Gene evolutionary trajectories in reveal temporal signs of selection.

Genetic differences between different Mycobacterium tuberculosis complex (MTBC) strains determine their ability to transmit within different host populations, their latency times, and their drug resistance profiles. Said differences usually emerge through de novo mutations and are maintained or discarded by the balance of evolutionary forces. Using a dataset of ∼5,000 strains representing global MTBC diversity, we determined the past and present selective forces that have shaped the current variability observed in the pathogen population.

An evolutionary functional genomics approach identifies novel candidate regions involved in isoniazid resistance in Mycobacterium tuberculosis.

Efforts to eradicate tuberculosis are hampered by the rise and spread of antibiotic resistance. Several large-scale projects have aimed to specifically link clinical mutations to resistance phenotypes, but they were limited in both their explanatory and predictive powers. Here, we combine functional genomics and phylogenetic associations using clinical strain genomes to decipher the architecture of isoniazid resistance and search for new resistance determinants.

Cryptic Resistance Mutations Associated With Misdiagnoses of Multidrug-Resistant Tuberculosis.

Understanding why some multidrug-resistant tuberculosis cases are not detected by rapid phenotypic and genotypic routine clinical tests is essential to improve diagnostic assays and advance toward personalized tuberculosis treatment. Here, we combine whole-genome sequencing with single-colony phenotyping to identify a multidrug-resistant strain that had infected a patient for 9 years. Our investigation revealed the failure of rapid testing and genome-based prediction tools to identify the multidrug-resistant strain.

The Future of TB Resistance Diagnosis: The Essentials on Whole Genome Sequencing and Rapid Testing Methods.

Tuberculosis resistance diagnostics have vastly improved in recent years thanks to the development of standardised phenotypic and molecular testing methods. However, these methods are either slow or limited in the number of resistant genotypes they can detect. With the advent of next-generation sequencing (NGS) we can sidestep all those problems, as we can sequence whole tuberculosis genomes at increasingly smaller costs and requiring less and less DNA.

Identifying and exploiting genes that potentiate the evolution of antibiotic resistance.

There is an urgent need to develop novel approaches for predicting and preventing the evolution of antibiotic resistance. Here, we show that the ability to evolve de novo resistance to a clinically important β-lactam antibiotic, ceftazidime, varies drastically across the genus Pseudomonas. This variation arises because strains possessing the ampR global transcriptional regulator evolve resistance at a high rate.

Persistence and resistance as complementary bacterial adaptations to antibiotics.

Bacterial persistence represents a simple of phenotypic heterogeneity, whereby a proportion of cells in an isogenic bacterial population can survive exposure to lethal stresses such as antibiotics. In contrast, genetically based antibiotic resistance allows for continued growth in the presence of antibiotics. It is unclear, however, whether resistance and persistence are complementary or alternative evolutionary adaptations to antibiotics.

Testing the role of genetic background in parallel evolution using the comparative experimental evolution of antibiotic resistance.

Parallel evolution is the independent evolution of the same phenotype or genotype in response to the same selection pressure. There are examples of parallel molecular evolution across divergent genetic backgrounds, suggesting that genetic background may not play an important role in determining the outcome of adaptation. Here, we measure the influence of genetic background on phenotypic and molecular adaptation by combining experimental evolution with comparative analysis.

18F-FDG PET-CT imaging in the neoadjuvant setting for stages II-III breast cancer: association of loco‑regional SUVmax with classical prognostic factors.

Aim: Classical prognostic and predictive factors serve to predict outcome and response to neoadjuvant treatment in stage II and III breast cancer. The purpose is to determine the relation between the SUVmax of the locoregional disease with these classical prognostic factors.

Methods: A prospective study including 43 stage II and III breast cancer patients was performed.

Assignment of tumor subtype by genomic testing and pathologic-based approximations: implications on patient's management and therapy selection.

Background: Breast cancer subtypes can be identified by genomic testing or pathology-based approximations. However, these classifications are not equivalent and the clinical relevance of both classifications needs to be fully explored.

Methods: Ninety-four patients were randomized to neoadjuvant single agent doxorubicin or docetaxel.

PAM50 proliferation score as a predictor of weekly paclitaxel benefit in breast cancer.

To identify a group of patients who might benefit from the addition of weekly paclitaxel to conventional anthracycline-containing chemotherapy as adjuvant therapy of node-positive operable breast cancer. The predictive value of PAM50 subtypes and the 11-gene proliferation score contained within the PAM50 assay were evaluated in 820 patients from the GEICAM/9906 randomized phase III trial comparing adjuvant FEC to FEC followed by weekly paclitaxel (FEC-P). Multivariable Cox regression analyses of the secondary endpoint of overall survival (OS) were performed to determine the significance of the interaction between treatment and the (1) PAM50 subtypes, (2) PAM50 proliferation score, and (3) clinical and pathological variables.

Correlation between response to neoadjuvant chemotherapy and survival in locally advanced breast cancer patients.

Background: Measurement of residual disease following neoadjuvant chemotherapy that accurately predicts long-term survival in locally advanced breast cancer (LABC) is an essential requirement for clinical trials development. Several methods to assess tumor response have been described. However, the agreement between methods and correlation with survival in independent cohorts has not been reported.

Relationship between within-host fitness and virulence in the vesicular stomatitis virus: correlation with partial decoupling.

Given the parasitic nature of viruses, it is sometimes assumed that rates of viral replication and dissemination within hosts (within-host fitness) correlate with virulence. However, there is currently little empirical evidence supporting this principle. To test this, we quantified the fitness and virulence of 21 single- or double-nucleotide mutants of the vesicular stomatitis virus in baby hamster kidney cells (BHK-21).

Glutathione S-transferase P1 c.313A > G polymorphism could be useful in the prediction of doxorubicin response in breast cancer patients.

Background: Identification of predicting factors for anthracyclines-based chemotherapy remains a clinical challenge. Glutathione S-transferase (GSTs) enzymes detoxify chemotherapy drugs and their metabolites. Several polymorphisms in GST genes result in reduced or no activity of the enzymes.

Prospective transGEICAM study of the impact of the 21-gene Recurrence Score assay and traditional clinicopathological factors on adjuvant clinical decision making in women with estrogen receptor-positive (ER+) node-negative breast cancer.

Background: This study examined the impact of the Recurrence Score (RS) in Spanish breast cancer patients and explored the associations between clinicopathological markers and likelihood of change in treatment recommendations.

Patients And Methods: Enrollment was offered consecutively to eligible women with estrogen receptor-positive; human epidermal growth factor receptor 2-negative, node-negative breast cancer. Oncologists recorded treatment recommendation and confidence in it before and after knowing the patient's RS.

Genomic predictors of response to doxorubicin versus docetaxel in primary breast cancer.

Unlabelled: Taxanes and anthracyclines improve the outcome of early breast cancer, although the benefit is limited to a small proportion of patients and are toxic. We prospectively looked for predictors of response to these drugs.

Experimental Design: Four cycles of doxorubicin (75 mg/m²) or docetaxel (100 mg/m²) were compared as presurgical chemotherapy for breast cancer.

Parkin deletion causes cerebral and systemic amyloidosis in human mutated tau over-expressing mice.

Deposition of proteins leading to amyloid takes place in some neurodegenerative diseases such as Alzheimer's disease and Huntington's disease. Mutations of tau and parkin proteins produce neurofibrillary abnormalities without deposition of amyloid. Here we report that mature, parkin null, over-expressing human mutated tau (PK(-/-)/Tau(VLW)) mice have altered behaviour and dopamine neurotransmission, tau pathology in brain and amyloid deposition in brain and peripheral organs.

Selection for robustness in mutagenized RNA viruses.

Mutational robustness is defined as the constancy of a phenotype in the face of deleterious mutations. Whether robustness can be directly favored by natural selection remains controversial. Theory and in silico experiments predict that, at high mutation rates, slow-replicating genotypes can potentially outcompete faster counterparts if they benefit from a higher robustness.

The cost of replication fidelity in human immunodeficiency virus type 1.

Mutation rates should be governed by at least three evolutionary factors: the need for beneficial mutations, the benefit of minimizing the mutational load and the cost of replication fidelity. RNA viruses show high mutation rates compared with DNA micro-organisms, and recent findings suggest that the cost of fidelity might play a role in the evolution of increased mutation rates. Here, by analysing previously published data from HIV-1 reverse transcriptase in vitro assays, we show a trade-off between enzymatic accuracy and the maximum rate of polymerization, thus providing a biochemical basis for the fitness cost of fidelity in HIV-1.

The cost of replication fidelity in an RNA virus.

It is often argued that high mutation rates are advantageous for RNA viruses, because they confer elevated rates of adaptation. However, there is no direct evidence showing a positive correlation between mutation and adaptation rates among RNA viruses. Moreover, theoretical work does not argue in favor of this prediction.

The CHEK2 1100delC allele is not relevant for risk assessment in HNPCC and HBCC Spanish families.

The frame-shift mutation 1100delC in the cell-cycle-checkpoint kinase 2 gene (CHEK2) has been reported to be a low penetrance breast cancer gene in Northern European populations. However, the variant may be relevant for breast cancer risk in other populations, due to its low prevalence. Recent studies have proposed a role for the mutation in colorectal cancer, finding a strong association between the CHEK21100delC mutation and hereditary breast and colorectal cancer (HBCC).

Ultrasonographic autopsy (echopsy): a new autopsy technique.

Autopsy has been one of the most important techniques for the development of modern medicine, mainly during the nineteenth century and the first half of last century. However, in the last few years, the number of autopsies performed in hospitals has dramatically decreased all over the world. This loss of interest can be attributed both to important advances in other diagnostic and therapeutic techniques and to the fear of malpractice suits.

Prognostic factors in invasive lobular carcinoma of the breast: a multivariate analysis. A multicentre study after seventeen years of follow-up.

Background And Goals: The purpose of this study was to characterize the biologic determinants that affect the behavior of invasive lobular carcinoma of the breast.

Material And Methods: A prospectively accrued data base containing 9,619 breast cancer cases was queried for specific pathological features. From this data base, 390 patients with invasive lobular carcinoma of the breast treated and followed at any of these three centers: San Carlos Hospital, Doce de Octubre Hospital or The Jimenez Diaz Foundation in Madrid (Spain) were reviewed and results, in terms of overall survival and disease-free survival were recorded for a long-term follow-up of 206 months (17 years).

[The cost effectiveness of echography biopsy].

Ecopsy is a postmortem technique which, by means of echography-guided puncture and/or aspiration obtains material for histological analysis. This study compared cost and time employed in 100 ecopsies and 100 classic necropsies and confirmed that cost of materials in ecopsy is 65% lower than that in necropsy. Physicians, necropsy technicians, laboratory technicians and secretary team personnel spent 33%, 54%, 19% and 32% less time than in necropsy.

Heterotopic gastric mucosa in the upper esophagus ("inlet patch"): a rare cause of esophageal perforation.

We report the case of a 21-yr-old woman who presented with a perforation of an upper esophageal ulcer on a patch of gastric-type mucosa. Despite surgical closure of the perforation and reinforcement with a pleuro-muscular flap the patient developed an esophageal leakage and died in the postoperative period. Heterotopic gastric mucosa in the upper esophagus is usually an asymptomatic abnormality, discovered incidentally during endoscopic studies carried out for some other reason; however, complications secondary to the inlet patch acid secreting capacity can arise, and this has to be kept in mind to elude life-threatening conditions.