (CCK2R) appears as a pharmacological target for the treatment of many major diseases. To complete the mapping of the CCK2R binding site and its activation processes, we have looked for the receptor residues that interact with Trp6, an essential residue for CCK binding and activity. In our molecular model of the CCK-occupied CCK2R, the indole group of Trp6 stacked with the phenyl ring of Phe120 (ECL1) and interacted with the imidazole group of His381(H7.39) and the phenyl ring of Tyr385(H7.43). Mutagenesis and pharmacological studies validated these interactions. It is noteworthy that the mutation of Phe120 to Trp conferred constitutive activity to the CCK2R. Molecular modeling and experimental works identified the residues involved in the activation cascade initiated by Trp6 and revealed that the constitutively active F120W mutation mimics the conformational changes induced by Trp6 resulting in: 1) the exposure of Glu151(E3.49) of the conserved E/DRY motif 2) the formation of an amphiphatic pocket involving protonated Glu151(E3.49) and Leu330 (ICL3), and 3) the opening of the intracellular loops 2 and 3 and the release of Arg158 (ICL2). The R158A mutation was shown to affect inositol phosphate production, whereas the E151A and L330E mutations induced constitutive inositol phosphate production. Given that a constitutively active variant of the CCK2R has been identified in different cancers and the fact that the E151A mutant has been reported to induce tumors, these studies should help in the development of potent inverse agonists to inhibit the constitutive activation of the CCK2R.     

Bleeding risk with concurrent use of anticoagulants and ibrutinib: A population-based nested case-control study

Data regarding the safety of co-administration of ibrutinib with anticoagulants in real-life settings are scarce. Using a nationwide database, we conducted a nested case-control study in a cohort of new users of ibrutinib to assess the risk of clinically relevant bleeding (CRB) associated with anticoagulation. Cases were patients with a diagnosis of CRB, defined as hospitalization with a diagnosis of bleeding. The date of CRB constituted the index date. Up to four controls were matched on sex, age at index date and duration of follow-up. The risk of CRB associated with anticoagulation in patients receiving ibrutinib was estimated using conditional logistic regression models, providing odds ratios (OR) adjusted for risk factors of bleeding. Among 614 cases and 2407 matched controls, the risk of CRB was significantly higher in patients receiving both ibrutinib and anticoagulants (adjusted OR [aOR] 2.54, confidence interval [CI] 95% [1.94; 3.32]). When considering anticoagulant class, aOR was 1.99 (CI 95% [1.19; 3.33]) for VKA, 2.48 (CI 95% [1.76; 3.47]) for direct oral anticoagulants and 3.40 (CI 95% [2.01; 5.75]) for parenteral anticoagulants. In conclusion, this study found a 2.5-fold increased risk of CRB in patients receiving both ibrutinib and anticoagulants in real-life settings, and similar aOR among oral anticoagulants.     

New methods for inferring population dynamics from microbial sequences.

The reduced cost of high throughput sequencing, increasing automation, and the amenability of sequence data for evolutionary analysis are making DNA data (or the corresponding amino acid sequences) the molecular marker of choice for studying microbial population genetics and phylogenetics. Concomitantly, due to the ever-increasing computational power, new, more accurate (and sometimes faster), sequence-based analytical approaches are being developed and applied to these new data. Here we review some commonly used, recently improved, and newly developed methodologies for inferring population dynamics and evolutionary relationships using nucleotide and amino acid sequence data, including: alignment, model selection, bifurcating and network phylogenetic approaches, and methods for estimating demographic history, population structure, and population parameters (recombination, genetic diversity, growth, and natural selection). Because of the extensive literature published on these topics this review cannot be comprehensive in its scope. Instead, for all the methods discussed we introduce the approaches we think are particularly useful for analyses of microbial sequences and where possible, include references to recent and more inclusive reviews.